1. Please check and comment entries here.
Table of Contents

    Topic review

    Therapeutics in Respiratory Pathology

    Subjects: Pathology
    View times: 14
    Submitted by: Josep M. Aran

    Definition

    As aerobic organisms, we are continuously and throughout our lifetime subjected to an oxidizing atmosphere and, most often, to environmental threats. The lung is the internal organ most highly exposed to this milieu. Therefore, it has evolved to confront both oxidative stress induced by reactive oxygen species (ROS) and a variety of pollutants, pathogens, and allergens that promote inflammation and can harm the airways to different degrees. Indeed, an excess of ROS, generated intrinsically or from external sources, can imprint direct damage to key structural cell components (nucleic acids, sugars, lipids, and proteins) and indirectly perturb ROS-mediated signaling in lung epithelia, impairing its homeostasis. These early events complemented with efficient recognition of pathogen- or damage-associated recognition patterns by the airway resident cells alert the immune system, which mounts an inflammatory response to remove the hazards, including collateral dead cells and cellular debris, in an attempt to return to homeostatic conditions.

    1. Introduction

    Due to its continuously exposed surface to the external environment, the lung exhibits a formidable defense system constituted by a high number of interacting mechanisms [1][2]. First, anatomical retention features such as the nasopharyngeal barrier filter particles or microorganisms higher than 2–3 µm [3][4][5]. Secondly, there are systems to expel the external elements, i.e., the cough [6], and the mucociliary system [7]. Whether or not the external and potentially harmful particles overcome these mechanisms, the humoral factors come into play, including bactericidal and antiviral secretions (mucins, defensins, lactoferrin, complement factors, etc.) [8][9], and cellular factors of the innate [10] and adaptive immune system. These include the airway epithelial cells [11]; the phagocytic cells that, in turn, comprise polymorphonuclear (PMN) cells such as neutrophils (the most abundant immune cell type) [12] or eosinophils [13]; monocytes and macrophages [14][15]; natural killer cells (NKC) [16]; mastocytes [17]; and dendritic cells [18]. All these cells recognize pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS) through pattern recognition receptors (PRRs) [19], and Toll-like receptors (TLR) are the most studied [20]. Their stimulation triggers the activation of antimicrobial genes and inflammatory cytokines and chemokines, as well as the direct response against antigens [21], activating the adaptive immune system, namely B and T lymphocytes [22][23].

    2. Reactive Oxygen Species Production in the Airways

    Environmental pollutants such as ozone (O3) and nitrogen dioxide (NO2) react with several molecules at the respiratory surface and generate secondary reactive oxygen species (ROS) such as superoxide radicals (O2·), hydrogen peroxide (H2O2), and hydroxyl radicals (OH·) [24][25]. Additionally, lung cells generate ROS as by-products of aerobic metabolism involving enzymatic reactions in the mitochondrial electron transport chain (e.g., through activity of amine oxidases, α-ketoglutarate dehydrogenase (α-KGDH), and pyruvate dehydrogenase (PDH), and activation of the p66shc adaptor protein) [26][27][28]. Furthermore, ROS can be produced in peroxisomes [29], or by cytochrome P450 enzymes, cyclooxygenases, and lipoxygenases [30]. Nitric oxidase synthases (NOS) expand the spectrum of ROS producing reactive nitrogen species (NO2 or ONOO) [31]. ROS are also produced as mediators of biological functions, with a role in inflammatory processes involving epithelial and endothelial cells, alveolar macrophages, and granulocytes [32][33]. NADPH oxidases (NOX) enzymes are involved in both bacterial killing and regulation of inflammatory mediators [34]. Indeed, dual oxidases, DUOX1 and DUOX2, the major isoform of NOX, are expressed preferentially in the respiratory epithelium [35][36][37].

    3. Respiratory Surface: Antioxidant Defenses

    The air–liquid interface covering the developed airways is an environment subjected to continuous oxidative stress. Accordingly, the respiratory epithelium is exposed to endogenous and also to environmental ROS. Therefore, it expresses a variety of antioxidant enzymes. Superoxide dismutases such as SOD3 (an extracellular SOD, EC-SOD) [38][39][40], highly-expressed in the lung at the extracellular matrix and at the cell surfaces [41], generate H2O2 which is detoxified by other enzymes. Catalase, decomposes H2O2 into H2O and O2, predominantly within alveolar macrophages and type II epithelial cells [42][43]. Glutathione (GSH) peroxidase (GPX) catalyzes the reduction of H2O2 or other peroxides to glutathione disulfide (GSSG) and H2O, of which GPX1 is thought to be responsible for 95% of overall lung tissue GPX activity [44]. Peroxiredoxins (PRX), with all six mammalian family members expressed in different compartments within the lung [45], particularly PRX I, III, V, and VI in the bronchial epithelium, PRX V and VI in the alveolar epithelium, and PRX I and III in alveolar macrophages, decompose H2O2 and protect against oxidative stress [46][47][48]. Thioredoxin (TRX), whose main antioxidant role is related to its ability to regenerate oxidized forms of PRX [49][50], catalyzes the reduction of disulfide bonds, modulates signal transduction pathways, and has anti-inflammatory properties [51][52]. Finally, glutaredoxins (GRX) participate in the reduction of oxidative modifications involving GSH [53][54].

    The following small non-enzymatic low-molecular-weight antioxidant molecules are highly relevant: ascorbic acid (vitamin C) [55], uric acid [56], GSH [57][58], and α-tocopherol (vitamin E) [59]. These non-enzymatic molecules are the most prominent antioxidants reacting with reactive oxidant gases such as O3 and NO2 [60][61][62][63] and with the secondary oxidants generated by them, which can increase the oxidative injury [64]. Furthermore, the enzymatic antioxidants complement the function of these small molecules. Nuclear factor erythroid 2-related factor (Nrf2) regulates the transcription of both antioxidant genes coding for many of the above-highlighted enzymes and phase II detoxification genes [65][66][67][68].

    4. Inflammation and Oxidative Stress in Pulmonary Diseases

    A variety of immune and non-immune cells are activated during an inflammatory process. Each cell type releases cytokines and mediators that modify the activities of other cells, inducing an inflammatory network that progresses and resolves towards healthy homeostatic, or pathological outcomes. The lung is a vital organ for gas exchange and is constantly exposed to harmful airborne pathogens. Therefore, an immediate and intense protective/defensive inflammatory action is required to eliminate the invaders as early as possible. Nevertheless, excessive inflammation can be life threatening [1]. Consequently, a delicate balance between inflammation and anti-inflammation is essential for lung homeostasis and for the prevention of chronic inflammation [69]. Among the main inflammatory mediators involved in the pathogenesis of respiratory diseases are biochemical mediators such as histamine, thrombin, complement anaphylatoxins, prostaglandins, nitric oxide (NO), and molecules induced by oxidative stress [70]. These compounds mediate cell signaling and enhance cytokine production, among other activities.

    Thus, airborne toxicants stimulate local ROS production inducing protein oxidation, lipoxidation, glycation end products, and DNA damage, and leading to mitochondrial dysfunction, cell death, the recruitment of inflammatory cells (mainly macrophages and neutrophils), profibrotic changes or mucus hypersecretion. These oxidative stress-mediated cellular processes drive the development of key environmental respiratory diseases such as acute lung injury/respiratory distress syndrome, asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis, and affect the progression of the most common hereditary disease affecting the lung, i.e., cystic fibrosis.

    5. Prospective Therapeutic Strategies

    5.1. ALI/ARDS

    The scientific rationale for emerging therapies in ARDS is to pursue fundamental processes and mediators of its complex pathophysiology [71]. There are emerging therapies in Phase 3 trials assessing the potential benefits of corticosteroids such as dexamethasone [72][73] or budesonide/formoterol [74][75]. Moreover, supplementation with vitamin D [76] in a Phase 2 trial has shown a reduction in markers of vascular permeability from lung injury patients following esophagectomy in the post-operative period [77], although another trial using vitamin D to prevent acute respiratory tract infections has been less conclusive [78]. Other emerging therapies in Phase 2 trials include aspirin, which has attracted interest as a repurposed drug for ARDS [79][80], with some clinical studies [81] that show significant reduction in neutrophil infiltration into the alveolar space. Alternatively, different studies using mesenchymal stem cells (MSCs) and multipotent adult progenitor cells (MAPCs) have shown a biological decline in angiopoietin and a concomitantly reduced 28-day mortality, higher ventilator-free days, and higher ICU-free days [82]. Vitamin C acts as ROS scavenger, modulator of inflammatory mediators, and cofactor. In mouse models, ALI prevents the activation of NF-κB, and therefore attenuates the production of proinflammatory cytokines and boosts ion channel and pump expression, enhancing fluid clearance in the alveolar epithelium [83]. The phase 2 CITRIS-ALI trial is presently investigating the usefulness of vitamin C in sepsis-induced ALI [84] but no positive results have been reported as yet [85]. It was found that nebulized liquid heparin increased the number of ventilator-free days [86], and a Phase 2 trial to confirm the findings is awaited [87]. Anti-tissue factor antibodies such as ALT-836, which blocks binding to coagulation factor VIIa, have demonstrated attenuation of sepsis-induced ALI in animal models, and was successfully tested in a Phase 1 trial for ARDS [88]. A Phase 2 trial has been recently completed and disclosure of the results is pending [89]. Dilmapimod, a p38 MAPK inhibitor, has proven useful for reducing the severity of ALI in animal studies, although in human trials it has been unreliable [90][91]. Neutrophil elastase inhibitors such as sivelestat, have been shown to increase the ventilator-free days in ARDS patients with a high extravascular lung water content (>10 mL/kg) as compared with those with low pulmonary edema [92], although contradictory results have also been obtained [93][94]. Ulinastatin (or urinary trypsin inhibitor) is another physiological inhibitor of human neutrophil elastase with positive results in preclinical studies [95]. A meta-analysis of 29 Chinese randomized controlled trials (RCTs) indicated that ulinastatin was effective ameliorating ARDS [96]. Another multi-center Phase 2 RCT is ongoing to assess its safety and efficacy in ARDS [97]. Regarding granulocyte-macrophage colony stimulating factor (GM-CSF), preclinical models have demonstrated that it can limit alveolar epithelial cell injury and promote alveolar macrophage maturation. Nevertheless, a Phase 2 RCT enrolled only two-thirds of its intended number of participants and, although GM-CSF treatment appeared to be safe, it did not decrease ventilator free days or mortality of the ALI/ARDS patients [98]. Anti-CD14 antibodies protected against septic hypotension in animal models of pneumonia [99]. Two Phase 2 trials have been initiated in this regard, the former, in 2007, failed in recruiting people; and the latter is still recruiting [100]. Inhaled prostaglandins, such as epoprostenol and alprostadil, have been suggested to regionally dilate the pulmonary vasculature increasing arterial oxygenation in ARDS. However, a meta-analysis of 25 studies concluded that, although indeed inhaled prostaglandins improved oxygenation in ARDS, they did not improve pulmonary physiology or mortality [101].

    5.2. Asthma

    Over the last few years, multiple biologics (typically mAbs) have been developed targeting various participants in allergies and asthma, but mainly directed toward the complex type 2 endotype [102][103]. In general, they are anti-inflammatory treatments [104]. The most prevalent biologics are omalizumab (anti-IgE) and mepolizumab (anti-IL-5). IL-5 has become a major target for both asthma and COPD due to the high proportion of patients with airway eosinophilia associated with disease severity [105]. Currently, three biologics, targeting IL-5 or its receptor, have been cleared by the Food and Drug Administration (FDA). Omalizumab was initially approved by the FDA in 2003 and binds to both the high-affinity and low-affinity IgE receptors, preventing free IgE from occupying the surface of mast cells and basophils [106]. It has several disadvantages, i.e., it must be administered by subcutaneous injection [107], it is expensive [108] and, moreover, an unusual form of anaphylaxis [109] and a possible higher rate of cardiac and cerebrovascular events can be ensued by this treatment. Anti-IL-5 (mepolizumab) was approved in late 2014 and receiving patients had decreased eosinophilic inflammation, reduced asthma exacerbations, improved asthma control markers, better quality of life [110][111], and reduced levels of some of the proteins that drive airway remodeling [112]. In another study on moderate persistent asthma, despite high-dose ICS, patients also showed decreased blood and sputum eosinophils but no change in FEV1, symptom scores, or need for rescue inhaler. After stopping anti-IL-5 treatment, eosinophils and asthma symptoms again increased [113]. Reslizumab, another mAb targeting IL- 5, approved in 2016 for patients with eosinophilic asthma, has proven beneficial on moderate-to-severe asthma symptoms, improving lung function and reducing exacerbations as compared with a placebo [114]. Reslizumab also decreased blood, sputum, and airway eosinophils and, more recently, reduced systemic corticosteroid dosing nearly 75% [115][116][117]. Benralizumab, a mAb targeting the IL-5Rα, was approved recently by the FDA [118] with positive results in asthma [119][120][121]. Finally, dupilumab, a mAb approved in 2017 that inhibits the IL- 4R subunit [122], has also shown encouraging results in asthma [123][124]. Regarding relevant future targets pending approval, lebrikizumab and tralokinumab, mAbs that target IL-13 [125][126], have not shown positive effects [127][128]. Tezepelumab (AMG157), a humanized mAb currently in Phase 3 [129] binds thymic stromal lymphopoietin, an epithelial cell-derived cytokine that drives allergic inflammatory responses [130]. Additionally, anti-IL-33 therapies are currently under development [131]. Conversely, non-Th2 inflammation targets are also being studied. IL-6 and IL-17 may promote both Th2 and non-Th2 inflammatory cascades. Brodalumab is a human mAb binding IL-17RA, which inhibits signaling of IL-17 and IL-25, with disappointing results in clinical trials [132]. Thus, this therapy has not been further pursued for asthma or COPD. C-X-C motif chemokine receptor 2 (CXCR2) antagonists such as navarixin (which decrease IL-8 levels) have reduced sputum and blood neutrophils, with no significant change in FEV1 [133], but has progressed to a Phase 2 trial [134]. An antisense oligonucleotide against C-C chemokine receptor 3 (CCR3) (co-administered with an antisense oligonucleotide that targets the c subunit of the IL-3, IL-5, and GM-CSF receptors), named TPI ASM8, has shown some efficacy in phase 2 trials [135]. Imatinib is a tyrosine kinases inhibitor that has shown promising results in a clinical study, reducing airway hyper-responsiveness as compared with a placebo [136]. Among drugs targeting TNF-α, etanercept stands out as a repositioning drug for asthma. A few studies employing etanercept have reported satisfactory results reducing bronchial hyperreactivity [137][138], whereas other studies have informed poor clinical efficacy in terms of lung function improvement and quality of life [139]. Others have shown a small but significant increase in the quality of life without changes on lung function [140].

    Among anti-inflammatory treatments, antioxidant treatments stand out [141][142]. Vitamins (E, C, D, and A), carotenoids (α-carotene, β-carotene, β-cryptoxanthin, lutein/zeaxanthin, and lycopene), and food supplements (selenium and zinc) seem to improve the prognosis of the disease [143][144][145]. Asthmatic adults with antioxidant-poor diets have lower forced expiratory volume in the first one second to the forced vital capacity (FEV1/FVC) ratio scores, increased plasma C-reactive protein, and were more likely to exacerbate than those on an antioxidant-rich diet [146]. Indeed, dietary antioxidant supplementation notably improved both symptoms and lung function in exercise induced asthma [147].

    5.3. COPD

    Thus far, no anti-IL-5 therapies have been approved for use in COPD. However, two Phase 3 studies using mepolizumab showed improvements in exacerbation frequency from subjects who had an eosinophilic phenotype and a history of COPD exacerbations, despite triple therapy [148]. Nevertheless, other studies have indicated no positive effects [149]. Reslizumab has yet to be formally evaluated in clinical trials for COPD. Conversely, in a Phase 2 trial including COPD patients with eosinophilia, benralizumab treatment did not significantly reduce the annual rate of moderate or severe exacerbations [150][151]. However, significant improvements in FEV1 were observed in the overall study population, and the results of pre-specified subgroup analyses by baseline blood eosinophil count in individuals with benralizumab versus placebo have led to an ongoing Phase 3 trial to evaluate this biologic in COPD [152]. As in asthma, non-Th2 inflammation targets include CXCR2 and CCR3. Regarding corticosteroids, in contrast to asthma, glucocorticoid treatment of established COPD is rather ineffective in reducing chronic airway inflammation and progressive airway obstruction [153]. Current national and international guidelines endorse the use of inhaled long acting bronchodilators, ICSs, and their combination for maintenance treatment of moderate-to-severe stable COPD [154], although adverse effects may arise [155]. In fact, large clinical trials assessing the combination therapy (ICSs + LABAs) in a single inhaler for stable COPD patients have shown a good safety profile, a discreet but statistically significant reduction of severe exacerbations, and improvements of FEV1, quality of life, and respiratory symptoms in these patients [156][157]. Overexpression of histone deacetylase 2 restores glucocorticoid sensitivity in BAL macrophages from COPD patients [158]. Anti-cytokine and anti-chemokine treatments are being exploited in COPD but scarce trials using blocking antibodies against cytokines and chemokines or their receptors have proven successful [153]. Among those showing positive effects, the CXCR2 inhibitor MK-7123 (also known as SCH527123 or navarixin, already described in asthma) could reduce the chemotaxis of neutrophils [153]. MK-7123 treatment resulted in a significant reduction of sputum neutrophils and of sputum and plasma MMP9 and myeloperoxidase levels [159]. Numerous other drugs, including antibodies directed against specific inflammatory mediators such as cytokines (IL-18, IL-22, IL-23, IL-33, TSLP) and growth factors (GM-CSF) are under investigation for COPD.

    5.4. Idiopathic Pulmonary Fibrosis (IPF)

    After several disappointing years of promising therapies that moved into clinical trials but failed to demonstrate efficacy in IPF [160], the anti-fibrotic drugs pirfenidone and nintedanib have been associated with significantly slower respiratory deterioration and perhaps prolonged survival [161][162][163], although with heterogenous responses and side effects. The understanding of the complex pathogenesis of IPF continues to increase [164][165]. Sustained alveolar epithelial cell injury and abnormal repair are increasingly recognized as the core mediators of the fibrotic process, with a relevant involvement of environmental triggers. The activation of multiple pathways related to maladaptive repair, involving fibroblast migration, proliferation, and extracellular matrix deposition has revealed a variety of prospective molecular targets of novel therapeutic agents currently being tested in early phase clinical trials. Pentraxin-2 (PTX-2) is a circulating protein that binds to monocytes, promoting epithelial healing and resolution of fibrosis. Thus, a recombinant human PTX-2 (serum amyloid P) analogue (PRM-151) has been shown to inhibit monocyte to fibrocyte differentiation and ameliorate fibrosis in a bleomycin-induced animal model of fibrosis [166][167]. A Phase 1 trial showed a non-significant but improving effect of PRM-151 on FVC and six-min walking distance (6MWD) during the treatment [168]. Further Phase 2 studies have demonstrated a significant reduction in pulmonary function deterioration and stability in 6MWD over 24 weeks as compared with a placebo, although with relevant adverse events [169][170]. The launch of a Phase 3 trial for PRM-151 in IPF has been announced, using FVC as a primary end point and 6MWD as a key secondary end point. Among the anti-connective tissue growth factor antibodies, the antagonist pamrevlumab (FG-3019) in the PRAISE study [171] was established to have a significant effect preventing lung function decline of 160 IPF patients, yet full peer-reviewed data are still awaited [172]. The re-initiation of Phase 3 trials has just been announced. PBI-4050 is a synthetic analogue of a medium-chain fatty acid acting through G protein-coupled receptors and showing anti-fibrotic activities such as inhibition of epithelial–mesenchymal transition and fibrocyte/fibroblast recruitment, migration, proliferation and differentiation, among others [173]. A Phase 2 trial has shown no safety concerns [174]. While there was slowing or stability in FVC, a statistically significant decrease was observed only combining PBI-4050 and pirfenidone but not PBI-4050 and nintedanib, implying a possible drug–drug interaction. Additional studies of PBI-4050, either alone or in combination with nintedanib, are currently being considered. In a Phase 2a study [175], GLPG1690, an oral selective inhibitor of autotaxin (an enzyme increased in IPF and involved in cell apoptosis and endothelial cell damage) was analyzed and was well tolerated by IPF patients, with a good safety profile. Moreover, as secondary end points, preliminary efficacy analyses demonstrated target engagement and encouraging results towards halting FVC decline [176]. International Phase 3 trials to assess the efficacy of GLPG1690 in IPF are ongoing [177]. Leukotrienes are also increased in IPF [178][179]. Thus, additional ongoing trials include leukotriene antagonists such as tipelukast, currently explored in a Phase 2 trial [180]. Among protein kinase inhibitors, a recent Phase 1 study showed proper safety and tolerability of a selective protein kinase inhibitor of the Rho-associated coiled-coil containing protein kinase 2 (ROCK2). The trial is currently in Phase 2 [181][182]. Moreover, a current Phase 2 [183] trial is evaluating CC-90001, a second-generation Jun N-terminal kinase (JNK) inhibitor after a first-generation JNK inhibitor (CC-930) showed a dose-dependent trend of reduction in MMP7 and surfactant protein D (SP-D) biomarker plasma levels [184]. Regarding anti-integrin antibodies, a partial inhibition of integrin αvβ6 in rodents blocked the development of pulmonary fibrosis processes without aggravating the inflammatory response [185]. The safety and tolerability of a humanized monoclonal antibody (BG00011) against this integrin has been analyzed in a Phase 2 trial [186]. The study has been completed recently, although its outcome is still pending. Phosphatidylinositol 3-kinase/Protein kinase B (PI3K/Akt) pathway inhibitors may be associated with halting fibrosing processes [187], as suggested in a Phase 1 trial [188][189] and evidenced in another recent study using omipalisib [190]. Sirolimus is currently under examination in a Phase 2 trial [191]. The B lymphocyte antigen CD20 is targeted by rituximab, which is currently being assessed in an IPF Phase 2 study [192]. Furthermore, a Phase 2 trial examined combined plasma exchange, rituximab, and steroids [193]. While peer-reviewed results are pending, a pilot trial stated good outcomes regarding autoantibody reduction for acute IPF exacerbations [194]. A Phase 3 trial testing the antibiotic combination co-trimoxazole (trimethoprim and sulfamethoxazole) is currently operating [195]. Finally, other anti-inflammatory drugs are likewise in clinical research for IPF, i.e., lebrikizumab [196], tralokinumab [197], and azithromycin [198].

    5.5. Cystic Fibrosis (CF)

    To address the most prevalent causal defects in the CFTR Cl– channel leading to CF, two biomolecular modulators are needed, i.e., CFTR correctors, to increase the amount of properly folded mutant CFTR protein at the plasma membrane, and CFTR potentiators, to allow effective gating (channel opening and closing) of the abnormal CFTR [199][200][201]. Nevertheless, a more thorough division might also include stabilizers, read-through agents, and amplifiers [202]. Either alone or combined, these modulators tend to restore transepithelial Cl transport to CF airway epithelia expressing CFTR mutations such as the most prevalent F508del, improving hydration and restoring mucociliary clearance [203][204]. Four drugs have been recently approved by the FDA for that purpose [201], the potentiator Ivacaftor (VX-770) for individuals with CF holding a G551D CFTR mutation, and the following three correctors: Lumacaftor (VX-809), developed to increase the amount of F508del CFTR that reaches the cell surface [205][206], Tezacaftor (VX-661), and Elexacaftor (VX-445). Furthermore, their combinations are also being assayed, i.e., Orkambi (lumacaftor/ivacaftor) for patients homozygous for F508del CFTR [207], Symdeko (tezacaftor/ivacaftor), and Trikafta (elexacaftor/tezacaftor/ivacaftor). Most recently, there has been an explosion of novel modulators [208] and others are under investigation including ELX-02, Posenacaftor (PTI-801), Galicaftor (ABBV-2222), ABBV-3221, FDL169, Deutivacaftor (VX-561), ABBC-974 (GLPG-1837), and Nesolicaftor (PTI-428) [209][210][211][212][213][214][215][216][217][218], among others.

    Despite a thorough knowledge of the undergoing inflammatory process in CF, there are relatively few anti-inflammatory drugs in clinical use [219]. Corticosteroids were shown to confer some benefit but their long-term use is associated with unacceptable side effects [220][221][222]. The non-steroidal anti-inflammatory agent ibuprofen has also demonstrated benefits [223][224]. Particularly in younger patients, it has been associated with an increased survival rate [225][226], but it requires a strict dose control and has associated renal and gastrointestinal side effects [223]. A large Phase 2 RCT of the leukotriene B4 (LTB4) receptor antagonist, BIIL 284 BS (amelubant), surprisingly demonstrated an excess of pulmonary exacerbations as compared with a placebo [227]. Conversely, CTX-4430 decreases the production of LTB4, an inflammatory mediator elevated in CF [228] and is presently undergoing a Phase 2 trial [229]. Andecaliximab, an antibody against MMP9, is undergoing a Phase 2b trial [230] but the baseline FEV1 required for this drug limits its use in very severe CF and this trial has been discontinued. Another compound in Phase 1 is POL6014, a synthetic neutrophil elastase blocker [231]. Other anti-inflammatory compounds under clinical development are α-1 anti-trypsin [232], the elastase inhibitor AZD9668 [233], and JBT-101 (ajulemic acid, or Lenabasum), an oral selective cannabinoid receptor type 2 (CB2) agonist that decreases neutrophilic inflammation inhibiting LTB4 and promotes resolution of inflammation through modulation of arachidonic acid metabolism [234]. A Phase 2, double-blind, placebo-controlled study, in adult CF patients, demonstrated decreased levels of several sputum inflammatory markers and reduced exacerbations in response to JBT-101, with no serious adverse effects reported [235][236]. A Phase 2b study is underway. Indeed, CB2 activation has shown anti-inflammatory effects including stimulating lipoxin A4 (LXA4) synthesis, decreasing proinflammatory cytokine secretion, and neutrophil trafficking to the lung [237][238].

    Anti-proteases have been under investigation in CF since 1990. For example, the already described α1-antitrypsin suppressed inflammatory markers including free neutrophil elastase, proinflammatory cytokines, and neutrophils [239][240]. Other neutrophil elastase inhibitors include recombinant secretory leukocyte protease inhibitor (rSLPI) and the small-molecule drug EPI-hNE4 (depelstat) [241]. Among other inflammatory therapies, hydroxychloroquine, a dihydrofolate reductase inhibitor that increases intracellular pH, was negatively evaluated in a small 28-day study in CF [242]. A CF clinical trial regarding SB-656933, a CXCR2 antagonist, concluded that this molecule might modulate airway inflammation [243]. Conversely to refractory asthma, few CF studies have considered the use of chemotherapeutics. Low dose of the immunosuppressant cyclosporin A diminished the need for systemic corticosteroids in one small case series. In a pilot study, methotrexate increased FEV1 and decreased total serum immunoglobulins in five CF patients after one year of treatment [244], showing tolerable adverse effects. IL-8 decoys are used as an anti-inflammatory anti-neutrophil elastase strategy [245][246]. Other novel anti-inflammatory compounds under review include the already mentioned lipoxins and resolvins. Arachidonic acid-derived lipoxins such as LXA4 attenuate neutrophil chemotaxis, respiratory burst, IL-8 production, and accelerate apoptosis [247][248][249]. Because of low LXA4 levels in CF airways, stable LXA4 agonists have been developed as prospective therapeutics. Decosahexanoic acid- and omega-3 eicosapentanoic acid-derived resolvins D1 and E1 also mitigate inflammation, preventing chemotaxis and promoting clearance of apoptotic neutrophils [250][251][252][253]. Analogously to LXA4, resolvins stimulate a cytoprotective effect on airway epithelial cells [254][255]. Retinoids foster extracellular matrix homeostasis. Recent Phase 1b studies involving LAU-7b, an oral solid-dosage form of the retinoid fenretinide, showed safety and tolerability in adult CF patients, encouraging progression to Phase 2 trials [256].

    Antioxidant therapies have not been yet settled in clinical practice [257]. In fact, despite the commercial development of many natural antioxidants as dietary supplements, there is no sound clinical trial evidence of their effectiveness in any clinical condition [258] with the exception of GSH (administered either orally or by inhalation) [259][260][261] with some drawbacks [262]. Though not quite clear [263], high doses of β-carotene appear to improve lung function and decrease oxidative stress in some cases [264]. The application of deferiprone (L1) as an iron chelating drug/pharmaceutical antioxidant is under way. Its use is being considered as a main, alternative, or adjuvant therapy in many diseases involving oxidative damage [265][266]. N-acetyl cysteine, initially developed as a mucolytic, is being repurposed as an antioxidant [267], inhibiting H2O2 and increasing GSH [260]. Of significance is the malabsorption of fat-soluble antioxidants in CF patients such as tocopherols, carotenoids, and coenzyme Q10 (Co-Q10), and that of essential fatty acids. Vitamin E might become a good supplementation to overcome this deficiency [268][269][270][271][272], along with carotenoids [273] and ascorbic acid (vitamin C) as nutritional supplements. Multivitamin supplements with high bioavailability containing Co-Q10 would also be a good alternative [274][275]. One recent study regarding multivitamin supplements showed a decrease in circulating inflammatory markers and a decrease in pulmonary exacerbations [276]. Alternatively, several hydro soluble antioxidants, oligoelements, and enzymatic antioxidants such as Vitamin C, selenium and selenium-dependent peroxidases [277][278][279], zinc, and copper [280] have yielded promising results awaiting further clinical trials. A randomized double-blind placebo-controlled trial has examined the outcome of short-term melatonin administration (3 mg for three weeks) on sleep and oxidative stress markers in CF [281]. Accordingly, with the expected activity synchronizing the sleep-wake cycle and its antioxidant properties, treatment with this hormonal substance reduced nitrite levels in exhaled breath condensate and improved sleep indices.

    This entry is adapted from 10.3390/ijms21239317

    References

    1. Moldoveanu, B.; Otmishi, P.; Jani, P.; Walker, J.; Sarmiento, X.; Guardiola, J.; Saad, M.; Yu, J. Inflammatory mechanisms in the lung. J. Inflamm. Res. 2009, 2, 1–11.
    2. García-Bellmunt, L.; Sibilia, O. Mecanismos de defensa pulmonar. Med. Respir. 2013, 6, 15–24.
    3. LeMessurier, K.S.; Tiwary, M.; Morin, N.P.; Samarasinghe, A.E. Respiratory Barrier as a Safeguard and Regulator of Defense Against Influenza A Virus and Streptococcus pneumoniae. Front. Immunol. 2020, 11, 3.
    4. Ganesan, S.; Comstock, A.T.; Sajjan, U.S. Barrier function of airway tract epithelium. Tissue Barriers 2013, 1, e24997.
    5. Yuksel, H.; Turkeli, A. Airway epithelial barrier dysfunction in the pathogenesis and prognosis of respiratory tract diseases in childhood and adulthood. Tissue Barriers 2017, 5, e1367458.
    6. Andrani, F.; Aiello, M.; Bertorelli, G.; Crisafulli, E.; Chetta, A. Cough, a vital reflex. Mechanisms, determinants and measurements. Acta Biomed. 2018, 89, 477–480.
    7. Nawroth, J.C.; Van Der Does, A.M.; Ryan, A.; Kanso, E. Multiscale mechanics of mucociliary clearance in the lung. Philos. Trans. R. Soc. B Biol. Sci. 2020, 375, 20190160.
    8. Twigg, H.L. Humoral immune defense (antibodies): Recent advances. Proc. Am. Thorac. Soc. 2005, 2, 417–421.
    9. Sheehan, G.; Garvey, A.; Croke, M.; Kavanagh, K. Innate humoral immune defences in mammals and insects: The same, with differences? Virulence 2018, 9, 1625–1639.
    10. Hartl, D.; Tirouvanziam, R.; Laval, J.; Greene, C.M.; Habiel, D.; Sharma, L.; Yildirim, A.Ö.; Dela Cruz, C.S.; Hogaboam, C.M. Innate Immunity of the Lung: From Basic Mechanisms to Translational Medicine. J. Innate Immun. 2018, 10, 487–501.
    11. Hiemstra, P.S.; McCray, P.B.; Bals, R. The innate immune function of airway epithelial cells in inflammatory lung disease. Eur. Respir. J. 2015, 45, 1150–1162.
    12. Aulakh, G.K. Neutrophils in the lung: “the first responders.” Cell Tissue Res. 2018, 371, 577–588.
    13. Ramirez, G.A.; Yacoub, M.-R.; Ripa, M.; Mannina, D.; Cariddi, A.; Saporiti, N.; Ciceri, F.; Castagna, A.; Colombo, G.; Dagna, L. Eosinophils from Physiology to Disease: A Comprehensive Review. Biomed Res. Int. 2018, 2018, 9095275.
    14. Chiu, S.; Bharat, A. Role of monocytes and macrophages in regulating immune response following lung transplantation. Curr. Opin. Organ Transplant. 2016, 21, 239–245.
    15. Byrne, A.J.; Mathie, S.A.; Gregory, L.G.; Lloyd, C.M. Pulmonary macrophages: Key players in the innate defence of the airways. Thorax 2015, 70, 1189–1196.
    16. Cong, J.; Wei, H. Natural killer cells in the lungs. Front. Immunol. 2019, 10, 1416.
    17. Erjefält, J.S. Mast cells in human airways: The culprit? Eur. Respir. Rev. 2014, 23, 299–307.
    18. Peters, M.; Peters, K.; Bufe, A. Regulation of lung immunity by dendritic cells: Implications for asthma, chronic obstructive pulmonary disease and infectious disease. Innate Immun. 2019, 25, 326–336.
    19. Kim, H.J.; Kim, C.H.; Kim, M.J.; Ryu, J.H.; Seong, S.Y.; Kim, S.; Lim, S.J.; Holtzman, M.J.; Yoon, J.H. The induction of pattern-recognition receptor expression against influenza a virus through Duox2-derived reactive oxygen species in nasal mucosa. Am. J. Respir. Cell Mol. Biol. 2015, 53, 525–535.
    20. Tengroth, L.; Millrud, C.R.; Kvarnhammar, A.M.; Georén, S.K.; Latif, L.; Cardell, L.O. Functional effects of Toll-Like Receptor (TLR)3, 7, 9, RIG-I and MDA-5 stimulation in nasal epithelial cells. PLoS ONE 2014, 9, e98239.
    21. El-Zayat, S.R.; Sibaii, H.; Mannaa, F.A. Toll-like receptors activation, signaling, and targeting: An overview. Bull. Natl. Res. Cent. 2019, 43, 1–12.
    22. Reynolds, J.M.; Dong, C. Toll-like receptor regulation of effector T lymphocyte function. Trends Immunol. 2013, 34, 511–519.
    23. Taher, T.E.; Bystrom, J.; Ong, V.H.; Isenberg, D.A.; Renaudineau, Y.; Abraham, D.J.; Mageed, R.A. Intracellular B Lymphocyte Signalling and the Regulation of Humoral Immunity and Autoimmunity. Clin. Rev. Allergy Immunol. 2017, 53, 237–264.
    24. Gomes, E.C.; Florida-James, G. Lung Inflammation, Oxidative Stress and Air Pollution. In Lung Inflammation; IntechOpen: London, UK, 2014.
    25. Lodovici, M.; Bigagli, E. Oxidative Stress and Air Pollution Exposure. J. Toxicol. 2011, 2011, 487074.
    26. Ozcan, A.; Ogun, M. Biochemistry of Reactive Oxygen and Nitrogen Species. In Basic Principles and Clinical Significance of Oxidative Stress; IntechOpen: London, UK, 2015.
    27. Dröse, S.; Brandt, U. Molecular mechanisms of superoxide production by the mitochondrial respiratory chain. Adv. Exp. Med. Biol. 2012, 748, 145–169.
    28. Lenaz, G. Mitochondria and reactive oxygen species. Which role in physiology and pathology? Adv. Exp. Med. Biol. 2012, 942, 93–136.
    29. Del Río, L.A.; López-Huertas, E. ROS generation in peroxisomes and its role in cell signaling. Plant Cell Physiol. 2016, 57, 1364–1376.
    30. Bae, Y.S.; Oh, H.; Rhee, S.G.; Yoo, Y. Do Regulation of reactive oxygen species generation in cell signaling. Mol. Cells 2011, 32, 491–509.
    31. Tejero, J.; Shiva, S.; Gladwin, M.T. Sources of vascular nitric oxide and reactive oxygen species and their regulation. Physiol. Rev. 2019, 99, 311–379.
    32. Chelombitko, M.A. Role of Reactive Oxygen Species in Inflammation: A Minireview. Mosc. Univ. Biol. Sci. Bull. 2018, 73, 199–202.
    33. Segal, B.H.; Grimm, M.J.; Khan, A.N.H.; Han, W.; Blackwell, T.S. Regulation of innate immunity by NADPH oxidase. Free Radic. Biol. Med. 2012, 53, 72–80.
    34. Mittal, M.; Siddiqui, M.R.; Tran, K.; Reddy, S.P.; Malik, A.B. Reactive oxygen species in inflammation and tissue injury. Antioxid. Redox Signal. 2014, 20, 1126–1167.
    35. van der Vliet, A.; Danyal, K.; Heppner, D.E. Dual oxidase: A novel therapeutic target in allergic disease. Br. J. Pharmacol. 2018, 175, 1401–1418.
    36. Yang, H.T.; Huang, Y.H.; Yang, G.W. Mini review: Immunologic functions of dual oxidases in mucosal systems of vertebrates. Braz. J. Biol. 2019, doi:10.1590/1519-6984.208749.
    37. Fischer, H. Mechanisms and function of DUOX in epithelia of the lung. Antioxid. Redox Signal. 2009, 11, 2453–2465.
    38. Hu, L.; Zachariae, E.D.; Larsen, U.G.; Vilhardt, F.; Petersen, S.V. The dynamic uptake and release of SOD3 from intracellular stores in macrophages modulates the inflammatory response. Redox Biol. 2019, 26, 101268.
    39. Kinnula, V.L.; Crapo, J.D. Superoxide dismutases in the lung and human lung diseases. Am. J. Respir. Crit. Care Med. 2003, 167, 1600–1619.
    40. Ganguly, K.; Depner, M.; Fattman, C.; Bein, K.; Oury, T.D.; Wesselkamper, S.C.; Borchers, M.T.; Schreiber, M.; Gao, F.; Von Mutius, E.; et al. Superoxide dismutase 3, extracellular (SOD3) variants and lung function. Physiol. Genom. 2009, 37, 260–267.
    41. Petersen, S.V.; Enghild, J.J. Extracellular superoxide dismutase: Structural and functional considerations of a protein shaped by two different disulfide bridge patterns. Biomed. Pharmacother. 2005, 59, 175–182.
    42. Rahman, I.; Biswas, S.K.; Kode, A. Oxidant and antioxidant balance in the airways and airway diseases. Eur. J. Pharmacol. 2006, 533, 222–239.
    43. Han, W.; Fessel, J.P.; Sherrill, T.; Kocurek, E.G.; Yull, F.E.; Blackwell, T.S. Enhanced Expression of Catalase in Mitochondria Modulates NF-κB–Dependent Lung Inflammation through Alteration of Metabolic Activity in Macrophages. J. Immunol. 2020, 205, 1125–1134.
    44. Yatmaz, S.; Seow, H.J.; Gualano, R.C.; Wong, Z.X.; Stambas, J.; Selemidis, S.; Crack, P.J.; Bozinovski, S.; Anderson, G.P.; Vlahos, R. Glutathione peroxidase-1 reduces influenza A virus-induced lung inflammation. Am. J. Respir. Cell Mol. Biol. 2013, 48, 17–26.
    45. Elko, E.A.; Cunniff, B.; Seward, D.J.; Chia, S.B.; Aboushousha, R.; Van De Wetering, C.; Van Der Velden, J.; Manuel, A.; Shukla, A.; Heintz, N.H.; et al. Peroxiredoxins and Beyond; Redox Systems Regulating Lung Physiology and Disease. Antioxid. Redox Signal. 2019, 31, 1070–1091.
    46. Schremmer, B.; Manevich, Y.; Feinstein, S.I.; Fisher, A.B. Peroxiredoxins in the lung with emphasis on peroxiredoxin VI. Subcell. Biochem. 2007, 44, 317–344.
    47. Kinnula, V.L.; Lehtonen, S.; Kaarteenaho-Wiik, R.; Lakari, E.; Pääkkö, P.; Kang, S.W.; Rhee, S.G.; Soini, Y. Cell specific expression of peroxiredoxins in human lung and pulmonary sarcoidosis. Thorax 2002, 57, 157–164.
    48. Park, J.H.; Kim, Y.S.; Lee, H.L.; Shim, J.Y.; Lee, K.S.; Oh, Y.J.; Shin, S.S.; Choi, Y.H.; Park, K.J.; Park, R.W.; et al. Expression of peroxiredoxin and thioredoxin in human lung cancer and paired normal lung. Respirology 2006, 11, 269–275.
    49. Xu, J.; Li, T.; Wu, H.; Xu, T. Role of thioredoxin in lung disease. Pulm. Pharmacol. Ther. 2012, 25, 154–162.
    50. Netto, L.E.S.; Antunes, F. The Roles of peroxiredoxin and thioredoxin in hydrogen peroxide sensing and in signal transduction. Mol. Cells 2016, 39, 65–71.
    51. Nakamura, T.; Nakamura, H.; Hoshino, T.; Ueda, S.; Wada, H.; Yodoi, J. Redox regulation of lung inflammation by thioredoxin. Antioxid. Redox Signal. 2005, 7, 60–71.
    52. Shao, R.; Yang, Y.; Zhang, Y.; Zhao, S.; Zheng, Z.; Chen, G. The expression of thioredoxin-1 and inflammatory cytokines in patients with sepsis. Immunopharmacol. Immunotoxicol. 2020, 42, 280–285.
    53. Janssen-Heininger, Y. Glutathione, Glutaredoxin And S-Glutathionylation In Lung Disease. Free Radic. Biol. Med. 2017, 112, 3.
    54. Chia, S.B.; Elko, E.A.; Aboushousha, R.; Manuel, A.M.; van de Wetering, C.; Druso, J.E.; van der Velden, J.; Seward, D.J.; Anathy, V.; Irvin, C.G.; et al. Dysregulation of the glutaredoxin/S-glutathionylation redox axis in lung diseases. Am. J. Physiol. Cell Physiol. 2020, 318, C304–C327.
    55. Hemilä, H.; Louhiala, P. Vitamin C may affect lung infections. J. R. Soc. Med. 2007, 100, 495–498.
    56. Shaheen, S.O. Antioxidants and respiratory disease: The uric acid paradox. Thorax 2014, 69, 978–979.
    57. Fitzpatrick, A.M.; Jones, D.P.; Brown, L.A.S. Glutathione redox control of asthma: From molecular mechanisms to therapeutic opportunities. Antioxid. Redox Signal. 2012, 17, 375–408.
    58. Gould, N.S.; Min, E.; Gauthier, S.; Martin, R.J.; Day, B.J. Lung glutathione adaptive responses to cigarette smoke exposure. Respir. Res. 2011, 12, 133.
    59. Miyazawa, T.; Burdeos, G.C.; Itaya, M.; Nakagawa, K.; Miyazawa, T. Vitamin E: Regulatory Redox Interactions. IUBMB Life 2019, 71, 430–441.
    60. Cross, C.E.; van der Vliet, A.; O’Neill, C.A.; Louie, S.; Halliwell, B. Oxidants, antioxidants, and respiratory tract lining fluids. Environ. Health Perspect. 1994, 102, 185–191.
    61. Behndig, A.F.; Blomberg, A.; Helleday, R.; Duggan, S.T.; Kelly, F.J.; Mudway, I.S. Antioxidant responses to acute ozone challenge in the healthy human airway. Inhal. Toxicol. 2009, 21, 933–942.
    62. Mudway, I.S.; Blomberg, A.; Frew, A.J.; Holgate, S.T.; Sandström, T.; Kelly, F.J. Antioxidant consumption and repletion kinetics in nasal lavage fluid following exposure of healthy human volunteers to ozone. Eur. Respir. J. 1999, 13, 1429–1438.
    63. Barthelemy, J.; Sanchez, K.; Miller, M.R.; Khreis, H. New opportunities to mitigate the burden of disease caused by traffic related air pollution: Antioxidant-rich diets and supplements. Int. J. Environ. Res. Public Health 2020, 17, 630.
    64. Ballinger, C.A.; Cueto, R.; Squadrito, G.; Coffin, J.F.; Velsor, L.W.; Pryor, W.A.; Postlethwait, E.M. Antioxidant-mediated augmentation of ozone-induced membrane oxidation. Free Radic. Biol. Med. 2005, 38, 515–526.
    65. Cho, H.Y.; Reddy, S.P.; Kleeberger, S.R. Nrf2 defends the lung from oxidative stress. Antioxid. Redox Signal. 2006, 8, 76–87.
    66. Kavian, N.; Mehlal, S.; Jeljeli, M.; Saidu, N.E.B.; Nicco, C.; Cerles, O.; Chouzenoux, S.; Cauvet, A.; Camus, C.; Ait-Djoudi, M.; et al. The Nrf2-antioxidant response element signaling pathway controls fibrosis and autoimmunity in scleroderma. Front. Immunol. 2018, 9, 1896.
    67. Müller, T.; Hengstermann, A. Nrf2: Friend and Foe in preventing cigarette smoking-dependent lung disease. Chem. Res. Toxicol. 2012, 25, 1805–1824.
    68. Osburn, W.O.; Kensler, T.W. Nrf2 signaling: An adaptive response pathway for protection against environmental toxic insults. Mutat. Res. Rev. Mutat. Res. 2008, 659, 31–39.
    69. Aghasafari, P.; George, U.; Pidaparti, R. A review of inflammatory mechanism in airway diseases. Inflamm. Res. 2019, 68, 59–74.
    70. Park, H.S.; Kim, S.R.; Lee, Y.C. Impact of oxidative stress on lung diseases. Respirology 2009, 14, 27–38.
    71. Shaw, T.D.; McAuley, D.F.; O’Kane, C.M. Emerging drugs for treating the acute respiratory distress syndrome. Expert Opin. Emerg. Drugs 2019, 24, 29–41.
    72. Villar, J.; Ferrando, C.; Martínez, D.; Ambrós, A.; Muñoz, T.; Soler, J.A.; Aguilar, G.; Alba, F.; González-Higueras, E.; Conesa, L.A.; et al. Dexamethasone treatment for the acute respiratory distress syndrome: A multicentre, randomised controlled trial. Lancet Respir. Med. 2020, 8, 267–276.
    73. Villar, J.; Belda, J.; Añón, J.M.; Blanco, J.; Pérez-Méndez, L.; Ferrando, C.; Martínez, D.; Soler, J.A.; Ambrós, A.; Muñoz, T.; et al. Evaluating the efficacy of dexamethasone in the treatment of patients with persistent acute respiratory distress syndrome: Study protocol for a randomized controlled trial. Trials 2016, 17, 342.
    74. Festic, E.; Carr, G.E.; Cartin-Ceba, R.; Hinds, R.F.; Banner-Goodspeed, V.; Bansal, V.; Asuni, A.T.; Talmor, D.; Rajagopalan, G.; Frank, R.D.; et al. Randomized clinical trial of a combination of an inhaled corticosteroid and beta agonist in patients at risk of developing the acute respiratory distress syndrome. Crit. Care Med. 2017, 45, 798–805.
    75. Matthay, M.A.; McAuley, D.F.; Ware, L.B. Clinical trials in acute respiratory distress syndrome: Challenges and opportunities. Lancet Respir. Med. 2017, 5, 524–534.
    76. NCT03096314 Vitamin D to Improve Outcomes by Leveraging Early Treatment. 2017. Available online: https://clinicaltrials.gov/show/NCT03096314 (accessed on 2 May 2020).
    77. Parekh, D.; Dancer, R.C.A.; Scott, A.; D’Souza, V.K.; Howells, P.A.; Mahida, R.Y.; Tang, J.C.Y.; Cooper, M.S.; Fraser, W.D.; Tan, L.C.; et al. Vitamin D to Prevent Lung Injury Following Esophagectomy-A Randomized, Placebo-Controlled Trial. Crit. Care Med. 2018, 46, e1128–e1135.
    78. Ginde, A.A.; Brower, R.G.; Caterino, J.M.; Finck, L.; Banner‑Goodspeed, V.M.; Grissom, C.K.; Hayden, D.; Hough, C.L.; Hyzy, R.C.; Khan, A.; et al. Early high-dose Vitamin D3 for critically ill, Vitamin D–deficient patients. N. Engl. J. Med. 2019, 381, 2529–2540.
    79. Toner, P.; McAuley, D.F.; Shyamsundar, M. Aspirin as a potential treatment in sepsis or acute respiratory distress syndrome. Crit. Care 2015, 19, 374.
    80. Harr, J.N.; Moore, E.E.; Johnson, J.; Chin, T.L.; Wohlauer, M.V.; Maier, R.; Cuschieri, J.; Sperry, J.; Banerjee, A.; Silliman, C.C.; et al. Antiplatelet therapy is associated with decreased transfusion-associated risk of lung dysfunction, multiple organ failure, and mortality in trauma patients. Crit. Care Med. 2013, 41, 399–404.
    81. Hamid, U.; Krasnodembskaya, A.; Fitzgerald, M.; Shyamsundar, M.; Kissenpfennig, A.; Scott, C.; Lefrancais, E.; Looney, M.R.; Verghis, R.; Scott, J.; et al. Aspirin reduces lipopolysaccharide-induced pulmonary inflammation in human models of ARDS. Thorax 2017, 72, 971–980.
    82. Matthay, M.A.; Calfee, C.S.; Zhuo, H.; Thompson, B.T.; Wilson, J.G.; Levitt, J.E.; Rogers, A.J.; Gotts, J.E.; Wiener-Kronish, J.P.; Bajwa, E.K.; et al. Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): A randomised phase 2a safety trial. Lancet Respir. Med. 2019, 7, 154–162.
    83. Fisher, B.J.; Kraskauskas, D.; Martin, E.J.; Farkas, D.; Wegelin, J.A.; Brophy, D.; Ward, K.R.; Voelkel, N.F.; Fowler, A.A.; Natarajan, R. Mechanisms of attenuation of abdominal sepsis induced acute lung injury by ascorbic acid. Am. J. Physiol. Lung Cell. Mol. Physiol. 2012, 303, L20–L32.
    84. NCT02106975 Vitamin C Infusion for Treatment in Sepsis Induced Acute Lung Injury—Full Text View—ClinicalTrials.gov. 2019. Available online: https://clinicaltrials.gov/show/NCT02106975 (accessed on 20 September 2020).
    85. Fowler, A.A.; Truwit, J.D.; Hite, R.D.; Morris, P.E.; Dewilde, C.; Priday, A.; Fisher, B.; Thacker, L.R.; Natarajan, R.; Brophy, D.F.; et al. Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients with Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial. JAMA J. Am. Med. Assoc. 2019, 322, 1261–1270.
    86. Dixon, B.; Schultz, M.J.; Smith, R.; Fink, J.B.; Santamaria, J.D.; Campbell, D.J. Nebulized heparin is associated with fewer days of mechanical ventilation in critically ill patients: A randomized controlled trial. Crit. Care 2010, 14, R180.
    87. ACTRN12612000418875 A multi-centre randomised, placebo controlled trial of nebulised heparin in patients with or at risk of developing Acute Respiratory Distress Syndrome, to determine if nebulised heparin improves long term physical function. Australian New Zealand Clinical Trials Registry. 2012. Available online: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=362354 (accesed on 2020-09-25).
    88. Morris, P.E.; Steingrub, J.S.; Huang, B.Y.; Tang, S.; Liu, P.M.; Rhode, P.R.; Wong, H.C. A phase I study evaluating the pharmacokinetics, safety and tolerability of an antibody-based tissue factor antagonist in subjects with acute lung injury or acute respiratory distress syndrome. BMC Pulm. Med. 2012, 12, 5.
    89. NCT00879606 Anti-TF Antibody (ALT-836) to Treat Septic Patients With Acute Lung Injury or Acute Respiratory Distress Syndrome—Full Text View—ClinicalTrials.gov. 2015. Available online: https://clinicaltrials.gov/show/NCT00879606 (accessed on 2 May 2020).
    90. Denham, W.; Yang, J.; Norman, J.; Wang, H.; Botchkina, G.; Tracey, K.J. Inhibition of p38 mitogen activate kinase attenuates the severity of pancreatitis-induced adult respiratory distress syndrome. Crit. Care Med. 2000, 28, 2567–2572.
    91. Christie, J.D.; Vaslef, S.; Chang, P.K.; May, A.K.; Gunn, S.R.; Yang, S.; Hardes, K.; Kahl, L.; Powley, W.M.; Lipson, D.A.; et al. A Randomized Dose-Escalation Study of the Safety and Anti-Inflammatory Activity of the p38 Mitogen-Activated Protein Kinase Inhibitor Dilmapimod in Severe Trauma Subjects at Risk for Acute Respiratory Distress Syndrome. Crit. Care Med. 2015, 43, 1859–1869.
    92. Tagami, T.; Tosa, R.; Omura, M.; Fukushima, H.; Kaneko, T.; Endo, T.; Rinka, H.; Murai, A.; Yamaguchi, J.; Yoshikawa, K.; et al. Effect of a selective neutrophil elastase inhibitor on mortality and ventilator-free days in patients with increased extravascular lung water: A post hoc analysis of the PiCCO Pulmonary Edema Study. J. Intensive Care 2014, 2, 67.
    93. Kido, T.; Muramatsu, K.; Yatera, K.; Asakawa, T.; Otsubo, H.; Kubo, T.; Fujino, Y.; Matsuda, S.; Mayumi, T.; Mukae, H. Efficacy of early sivelestat administration on acute lung injury and acute respiratory distress syndrome. Respirology 2017, 22, 708–713.
    94. Pu, S.; Wang, D.; Liu, D.; Zhao, Y.; Qi, D.; He, J.; Zhou, G. Effect of sivelestat sodium in patients with acute lung injury or acute respiratory distress syndrome: A meta-analysis of randomized controlled trials. BMC Pulm. Med. 2017, 17, 148.
    95. Cao, Y.Z.; Tu, Y.Y.; Chen, X.; Wang, B.L.; Zhong, Y.X.; Liu, M.H. Protective effect of Ulinastatin against murine models of sepsis: Inhibition of TNF-α and IL-6 and augmentation of IL-10 and IL-13. Exp. Toxicol. Pathol. 2012, 64, 543–547.
    96. Leng, Y.-X. Ulinastatin for acute lung injury and acute respiratory distress syndrome: A systematic review and meta-analysis. World J. Crit. Care Med. 2014, 3, 34.
    97. NCT02895191 The Safety and Dose Response Relationship of Ulinastatin for Acute Respiratory Distress Syndrome(ARDS)—Full Text View—ClinicalTrials.gov; 2018. Available online: https://clinicaltrials.gov/show/NCT02895191 (accessed on 2 May 2020).
    98. Paine, R.; Standiford, T.J.; Dechert, R.E.; Moss, M.; Martin, G.S.; Rosenberg, A.L.; Thannickal, V.J.; Burnham, E.L.; Brown, M.B.; Hyzy, R.C. A randomized Trial of recombinant human granulocyte-macrophage colony stimulating factor for Patients with acute lung injury. Crit. Care Med. 2012, 40, 90–97.
    99. Frevert, C.W.; Matute-Bello, G.; Skerrett, S.J.; Goodman, R.B.; Kajikawa, O.; Sittipunt, C.; Martin, T.R. Effect of CD14 Blockade in Rabbits with Escherichia coli Pneumonia and Sepsis. J. Immunol. 2000, 164, 5439–5445.
    100. NCT03017547 A Phase 2 Study of IC14 in Acute Respiratory Distress Syndrome—Full Text View—ClinicalTrials.gov; 2019. Available online: https://clinicaltrials.gov/show/NCT03017547 (accessed on 2 May 2020).
    101. Fuller, B.M.; Mohr, N.M.; Skrupky, L.; Fowler, S.; Kollef, M.H.; Carpenter, C.R. The use of inhaled prostaglandins in patients with ARDS: A systematic review and meta-analysis. Chest 2015, 147, 1510–1522.
    102. Wechsler, M.E. Current and emerging biologic therapies for asthma and copd. Respir. Care 2018, 63, 699–707.
    103. Calhoun, K.H. Asthma treatments: New and emerging therapies. Int. Forum Allergy Rhinol. 2015, 5, S76–S81.
    104. Durham, A.L.; Caramori, G.; Chung, K.F.; Adcock, I.M. Targeted anti-inflammatory therapeutics in asthma and chronic obstructive lung disease. Transl. Res. 2016, 167, 192–203.
    105. Tashkin, D.P.; Wechsler, M.E. Role of eosinophils in airway inflammation of chronic obstructive pulmonary disease. Int. J. COPD 2018, 13, 335–349.
    106. Corren, J.; Casale, T.; Deniz, Y.; Ashby, M. Omalizumab, a recombinant humanized anti-IgE antibody, reduces asthma-related emergency room visits and hospitalizations in patients with allergic asthma. J. Allergy Clin. Immunol. 2003, 111, 87–90.
    107. Cowan, D.C.; Taylor, D.R.; Peterson, L.E.; Cowan, J.O.; Palmay, R.; Williamson, A.; Hammel, J.; Erzurum, S.C.; Hazen, S.L.; Comhair, S.A.A. Biomarker-based asthma phenotypes of corticosteroid response. J. Allergy Clin. Immunol. 2015, 135, 877–883.e1.
    108. Fajt, M.L.; Wenzel, S.E. Biologic therapy in asthma: Entering the new age of personalized medicine. J. Asthma 2014, 51, 669–676.
    109. Apter, A.J. Advances in adult asthma diagnosis and treatment in 2014. J. Allergy Clin. Immunol. 2015, 135, 46–53.
    110. Ortega, H.G.; Liu, M.C.; Pavord, I.D.; Brusselle, G.G.; FitzGerald, J.M.; Chetta, A.; Humbert, M.; Katz, L.E.; Keene, O.N.; Yancey, S.W.; et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N. Engl. J. Med. 2014, 371, 1198–1207.
    111. Albers, F.C.; Hozawa, S.; Bratton, D.J.; Yancey, S.W.; Prazma, C.M.; Humbert, M.; Liu, M.C. Update: Mepolizumab treatment in patients with severe eosinophilic asthma and prior omalizumab use. Allergy Eur. J. Allergy Clin. Immunol. 2020, 75, 942–946.
    112. Flood-Page, P.T.; Menzies-Gow, A.N.; Kay, A.B.; Robinson, D.S. Eosinophil’s role remains uncertain as anti-interleukin-5 only partially depletes numbers in asthmatic airway. Am. J. Respir. Crit. Care Med. 2003, 167, 199–204.
    113. Haldar, P.; Brightling, C.E.; Singapuri, A.; Hargadon, B.; Gupta, S.; Monteiro, W.; Bradding, P.; Green, R.H.; Wardlaw, A.J.; Ortega, H.; et al. Outcomes after cessation of mepolizumab therapy in severe eosinophilic asthma: A 12-month follow-up analysis. J. Allergy Clin. Immunol. 2014, 133, 921–923.
    114. Castro, M.; Zangrilli, J.; Wechsler, M.E.; Bateman, E.D.; Brusselle, G.G.; Bardin, P.; Murphy, K.; Maspero, J.F.; O’Brien, C.; Korn, S. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: Results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir. Med. 2015, 3, 355–366.
    115. Castro, M.; King, T.S.; Kunselman, S.J.; Cabana, M.D.; Denlinger, L.; Holguin, F.; Kazani, S.D.; Moore, W.C.; Moy, J.; Sorkness, C.A.; et al. Effect of vitamin D3 on asthma treatment failures in adults with symptomatic asthma and lower vitamin D levels: The VIDA randomized clinical trial. JAMA J. Am. Med. Assoc. 2014, 311, 2083–2091.
    116. Ibrahim, H.; O’Sullivan, R.; Casey, D.; Murphy, J.; MacSharry, J.; Plant, B.J.; Murphy, D.M. The effectiveness of Reslizumab in severe asthma treatment: A real-world experience. Respir. Res. 2019, 20, 289.
    117. Christian Virchow, J.; McDonald, M.; Garin, M.; Korn, S. Reslizumab as add-on therapy in patients with refractory asthma. BMJ Open Respir. Res. 2020, 7, e000494.
    118. Markham, A. Benralizumab: First Global Approval. Drugs 2018, 78, 505–511.
    119. Saco, T.V.; Pepper, A.N.; Lockey, R.F. Benralizumab for the treatment of asthma. Expert Rev. Clin. Immunol. 2017, 13, 405–413.
    120. Bleecker, E.R.; FitzGerald, J.M.; Chanez, P.; Papi, A.; Weinstein, S.F.; Barker, P.; Sproule, S.; Gilmartin, G.; Aurivillius, M.; Werkström, V.; et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO): A randomised, multicentre, placebo-controlled phase 3 trial. Lancet 2016, 388, 2115–2127.
    121. Nair, P.; Wenzel, S.; Rabe, K.F.; Bourdin, A.; Lugogo, N.L.; Kuna, P.; Barker, P.; Sproule, S.; Ponnarambil, S.; Goldman, M. Oral glucocorticoid-sparing effect of benralizumab in severe asthma. N. Engl. J. Med. 2017, 376, 2448–2458.
    122. Shirley, M. Dupilumab: First Global Approval. Drugs 2017, 77, 1115–1121.
    123. Rabe, K.F.; Nair, P.; Brusselle, G.; Maspero, J.F.; Castro, M.; Sher, L.; Zhu, H.; Hamilton, J.D.; Swanson, B.N.; Khan, A.; et al. Efficacy and safety of dupilumab in glucocorticoid-dependent severe asthma. N. Engl. J. Med. 2018, 378, 2475–2485.
    124. Castro, M.; Corren, J.; Pavord, I.D.; Maspero, J.; Wenzel, S.; Rabe, K.F.; Busse, W.W.; Ford, L.; Sher, L.; FitzGerald, J.M.; et al. Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma. N. Engl. J. Med. 2018, 378, 2486–2496.
    125. Hanania, N.A.; Korenblat, P.; Chapman, K.R.; Bateman, E.D.; Kopecky, P.; Paggiaro, P.; Yokoyama, A.; Olsson, J.; Gray, S.; Holweg, C.T.J.; et al. Efficacy and safety of lebrikizumab in patients with uncontrolled asthma (LAVOLTA I and LAVOLTA II): Replicate, phase 3, randomised, double-blind, placebo-controlled trials. Lancet Respir. Med. 2016, 4, 781–796.
    126. Brightling, C.E.; Chanez, P.; Leigh, R.; O’Byrne, P.M.; Korn, S.; She, D.; May, R.D.; Streicher, K.; Ranade, K.; Piper, E. Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: A randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Respir. Med. 2015, 3, 692–701.
    127. Korenblat, P.; Kerwin, E.; Leshchenko, I.; Yen, K.; Holweg, C.T.J.; Anzures-Cabrera, J.; Martin, C.; Putnam, W.S.; Governale, L.; Olsson, J.; et al. Efficacy and safety of lebrikizumab in adult patients with mild-to-moderate asthma not receiving inhaled corticosteroids. Respir. Med. 2018, 134, 143–149.
    128. Busse, W.W.; Brusselle, G.G.; Korn, S.; Kuna, P.; Magnan, A.; Cohen, D.; Bowen, K.; Piechowiak, T.; Wang, M.M.; Colice, G. Tralokinumab did not demonstrate oral corticosteroid-sparing effects in severe asthma. Eur. Respir. J. 2019, 53, 1800948.
    129. NCT03927157 Study to Evaluate Tezepelumab in Adults With Severe Uncontrolled Asthma—Full Text View—ClinicalTrials.gov; 2020. Available online: https://clinicaltrials.gov/show/NCT03927157 (accessed on 2 May 2020).
    130. Marone, G.; Spadaro, G.; Braile, M.; Poto, R.; Criscuolo, G.; Pahima, H.; Loffredo, S.; Levi-Schaffer, F.; Varricchi, G. Tezepelumab: A novel biological therapy for the treatment of severe uncontrolled asthma. Expert Opin. Investig. Drugs 2019, 28, 931–940.
    131. Ding, W.; Zou, G.L.; Zhang, W.; Lai, X.N.; Chen, H.W.; Xiong, L.X. Interleukin-33: Its emerging role in allergic diseases. Molecules 2018, 23, 1–16.
    132. Busse, W.W.; Holgate, S.; Kerwin, E.; Chon, Y.; Feng, J.; Lin, J.; Lin, S. Study of Brodalumab , a Human Anti – IL-17 Receptor Monoclonal Antibody , in Moderate to Severe Asthma. Am. J. Respir. Crit. Care Med. 2013, 188, 1294–1302.
    133. Nair, P.; Gaga, M.; Zervas, E.; Alagha, K.; Hargreave, F.E.; O’Byrne, P.M.; Stryszak, P.; Gann, L.; Sadeh, J.; Chanez, P. Safety and efficacy of a CXCR2 antagonist in patients with severe asthma and sputum neutrophils: A randomized, placebo-controlled clinical trial. Clin. Exp. Allergy 2012, 42, 1097–1103.
    134. NCT00632502 Neutrophilic Asthma Study With Navarixin (MK-7123, SCH 527123) (MK-7123-017)(COMPLETED)—Full Text View—ClinicalTrials.gov; 2019. Available online: https://clinicaltrials.gov/show/NCT00632502 (accessed on 2 May 2020).
    135. Imaoka, H.; Campbell, H.; Babirad, I.; Watson, R.M.; Mistry, M.; Sehmi, R.; Gauvreau, G.M. TPI ASM8 reduces eosinophil progenitors in sputum after allergen challenge. Clin. Exp. Allergy 2011, 41, 1740–1746.
    136. Cahill, K.N.; Katz, H.R.; Cui, J.; Lai, J.; Kazani, S.; Crosby-Thompson, A.; Garofalo, D.; Castro, M.; Jarjour, N.; DiMango, E.; et al. KIT inhibition by imatinib in patients with severe refractory asthma. N. Engl. J. Med. 2017, 376, 1911–1920.
    137. Howarth, P.H.; Babu, K.S.; Arshad, H.S.; Lau, L.; Buckley, M.; McConnell, W.; Beckett, P.; Al Ali, M.; Chauhan, A.; Wilson, S.J.; et al. Tumour necrosis factor (TNFα) as a novel therapeutic target in symptomatic corticosteroid dependent asthma. Thorax 2005, 60, 1012–1018.
    138. Oliveri, C.; Polosa, R. Etanercept in chronic severe asthma. Thorax 2006, 61, 640.
    139. Holgate, S.T.; Noonan, M.; Chanez, P.; Busse, W.; Dupont, L.; Pavord, I.; Hakulinen, A.; Paolozzi, L.; Wajdula, J.; Zang, C.; et al. Efficacy and safety of etanercept in moderate-to-severe asthma: A randomised, controlled trial. Eur. Respir. J. 2011, 37, 1352–1359.
    140. Morjaria, J.B.; Chauhan, A.J.; Babu, K.S.; Polosa, R.; Davies, D.E.; Holgate, S.T. The role of a soluble TNFα receptor fusion protein (etanercept) in corticosteroid refractory asthma: A double blind, randomised, placebo controlled trial. Thorax 2008, 63, 584–591.
    141. Antczak, A.; Kurmanowska, Z.; Kasielski, M.; Nowak, D. Inhaled glucocorticosteroids decrease hydrogen peroxide level in expired air condensate in asthmatic patients. Respir. Med. 2000, 94, 416–421.
    142. Zhu, L.-Y.; Ni, Z.-H.; Luo, X.-M.; Wang, X.-B. Advance of antioxidants in asthma treatment. World J. Respirol. 2017, 7, 17.
    143. Lan, N.; Luo, G.; Yang, X.; Cheng, Y.; Zhang, Y.; Wang, X.; Wang, X.; Xie, T.; Li, G.; Liu, Z.; et al. 25-hydroxyvitamin D3-deficiency enhances oxidative stress and corticosteroid resistance in severe asthma exacerbation. PLoS ONE 2014, 9, e111599.
    144. Bray, T.M.; Bettger, W.J. The physiological role of zinc as an antioxidant. Free Radic. Biol. Med. 1990, 8, 281–291.
    145. Machlin, L.J.; Bendich, A. Free radical tissue damage: Protective role of antioxidant nutrients. FASEB J. 1987, 1, 441–445.
    146. Wood, L.G.; Garg, M.L.; Smart, J.M.; Scott, H.A.; Barker, D.; Gibson, P.G. Manipulating antioxidant intake in asthma: A randomized controlled trial1-3. Am. J. Clin. Nutr. 2012, 96, 534–543.
    147. Kurti, S.P.; Rosenkranz, S.K.; Chapes, S.K.; Teeman, C.S.; Cull, B.J.; Emerson, S.R.; Levitt, M.H.; Smith, J.R.; Harms, C.A. Does chronic physical activity level modify the airway inflammatory response to an acute bout of exercise in the postprandial period? Appl. Physiol. Nutr. Metab. 2017, 42, 173–180.
    148. Pavord, I.D.; Chanez, P.; Criner, G.J.; Kerstjens, H.A.M.; Korn, S.; Lugogo, N.; Martinot, J.B.; Sagara, H.; Albers, F.C.; Bradford, E.S.; et al. Mepolizumab for eosinophilic chronic obstructive pulmonary disease. N. Engl. J. Med. 2017, 377, 1613–1629.
    149. Fernandez Romero, G.A.; Beros, J.; Criner, G. Mepolizumab for the prevention of chronic obstructive pulmonary disease exacerbations. Expert Rev. Respir. Med. 2019, 13, 125–132.
    150. Criner, G.J.; Celli, B.R.; Brightling, C.E.; Agusti, A.; Papi, A.; Singh, D.; Sin, D.D.; Vogelmeier, C.F.; Sciurba, F.C.; Bafadhel, M.; et al. Benralizumab for the prevention of COPD exacerbations. N. Engl. J. Med. 2019, 381, 1023–1034.
    151. Brightling, C.E.; Bleecker, E.R.; Panettieri, R.A.; Bafadhel, M.; She, D.; Ward, C.K.; Xu, X.; Birrell, C.; van der Merwe, R. Benralizumab for chronic obstructive pulmonary disease and sputum eosinophilia: A randomised, double-blind, placebo-controlled, phase 2a study. Lancet Respir. Med. 2014, 2, 891–901.
    152. NCT02138916 Benralizumab Efficacy in Moderate to Very Severe Chronic Obstructive Pulmonary Disease (COPD) With Exacerbation History—Full Text View—ClinicalTrials.gov; 2019. Available online: https://clinicaltrials.gov/show/NCT02138916 (accessed on 2 May 2020).
    153. Barnes, P.J. New anti-inflammatory targets for chronic obstructive pulmonary disease. Nat. Rev. Drug Discov. 2013, 12, 543–559.
    154. Global Initiative for Chronic Obstructive Lung Disease : Pocket Guide To COPD Diagnosis, Management, and Prevention, A Guide for Health Care Professionals. 2017 Report. Available online: https://goldcopd.org/wp-content/uploads/2016/12/wms-GOLD-2017-Pocket-Guide.pdf (accessed on 25 September 2020).
    155. Yang, I.A.; Clarke, M.S.; Sim, E.H.; Fong, K.M. Inhaled corticosteroids for stable chronic obstructive pulmonary disease. Cochrane Database Syst. Rev. 2012, 2012, CD002991.
    156. Nannini, L.J.; Poole, P.; Milan, S.J.; Holmes, R.; Normansell, R. Combined corticosteroid and long-acting beta2-agonist in one inhaler versus placebo for chronic obstructive pulmonary disease. Cochrane Database Syst. Rev. 2013, 2017, CD003794.
    157. Calzetta, L.; Di Marco, F.; Blasi, F.; Cazzola, M.; Centanni, S.; Micheletto, C.; Rossi, A.; Rogliani, P. Impact of ICS/LABA and LABA/LAMA FDCs on functional and clinical outcomes in COPD: A network meta-analysis. Pulm. Pharmacol. Ther. 2019, 59, 101855.
    158. Barnes, P.J. Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease. J. Allergy Clin. Immunol. 2013, 131, 636–645.
    159. Rennard, S.I.; Dale, D.C.; Donohue, J.F.; Kanniess, F.; Magnussen, H.; Sutherland, E.R.; Watz, H.; Lu, S.; Stryszak, P.; Rosenberg, E.; et al. CXCR2 antagonist MK-7123 a phase 2 proof-of-concept trial for chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 2015, 191, 1001–1011.
    160. Raghu, G. Pharmacotherapy for idiopathic pulmonary fibrosis: Current landscape and future potential. Eur. Respir. Rev. 2017, 26, 170071.
    161. Richeldi, L.; Du Bois, R.M.; Raghu, G.; Azuma, A.; Brown, K.K.; Costabel, U.; Cottin, V.; Flaherty, K.R.; Hansell, D.M.; Inoue, Y.; et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N. Engl. J. Med. 2014, 370, 2071–2082.
    162. King, T.E.; Bradford, W.Z.; Castro-Bernardini, S.; Fagan, E.A.; Glaspole, I.; Glassberg, M.K.; Gorina, E.; Hopkins, P.M.; Kardatzke, D.; Lancaster, L.; et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N. Engl. J. Med. 2014, 370, 2083–2092.
    163. Margaritopoulos, G.A.; Trachalaki, A.; Wells, A.U.; Vasarmidi, E.; Bibaki, E.; Papastratigakis, G.; Detorakis, S.; Tzanakis, N.; Antoniou, K.M. Pirfenidone improves survival in IPF: Results from a real-life study. BMC Pulm. Med. 2018, 18, 177.
    164. Somogyi, V.; Chaudhuri, N.; Torrisi, S.E.; Kahn, N.; Müller, V.; Kreuter, M. The therapy of idiopathic pulmonary fibrosis: What is next? Eur. Respir. Rev. 2019, 28, 190021.
    165. Lederer, D.J.; Martinez, F.J. Idiopathic Pulmonary Fibrosis. N. Engl. J. Med. 2018, 378, 1811–1823.
    166. Murray, L.A.; Rosada, R.; Moreira, A.P.; Joshi, A.; Kramer, M.S.; Hesson, D.P.; Argentieri, R.L.; Mathai, S.; Gulati, M.; Herzog, E.L.; et al. Serum amyloid P therapeutically attenuates murine bleomycin-induced pulmonary fibrosis via its effects on macrophages. PLoS ONE 2010, 5, e9683.
    167. Santhiago, M.R.; Singh, V.; Barbosa, F.L.; Agrawal, V.; Wilson, S.E. Monocyte development inhibitor PRM-151 decreases corneal myofibroblast generation in rabbits. Exp. Eye Res. 2011, 93, 786–789.
    168. Van Den Blink, B.; Dillingh, M.R.; Ginns, L.C.; Morrison, L.D.; Moerland, M.; Wijsenbeek, M.; Trehu, E.G.; Bartholmai, B.J.; Burggraaf, J. Recombinant human pentraxin-2 therapy in patients with idiopathic pulmonary fibrosis: Safety, pharmacokinetics and exploratory efficacy. Eur. Respir. J. 2016, 47, 889–897.
    169. Raghu, G.; Van Den Blink, B.; Hamblin, M.J.; Whitney Brown, A.; Golden, J.A.; Ho, L.A.; Wijsenbeek, M.S.; Vasakova, M.; Pesci, A.; Antin-Ozerkis, D.E.; et al. Effect of recombinant human pentraxin 2 vs placebo on change in forced vital capacity in patients with idiopathic pulmonary fibrosis a randomized clinical trial. JAMA J. Am. Med. Assoc. 2018, 319, 2299–2307.
    170. Raghu, G.; van den Blink, B.; Hamblin, M.J.; Brown, A.W.; Golden, J.A.; Ho, L.A.; Wijsenbeek, M.S.; Vasakova, M.; Pesci, A.; Antin-Ozerkis, D.E.; et al. Long-term treatment with recombinant human pentraxin 2 protein in patients with idiopathic pulmonary fibrosis: An open-label extension study. Lancet Respir. Med. 2019, 7, 657–664.
    171. NCT01890265 Evaluate the Safety and Efficacy of FG-3019 (Pamrevlumab) in Participants With Idiopathic Pulmonary Fibrosis (IPF)—Full Text View—ClinicalTrials.gov; 2020. Available online: https://clinicaltrials.gov/show/NCT01890265 (accessed on 20 September 2020).
    172. Gorina, E.; Richeldi, L.; Raghu, G.; Fernandez Perez, E.; Costabel, U.; Albera, C.; Lederer, D.; Flaherty, K.; Ettinger, N.; Bercz, P.; et al. PRAISE, a randomized, placebo-controlled, double-blind Phase 2 clinical trial of pamrevlumab (FG-3019) in IPF patients. Eur. Respir. J. 2017, 50, OA3400.
    173. Gagnon, L.; Leduc, M.; Thibodeau, J.F.; Zhang, M.Z.; Grouix, B.; Sarra-Bournet, F.; Gagnon, W.; Hince, K.; Tremblay, M.; Geerts, L.; et al. A Newly Discovered Antifibrotic Pathway Regulated by Two Fatty Acid Receptors: GPR40 and GPR84. Am. J. Pathol. 2018, 188, 1132–1148.
    174. Khalil, N.; Manganas, H.; Ryerson, C.J.; Shapera, S.; Cantin, A.M.; Hernandez, P.; Turcotte, E.E.; Parker, J.M.; Moran, J.E.; Albert, G.R.; et al. Phase 2 clinical trial of PBI-4050 in patients with idiopathic pulmonary fibrosis. Eur. Respir. J. 2019, 53, 1800663.
    175. NCT02738801 Study to Assess Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Properties of GLPG1690, 2017. Available online: https://clinicaltrials.gov/show/NCT02738801 (accessed on 20 September 2020).
    176. Maher, T.M.; van der Aar, E.M.; Van de Steen, O.; Allamassey, L.; Desrivot, J.; Dupont, S.; Fagard, L.; Ford, P.; Fieuw, A.; Wuyts, W. Safety, tolerability, pharmacokinetics, and pharmacodynamics of GLPG1690, a novel autotaxin inhibitor, to treat idiopathic pulmonary fibrosis (FLORA): A phase 2a randomised placebo-controlled trial. Lancet Respir. Med. 2018, 6, 627–635.
    177. Maher, T.M.; Kreuter, M.; Lederer, D.J.; Brown, K.K.; Wuyts, W.; Verbruggen, N.; Stutvoet, S.; Fieuw, A.; Ford, P.; Abi-Saab, W.; et al. Rationale, design and objectives of two phase III, randomised, placebo-controlled studies of GLPG1690, a novel autotaxin inhibitor, in idiopathic pulmonary fibrosis (ISABELA 1 and 2). BMJ Open Respir. Res. 2019, 6, e000422.
    178. Peters-Golden, M.; Henderson, W.R. University of Michigan Health Sys-tem, 6301 MSRB III, 1150 W. Medical Cen-ter Dr. N Engl J Med 2007, 357, 1841–1854.
    179. Izumo, T.; Kondo, M.; Nagai, A. Effects of a leukotriene B4 receptor antagonist on bleomycin-induced pulmonary fibrosis. Eur. Respir. J. 2009, 34, 1444–1451.
    180. NCT02503657 Safety and Tolerability Study in Subjects With Idiopathic Pulmonary Fibrosis (IPF)—Full Text View—ClinicalTrials.gov; 2020. Available online: https://clinicaltrials.gov/show/NCT02503657 (accessed on: 20 September 2020).
    181. NCT02688647 A Study to Evaluate the Safety, Tolerability, and Activity of KD025 in Subjects With Idiopathic Pulmonary Fibrosis; 2019. Available online: https://clinicaltrials.gov/show/NCT02688647 (accessed on 20 September 2020).
    182. Zanin-Zhorov, A.; Weiss, J.M.; Nyuydzefe, M.S.; Chen, W.; Scher, J.U.; Mo, R.; Depoil, D.; Rao, N.; Liu, B.; Wei, J.; et al. Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism. Proc. Natl. Acad. Sci. USA 2014, 111, 16814–16819.
    183. NCT03142191 A Study to Evaluate the Efficacy and Safety of CC-90001 in Subjects With Idiopathic Pulmonary Fibrosis—Full Text View—ClinicalTrials.gov; 2020. Available online: https://clinicaltrials.gov/show/NCT03142191 (accessed on 20 September 2020).
    184. van der Velden, J.L.J.; Ye, Y.; Nolin, J.D.; Hoffman, S.M.; Chapman, D.G.; Lahue, K.G.; Abdalla, S.; Chen, P.; Liu, Y.; Bennett, B.; et al. JNK inhibition reduces lung remodeling and pulmonary fibrotic systemic markers. Clin. Transl. Med. 2016, 5, 36.
    185. Horan, G.S.; Wood, S.; Ona, V.; Dan, J.L.; Lukashev, M.E.; Weinreb, P.H.; Simon, K.J.; Hahm, K.; Allaire, N.E.; Rinaldi, N.J.; et al. Partial inhibition of integrin αvβ6 prevents pulmonary fibrosis without exacerbating inflammation. Am. J. Respir. Crit. Care Med. 2008, 177, 56–65.
    186. NCT01371305 STX-100 in Patients With Idiopathic Pulmonary Fibrosis (IPF)—Full Text View—ClinicalTrials.gov; 2020. Available online: https://clinicaltrials.gov/show/NCT01371305 (accessed on 20 September 2020).
    187. Zhang, X.L.; Xing, R.G.; Chen, L.; Liu, C.R.; Miao, Z.G. PI3K/Akt signaling is involved in the pathogenesis of bleomycin-induced pulmonary fibrosis via regulation of epithelial-mesenchymal transition. Mol. Med. Rep. 2016, 14, 5699–5706.
    188. NCT01725139 A Proof of Mechanism Study With GSK2126458 in Patients With Idiopathic Pulmonary Fibrosis (IPF)—Full Text View—ClinicalTrials.gov; 2019. Available online: https://clinicaltrials.gov/show/NCT01725139 (accessed on20 September 2020).
    189. Mercer, P.F.; Woodcock, H.V.; Eley, J.D.; Platé, M.; Sulikowski, M.G.; Durrenberger, P.F.; Franklin, L.; Nanthakumar, C.B.; Man, Y.; Genovese, F.; et al. Exploration of a potent PI3 kinase/mTOR inhibitor as a novel anti-fibrotic agent in IPF. Thorax 2016, 71, 701–711.
    190. Lukey, P.T.; Harrison, S.A.; Yang, S.; Man, Y.; Holman, B.F.; Rashidnasab, A.; Azzopardi, G.; Grayer, M.; Simpson, J.K.; Bareille, P.; et al. A randomised, placebo-controlled study of omipalisib (PI3K/mTOR) in idiopathic pulmonary fibrosis. Eur. Respir. J. 2019, 53, 1801992.
    191. NCT01462006 Double-blind Placebo-controlled Pilot Study of Sirolimus in Idiopathic Pulmonary Fibrosis (IPF); 2018. Available online: https://clinicaltrials.gov/show/NCT01462006 (accessed on 20 September 2020).
    192. NCT01969409 Autoantibody Reduction Therapy in Patients With Idiopathic Pulmonary Fibrosis. 2020. Available online: https://clinicaltrials.gov/show/NCT01969409 (accessed on 20 September 2020).
    193. NCT01266317 Combined PEX, Rituximab and Steroids in Acute Idiopathic Pulmonary Fibrosis Exacerbations—Full Text View—ClinicalTrials.gov. 2018. Available online: https://clinicaltrials.gov/show/NCT01266317 (accessed on 20 September 2020).
    194. Donahoe, M.; Valentine, V.G.; Chien, N.; Gibson, K.F.; Raval, J.S.; Saul, M.; Xue, J.; Zhang, Y.; Duncan, S.R. Autoantibody-targeted treatments for acute exacerbations of idiopathic pulmonary fibrosis. PLoS ONE 2015, 10, e0127771.
    195. NCT01777737 Study to Test the Validity of the Treatment of Idiopathic Pulmonary Fibrosis With Cotrimoxazole. 2017. Available online: https://clinicaltrials.gov/show/nct01777737 (accessed on 20 September 2020).
    196. NCT01872689 A Study of Lebrikizumab in Patients With Idiopathic Pulmonary Fibrosis—Full Text View—ClinicalTrials.gov. 2018. pp. 5–7. Available online: https://clinicaltrials.gov/show/NCT01872689 (accessed on 20 September 2020).
    197. NCT01629667 A Phase 2, Randomized Dose-ranging Study to Evaluate the Efficacy of Tralokinumab in Adults With Idiopathic Pulmonary Fibrosis—Full Text View—ClinicalTrials.gov. 2017. Available online: https://clinicaltrials.gov/show/NCT01629667 (accessed on20 September 2020).
    198. NCT02173145 Azithromycin in Idiopathic Pulmonary Fibrosis—Full Text View—ClinicalTrials.gov. 2019. Available online: https://clinicaltrials.gov/show/NCT02173145 (accessed on 20 September 2020).
    199. Habib, A.R.R.; Kajbafzadeh, M.; Desai, S.; Yang, C.L.; Skolnik, K.; Quon, B.S. A Systematic Review of the Clinical Efficacy and Safety of CFTR Modulators in Cystic Fibrosis. Sci. Rep. 2019, 9, 7234.
    200. Clancy, J.P.; Cotton, C.U.; Donaldson, S.H.; Solomon, G.M.; VanDevanter, D.R.; Boyle, M.P.; Gentzsch, M.; Nick, J.A.; Illek, B.; Wallenburg, J.C.; et al. CFTR modulator theratyping: Current status, gaps and future directions. J. Cyst. Fibros. 2019, 18, 22–34.
    201. Lopes-Pacheco, M. CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine. Front. Pharmacol. 2020, 10, 1662.
    202. Lopes-Pacheco, M. CFTR modulators: Shedding light on precision medicine for cystic fibrosis. Front. Pharmacol. 2016, 7, 275.
    203. Li, H.; Pesce, E.; Sheppard, D.N.; Singh, A.K.; Pedemonte, N. Therapeutic approaches to CFTR dysfunction: From discovery to drug development. J. Cyst. Fibros. 2018, 17, S14–S21.
    204. Van Goor, F.; Hadida, S.; Grootenhuis, P.D.J.; Burton, B.; Stack, J.H.; Straley, K.S.; Decker, C.J.; Miller, M.; McCartney, J.; Olson, E.R.; et al. Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. Proc. Natl. Acad. Sci. USA 2011, 108, 18843–18848.
    205. Ratjen, F.; Hug, C.; Marigowda, G.; Tian, S.; Huang, X.; Stanojevic, S.; Milla, C.E.; Robinson, P.D.; Waltz, D.; Davies, J.C.; et al. Efficacy and safety of lumacaftor and ivacaftor in patients aged 6–11 years with cystic fibrosis homozygous for F508del-CFTR: A randomised, placebo-controlled phase 3 trial. Lancet Respir. Med. 2017, 5, 557–567.
    206. Konstan, M.W.; McKone, E.F.; Moss, R.B.; Marigowda, G.; Tian, S.; Waltz, D.; Huang, X.; Lubarsky, B.; Rubin, J.; Millar, S.J.; et al. Assessment of safety and efficacy of long-term treatment with combination lumacaftor and ivacaftor therapy in patients with cystic fibrosis homozygous for the F508del-CFTR mutation (PROGRESS): A phase 3, extension study. Lancet Respir. Med. 2017, 5, 107–118.
    207. Wainwright, C.E.; Elborn, J.S.; Ramsey, B.W.; Marigowda, G.; Huang, X.; Cipolli, M.; Colombo, C.; Davies, J.C.; De Boeck, K.; Flume, P.A.; et al. Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for phe508del CFTR. N. Engl. J. Med. 2015, 373, 220–231.
    208. McElvaney, O.J.; Gunaratnam, C.; McElvaney, O.F.; Bagwe, I.; Reeves, E.P.; McElvaney, N.G. Emerging pharmacotherapies in cystic fibrosis. Expert Rev. Respir. Med. 2018, 12, 843–855.
    209. Pedemonte, N.; Lukacs, G.L.; Du, K.; Caci, E.; Zegarra-Moran, O.; Galietta, L.J.V.; Verkman, A.S. Small-molecule correctors of defective ΔF508-CFTR cellular processing identified by high-throughput screening. J. Clin. Investig. 2005, 115, 2564–2571.
    210. Phuan, P.W.; Veit, G.; Tan, J.A.; Finkbeiner, W.E.; Lukacs, G.L.; Verkman, A.S. Potentiators of defective DF508-CFTR gating that do not interfere with corrector action. Mol. Pharmacol. 2015, 88, 791–799.
    211. Liang, F.; Shang, H.; Jordan, N.J.; Wong, E.; Mercadante, D.; Saltz, J.; Mahiou, J.; Bihler, H.J.; Mense, M. High-Throughput Screening for Readthrough Modulators of CFTR PTC Mutations. SLAS Technol. 2017, 22, 315–324.
    212. Giuliano, K.A.; Wachi, S.; Drew, L.; Dukovski, D.; Green, O.; Bastos, C.; Cullen, M.D.; Hauck, S.; Tait, B.D.; Munoz, B.; et al. Use of a High-Throughput Phenotypic Screening Strategy to Identify Amplifiers, a Novel Pharmacological Class of Small Molecules That Exhibit Functional Synergy with Potentiators and Correctors. SLAS Discov. 2018, 23, 111–121.
    213. Van Der Plas, S.E.; Kelgtermans, H.; De Munck, T.; Martina, S.L.X.; Dropsit, S.; Quinton, E.; De Blieck, A.; Joannesse, C.; Tomaskovic, L.; Jans, M.; et al. Discovery of N-(3-Carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-lH-pyrazole-5-carboxamide (GLPG1837), a Novel Potentiator Which Can Open Class III Mutant Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Channels to a High. J. Med. Chem. 2018, 61, 1425–1435.
    214. Veit, G.; Xu, H.; Dreano, E.; Avramescu, R.G.; Bagdany, M.; Beitel, L.K.; Roldan, A.; Hancock, M.A.; Lay, C.; Li, W.; et al. Structure-guided combination therapy to potently improve the function of mutant CFTRs. Nat. Med. 2018, 24, 1732–1742.
    215. Wang, X.; Liu, B.; Searle, X.; Yeung, C.; Bogdan, A.; Greszler, S.; Singh, A.; Fan, Y.; Swensen, A.M.; Vortherms, T.; et al. Discovery of 4-[(2R,4R)-4-({[1-(2,2-Difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic Acid (ABBV/GLPG-2222), a Potent Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Corrector for. J. Med. Chem. 2018, 61, 1436–1449.
    216. Berg, A.; Hallowell, S.; Tibbetts, M.; Beasley, C.; Brown-Phillips, T.; Healy, A.; Pustilnik, L.; Doyonnas, R.; Pregel, M. High-Throughput Surface Liquid Absorption and Secretion Assays to Identify F508del CFTR Correctors Using Patient Primary Airway Epithelial Cultures. SLAS Discov. 2019, 24, 724–737.
    217. De Wilde, G.; Gees, M.; Musch, S.; Verdonck, K.; Jans, M.; Wesse, A.S.; Singh, A.K.; Hwang, T.C.; Christophe, T.; Pizzonero, M.; et al. Identification of GLPG/ABBV-2737, a novel class of corrector, which exerts functional synergy with other CFTR modulators. Front. Pharmacol. 2019, 10, 514.
    218. Merkert, S.; Schubert, M.; Olmer, R.; Engels, L.; Radetzki, S.; Veltman, M.; Scholte, B.J.; Zöllner, J.; Pedemonte, N.; Galietta, L.J.V.; et al. High-Throughput Screening for Modulators of CFTR Activity Based on Genetically Engineered Cystic Fibrosis Disease-Specific iPSCs. Stem Cell Rep. 2019, 12, 1389–1403.
    219. Rafeeq, M.M.; Murad, H.A.S. Cystic fibrosis: Current therapeutic targets and future approaches. J. Transl. Med. 2017, 15, 84.
    220. Cheng, K.; Ashby, D.; Smyth, R.L. Oral steroids for long-term use in cystic fibrosis. Cochrane Database Syst. Rev. 2015, 2015, CD000407.
    221. Balfour-Lynn, I.M.; Welch, K.; Smith, S. Inhaled corticosteroids for cystic fibrosis. Cochrane Database Syst. Rev. 2019, 2019, CD001915.
    222. Ross, K.R.; Chmiel, J.F.; Konstan, M.W. The role of inhaled corticosteroids in the management of cystic fibrosis. Pediatr. Drugs 2009, 11, 101–113.
    223. Konstan, M.W. Ibuprofen therapy for cystic fibrosis lung disease: Revisited. Curr. Opin. Pulm. Med. 2008, 14, 567–573.
    224. Lands, L.C.; Stanojevic, S. Oral non-steroidal anti-inflammatory drug therapy for cystic fibrosis. Cochrane Database Syst. Rev. 1999, CD001505, doi:10.1002/14651858.CD001505
    225. Lands, L.C.; Stanojevic, S. Oral non-steroidal anti-inflammatory drug therapy for lung disease in cystic fibrosis. Cochrane Database Syst. Rev. 2019, 2019, CD001505.
    226. Konstan, M.W.; VanDevanter, D.R.; Sawicki, G.S.; Pasta, D.J.; Foreman, A.J.; Neiman, E.A.; Morgan, W.J. Association of high-dose ibuprofen use, lung function decline, and long-term survival in children with cystic fibrosis. Ann. Am. Thorac. Soc. 2018, 15, 485–493.
    227. Konstan, M.W.; Döring, G.; Heltshe, S.L.; Lands, L.C.; Hilliard, K.A.; Koker, P.; Bhattacharya, S.; Staab, A.; Hamilton, A. A randomized double blind, placebo controlled phase 2 trial of BIIL 284 BS (an LTB4 receptor antagonist) for the treatment of lung disease in children and adults with cystic fibrosis. J. Cyst. Fibros. 2014, 13, 148–155.
    228. Elborn, J.S.; Bhatt, L.; Grosswald, R.; Ahuja, S.; Springman, E.B. Phase I Studies of Acebilustat: Pharmacokinetics, Pharmacodynamics, Food Effect, and CYP3A Induction. Clin. Transl. Sci. 2017, 10, 20–27.
    229. Elborn, J.S.; Ahuja, S.; Springman, E.; Mershon, J.; Grosswald, R.; Rowe, S.M. EMPIRE-CF: A phase II randomized placebo-controlled trial of once-daily, oral acebilustat in adult patients with cystic fibrosis—Study design and patient demographics. Contemp. Clin. Trials 2018, 72, 86–94.
    230. NCT02759562 Effect of Andecaliximab on FEV1 in Adults With Cystic Fibrosis—Full Text View—ClinicalTrials.gov. 2018. Available online: https://clinicaltrials.gov/show/NCT02759562 (accessed on 3 May 2020).
    231. NCT03748199 Clinical Study to Investigate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of POL6014 in Patients with CF—Full Text View—ClinicalTrials.gov. 2018. Available online: https://clinicaltrials.gov/show/NCT03748199 (accessed on 3 May 2020).
    232. McElvaney, N.G. Alpha-1 antitrypsin therapy in cystic fibrosis and the lung disease associated with alpha-1 antitrypsin deficiency. Ann. Am. Thorac. Soc. 2016, 13, S191–S196.
    233. Elborn, J.S.; Perrett, J.; Forsman-Semb, K.; Marks-Konczalik, J.; Gunawardena, K.; Entwistle, N. Efficacy, safety and effect on biomarkers of AZD9668 in cystic fibrosis. Eur. Respir. J. 2012, 40, 969–976.
    234. Motwani M.; Bennett, F.; Tepper, M.; White, B.; Norris, P.; MacAllister, R.; Serhan, C.; Gilroy, D. Anabasum (JBT-101) enhances resolution of inflammation in humans. Arthritis Rheumatol. 2017, 69 (suppl 10).
    235. NCT03748199 Safety, Tolerability, Pharmacokinetics, and Efficacy of JBT-101 (Lenabasum) in Cystic Fibrosis—Full Text View—ClinicalTrials.gov. Available online: https://clinicaltrials.gov/show/ NCT03748199 (accessed on 20 September 2020).
    236. Burstein, S.H. Ajulemic acid: Potential treatment for chronic inflammation. Pharmacol. Res. Perspect. 2018, 6, e00394.
    237. Pertwee, R.G. Endocannabinoids and their pharmacological actions. In Handbook of Experimental Pharmacology; Springer: New York, NY, USA, 2015; Volume 231, pp. 1–37.
    238. Gkoumassi, E.; Dekkers, B.G.J.; Dröge, M.J.; Elzinga, C.R.S.; Schmidt, M.; Meurs, H.; Zaagsma, J.; Nelemans, S.A. Virodhamine and CP55,940 modulate cAMP production and IL-8 release in human bronchial epithelial cells. Br. J. Pharmacol. 2007, 151, 1041–1048.
    239. McElvaney, N.G.; Hubbard, R.C.; Birrer, P.; Crystal, R.G.; Chernick, M.S.; Frank, M.M.; Caplan, D.B. Aerosol α1 -antitrypsin treatment for cystic fibrosis. Lancet 1991, 337, 392–394.
    240. Griese, M.; Latzin, P.; Kappler, M.; Weckerle, K.; Heinzimaier, T.; Bernhardt, T.; Hartl, D. α1-Antitrypsin inhalation reduces airway inflammation in cystic fibrosis patients. Eur. Respir. J. 2007, 29, 240–250.
    241. Grimbert, D.; Vecellio, L.; Delépine, P.; Attucci, S.; Boissinot, E.; Poncin, A.; Gauthier, F.; Valat, C.; Saudubray, F.; Antonioz, P.; et al. Characteristics of EPI-hNE4 aerosol: A new elastase inhibitor for treatment of cystic fibrosis. J. Aerosol Med. Depos. Clear. Eff. Lung 2003, 16, 121–129.
    242. Williams, B.; Robinette, M.; Slovis, B.; Deretci, V.; Perkett, E. Hydroxychloroquine—Pilot study of anti-inflammatory effects in cystic fibrosis. Pediatr. Pulmonol. 2008, 43, 314.
    243. Moss, R.B.; Mistry, S.J.; Konstan, M.W.; Pilewski, J.M.; Kerem, E.; Tal-Singer, R.; Lazaar, A.L. Safety and early treatment effects of the CXCR2 antagonist SB-656933 in patients with cystic fibrosis. J. Cyst. Fibros. 2013, 12, 241–248.
    244. Ballmann, M.; Junge, S.; von der Hardt, H. Low-dose methotrexate for advanced pulmonary disease in patients with cystic fibrosis. Respir. Med. 2003, 97, 498–500.
    245. McElvaney, O.J.; McElvaney, N.G. Targeting IL-8 in cystic fibrosis: Enough but not too much. Am. J. Respir. Cell Mol. Biol. 2018, 59, 401–402.
    246. McElvaney, O.J.; O’Reilly, N.; White, M.; Lacey, N.; Pohl, K.; Gerlza, T.; Bergin, D.A.; Kerr, H.; McCarthy, C.; O’Brien, M.E.; et al. The effect of the decoy molecule PA401 on CXCL8 levels in bronchoalveolar lavage fluid of patients with cystic fibrosis. Mol. Immunol. 2015, 63, 550–558.
    247. Karp, C.L.; Flick, L.M.; Park, K.W.; Softic, S.; Greer, T.M.; Keledjian, R.; Yang, R.; Uddin, J.; Guggino, W.B.; Atabani, S.F.; et al. Defective lipoxin-mediated anti-inflammatory activity in the cystic fibrosis airway. Nat. Immunol. 2004, 5, 388–392.
    248. József, L.; Zouki, C.; Petasis, N.A.; Serhan, C.N.; Filep, J.G. Lipoxin A4 and aspirin-triggered 15-epi-lipoxin A4 inhibit peroxynitrite formation, NF-κB and AP-1 activation, and IL-8 gene expression in human leukocytes. Proc. Natl. Acad. Sci. USA 2002, 99, 13266–13271.
    249. Nagaoka, I.; Tamura, H.; Hirata, M. An Antimicrobial Cathelicidin Peptide, Human CAP18/LL-37, Suppresses Neutrophil Apoptosis via the Activation of Formyl-Peptide Receptor-Like 1 and P2X 7. J. Immunol. 2006, 176, 3044–3052.
    250. Herrera, B.S.; Hasturk, H.; Kantarci, A.; Freire, M.O.; Nguyen, O.; Kansal, S.; van Dyke, T.E. Impact of resolvin E1 on murine neutrophil phagocytosis in type 2 diabetes. Infect. Immun. 2015, 83, 792–801.
    251. Freire, M.O.; Dalli, J.; Serhan, C.N.; Van Dyke, T.E. Neutrophil Resolvin E1 Receptor Expression and Function in Type 2 Diabetes. J. Immunol. 2017, 198, 718–728.
    252. Kurihara, T.; Jones, C.N.; Yu, Y.M.; Fischman, A.J.; Watada, S.; Tompkins, R.G.; Fagan, S.P.; Irimia, D. Resolvin D2 restores neutrophil directionality and improves survival after burns. FASEB J. 2013, 27, 2270–2281.
    253. Schwab, J.M.; Chiang, N.; Arita, M.; Serhan, C.N. Resolvin E1 and protectin D1 activate inflammation-resolution programmes. Nature 2007, 447, 869–874.
    254. Hsiao, H.-M.; Thatcher, T.H.; Levy, E.P.; Fulton, R.A.; Owens, K.M.; Phipps, R.P.; Sime, P.J. Resolvin D1 Attenuates Polyinosinic-Polycytidylic Acid–Induced Inflammatory Signaling in Human Airway Epithelial Cells via TAK1. J. Immunol. 2014, 193, 4980–4987.
    255. Ringholz, F.C.; Higgins, G.; Hatton, A.; Sassi, A.; Moukachar, A.; Fustero-Torre, C.; Hollenhorst, M.; Sermet-Gaudelus, I.; Harvey, B.J.; McNally, P.; et al. Resolvin D1 regulates epithelial ion transport and inflammation in cystic fibrosis airways. J. Cyst. Fibros. 2018, 17, 607–615.
    256. NCT03265288 Study of LAU-7b in the Treatment of Cystic Fibrosis in Adults—Full Text View—ClinicalTrials.gov. 2020. Available online: https://clinicaltrials.gov/show/NCT03265288 (accessed on 3 May 2020).
    257. Kontoghiorghes, G.J.; Kontoghiorghe, C.N. Prospects for the introduction of targeted antioxidant drugs for the prevention and treatment of diseases related to free radical pathology. Expert Opin. Investig. Drugs 2019, 28, 593–603.
    258. Cantin, A.M. Low-hanging fruit and antioxidant therapy in cystic fibrosis. Am. J. Respir. Crit. Care Med. 2018, 198, 555–557.
    259. Calabrese, C.; Tosco, A.; Abete, P.; Carnovale, V.; Basile, C.; Magliocca, A.; Quattrucci, S.; De Sanctis, S.; Alatri, F.; Mazzarella, G.; et al. Randomized, single blind, controlled trial of inhaled glutathione vs placebo in patients with cystic fibrosis. J. Cyst. Fibros. 2015, 14, 203–210.
    260. Skov, M.; Pressler, T.; Lykkesfeldt, J.; Poulsen, H.E.; Jensen, P.Ø.; Johansen, H.K.; Qvist, T.; Kræmer, D.; Høiby, N.; Ciofu, O. The effect of short-term, high-dose oral N-acetylcysteine treatment on oxidative stress markers in cystic fibrosis patients with chronic P. aeruginosa infection—A pilot study. J. Cyst. Fibros. 2015, 14, 211–218.
    261. Hector, A.; Griese, M.; Hartl, D. Oxidative stress in cystic fibrosis lung disease: An early event, but worth targeting? Eur. Respir. J. 2014, 44, 17–19.
    262. Griese, M.; Kappler, M.; Eismann, C.; Ballmann, M.; Junge, S.; Rietschel, E.; Van Koningsbruggen-Rietschel, S.; Staab, D.; Rolinck-Werninghaus, C.; Mellies, U.; et al. Inhalation treatment with glutathione in patients with cystic fibrosis: A randomized clinical trial. Am. J. Respir. Crit. Care Med. 2013, 188, 83–89.
    263. de Vries, J.J.V.; Chang, A.B.; Bonifant, C.M.; Shevill, E.; Marchant, J.M. Vitamin A and beta (β)-carotene supplementation for cystic fibrosis. Cochrane Database Syst. Rev. 2018, 2018, CD006751.
    264. González Jiménez, D.; Díaz Martín, J.J.; Arias Llorente, R.P.; Bousoño García, C. Oxidative Stress in Cystic Fibrosis. In Cystic Fibrosis in the Light of New Research; IntechOpen: London, UK, 2015.
    265. Kontoghiorghe, C.N.; Kolnagou, A.; Kontoghiorghes, G.J. Antioxidant targeting by deferiprone in diseases related to oxidative damage. Front. Biosci. Landmark 2014, 19, 862–885.
    266. Kontoghiorghes, G.J. Prospects for introducing deferiprone as potent pharmaceutical antioxidant. Front. Biosci. Elit. 2009, 1, 161–178.
    267. Conrad, C.; Lymp, J.; Thompson, V.; Dunn, C.; Davies, Z.; Chatfield, B.; Nichols, D.; Clancy, J.; Vender, R.; Egan, M.E.; et al. Long-term treatment with oral N-acetylcysteine: Affects lung function but not sputum inflammation in cystic fibrosis subjects. A phase II randomized placebo-controlled trial. J. Cyst. Fibros. 2015, 14, 219–227.
    268. Peters, S.A.; Kelly, F.J. Vitamin E supplementation in cystic fibrosis. J. Pediatr. Gastroenterol. Nutr. 1996, 22, 341–345.
    269. Maqbool, A.; Stallings, V.A. Update on fat-soluble vitamins in cystic fibrosis. Curr. Opin. Pulm. Med. 2008, 14, 574–581.
    270. Galli, F.; Azzi, A. Present trends in vitamin E research. BioFactors 2010, 36, 33–42.
    271. Hamahata, A.; Enkhbaatar, P.; Kraft, E.R.; Lange, M.; Leonard, S.W.; Traber, M.G.; Cox, R.A.; Schmalstieg, F.C.; Hawkins, H.K.; Whorton, E.B.; et al. γ-Tocopherol nebulization by a lipid aerosolization device improves pulmonary function in sheep with burn and smoke inhalation injury. Free Radic. Biol. Med. 2008, 45, 425–433.
    272. Anais, J.P.; Razzouq, N.; Carvalho, M.; Fernandez, C.; Astier, A.; Paul, M.; Astier, A.; Fessi, H.; Lorino, A.M. Development of α-tocopherol acetate nanoparticles: Influence of preparative processes. Drug Dev. Ind. Pharm. 2009, 35, 216–223.
    273. Rust, P.; Eichler, I.; Renner, S.; Elmadfa, I. Long-term oral β-carotene supplementation in patients with cystic fibrosis—Effects on antioxidative status and pulmonary function. Ann. Nutr. Metab. 2000, 44, 30–37.
    274. Sagel, S.D.; Sontag, M.K.; Anthony, M.M.; Emmett, P.; Papas, K.A. Effect of an antioxidant-rich multivitamin supplement in cystic fibrosis. J. Cyst. Fibros. 2011, 10, 31–36.
    275. Papas, K.A.; Sontag, M.K.; Pardee, C.; Sokol, R.J.; Sagel, S.D.; Accurso, F.J.; Wagener, J.S. A pilot study on the safety and efficacy of a novel antioxidant rich formulation in patients with cystic fibrosis. J. Cyst. Fibros. 2008, 7, 60–67.
    276. Sagel, S.D.; Khan, U.; Jain, R.; Graff, G.; Daines, C.L.; Dunitz, J.M.; Borowitz, D.; Orenstein, D.M.; Abdulhamid, I.; Noe, J.; et al. Effects of an antioxidant-enriched multivitamin in cystic fibrosis. Am. J. Respir. Crit. Care Med. 2018, 198, 639–647.
    277. Foucaud, P.; Therond, P.; Marchand, M.; Brion, F.; Demelier, J.F.; Navarro, J. Selenium and vitamin E in cystic fibrosis. Arch. Fr. Pediatr. 1988, 45, 383–386.
    278. Tsavachidou, D.; McDonnell, T.J.; Wen, S.; Wang, X.; Vakar-Lopez, F.; Pisters, L.L.; Pettaway, C.A.; Wood, C.G.; Do, K.A.; Thall, P.F.; et al. Selenium and vitamin E: Cell type- and intervention-specific tissue effects in prostate cancer. J. Natl. Cancer Inst. 2009, 101, 306–320.
    279. Winklhofer-Roob, B.M.; Ellemunter, H.; Frühwirth, M.; Schlegel-Haueter, S.E.; Khoschsorur, G.; Van’t Hof, M.A.; Shmerling, D.H. Plasma vitamin C concentrations in patients with cystic fibrosis: Evidence of associations with lung inflammation. Am. J. Clin. Nutr. 1997, 65, 1858–1866.
    280. Van Biervliet, S.; Vande Velde, S.; Van Biervliet, J.P.; Robberecht, E. The effect of zinc supplements in cystic fibrosis patients. Ann. Nutr. Metab. 2008, 52, 152–156.
    281. De Castro-Silva, C.; De Bruin, V.M.S.; Cunha, G.M.A.; Nunes, D.M.; Medeiros, C.A.M.; De Bruin, P.F.C. Melatonin improves sleep and reduces nitrite in the exhaled breath condensate in cystic fibrosis—A randomized, double-blind placebo-controlled study. J. Pineal Res. 2010, 48, 65–71.
    More