Salivary myeloperoxidase in Patients with Systemic Diseases: Comparison
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Please note this is a comparison between Version 2 by Dean Liu and Version 1 by Kacper Nijakowski.

Salivary myeloperoxidase (MPO) is a key mediator of the oral immune system, acting as an enzyme that utilises H2O2 to generate molecules with high bactericidal activity. While MPO determination in plasma is quite common, the use of saliva is still rare.

  • myeloperoxidase
  • systemic disease
  • coronary artery disease
  • inflammatory bowel disease

1. Introduction

Myeloperoxidase (MPO) is a heme-containing enzyme (E.C.1.11.1.7) found primarily in neutrophils that catalyses the formation of reactive oxygen and nitrogen species with potent antimicrobial activity [1]. Typically, MPO utilises H2O2 generated by NADPH oxidases, xanthine oxidase, or nitric oxide synthase to produce hypochlorous acid with strong bactericidal properties [2]. In addition, by consuming H2O2, MPO protects the host from the toxicity of bacterial H2O2. For these reasons, MPO is viewed as a key component of innate immunity and an inflammatory mediator [3,4][3][4].
On the other hand, however, uncontrolled MPO activity can lead to excessive oxidant production, oxidative modifications of macromolecules, and tissue damage. In this respect, MPO-derived oxidants have been implicated in the pathogenesis of many diseases characterised by chronic inflammation, including atherosclerosis and cardiovascular disease, renal, liver and gastrointestinal diseases, cancer, rheumatoid arthritis, and neurodegenerative diseases [5]. Therefore, it has been proposed that MPO may serve as a biomarker to assess the risk of developing these conditions [6,7][6][7].
While the measurement of MPO in plasma is recognised in biomedical research, the use of saliva for this purpose is rare. In turn, the use of saliva as a biological fluid in the diagnosis of systemic diseases (e.g., gastrointestinal diseases, oncological diseases) is already better understood [8,9,10][8][9][10].

2. Cardiovascular Diseases

The levels of neutrophil-associated plasma proteins, such as MPO and matrix metalloproteinase 9 (MMP-9), could predict the risk of cardiovascular events related to the severity of atherosclerosis [42,43][11][12]. In patients with cardiovascular diseases, neutrophils are more prone to release these mediators than neutrophils from healthy controls [44][13]. MPO and MMP-9 are related to such processes as inflammation, tissue damage, and tissue remodelling in individuals with myocardial infarction [45][14]. MPO and MPO-derived oxidants can contribute to atherosclerosis by foam cell formation and endothelial dysfunction demonstrated by increased endothelial cell permeability and apoptosis [46][15]. Also, they activate latent matrix metalloproteinases (MMPs) and tissue factor expression, promoting the vulnerable plaque [47][16]. Unstable or ruptured plaque may be caused by MPO-induced superficial plaque erosion and increased susceptibility to thrombus formation [48][17]. The MPO-mediated modification of cholesterol efflux from lipid-laden cells attenuates the anti-atherogenic properties of high-density lipoproteins [49,50][18][19]. In contrast, MPO is involved in the formation of atherogenic oxidised low-density lipoproteins, which lead to the development of atherosclerotic plaques with an enlarged lipid core pressing on the fibrous cap matrix [51][20]. The study by Polizzi et al. [35][21] presented that patients with coronary heart disease demonstrated significantly elevated salivary and plasma levels of MPO, regardless of periodontal status. Based on the multivariate regression analysis, in these patients, salivary MPO concentrations could be predicted by CRP and total cholesterol levels. In turn, Lahdentausta et al. [26][22] suggested that MPO may be a reliable marker for both acute coronary syndrome (ACS) and periodontal disease, but this depends on the type of biological material. Salivary levels were useful for diagnosing periodontitis but not for diagnosing ACS. The opposite finding was true for serum MPO. Moreover, Mahmood et al. [29][23] observed a significant increase in salivary MPO levels after exercise in patients with coronary artery disease. However, the protein-adjusted levels did not differ significantly from those at rest. MPO levels in saliva were 4-fold higher than in plasma and did not correlate with each other. Interestingly, Foley et al. [21][24] evaluated if salivary biomarkers could demonstrate utility for identifying myocardial necrosis. Salivary MPO was characterised by a downward trend with a significantly lower level than the baseline at 48 h after the alcohol septal ablation in patients with hypertrophic cardiomyopathy. Rathnayake et al. [36][25] investigated salivary MPO levels in patients with myocardial infarction (MI). After adjusting for gingival status and smoking habits, MPO concentrations in saliva were significantly lower than in the control group. Males demonstrated significantly higher MPO levels compared with females. Also, clinical signs of periodontal inflammation positively correlated with salivary MPO concentrations. Similarly, Floriano et al. [20][26] investigated the utility of saliva for identifying alternative biomarkers of acute myocardial infarction (AMI). In contrast, MPO levels were increased in AMI patients compared to controls in both saliva and serum, almost 2- and 3-fold, respectively. The salivary panel of MPO, myoglobin, and C-reactive protein presented a significant diagnostic capability for AMI (AUC = 0.85), which increased when an electrocardiogram (ECG) was added (AUC = 0.94). At that time, the screening value was comparable to the panel of troponin-I, creatine kinase-MB, myoglobin, and brain natriuretic peptide (AUC = 0.98), and was significantly higher than ECG itself. In addition, Palm et al. [34][27] determined that patients with ischemic stroke had significantly lower salivary MPO concentrations than the control subjects. Similar findings were presented for serum MPO concentrations. After adjustment, differences remained significant.

3. Respiratory Disorders

The role of neutrophils in airway inflammation in the course of asthma is confirmed. In children and adults with severe asthma, blood or sputum MPO is increased, reflecting elevated neutrophil activity [52][28]. Also, the catalytic activity of MPO is modulated by plasma nitric oxide released during chronic inflammation in patients with bronchial asthma [53][29]. In 1998, Lenander-Lumikari et al. [27][30] observed decreased stimulated salivary flow rates and increased MPO concentrations in asthmatic adults compared with non-asthmatic ones. They speculated that higher MPO levels might be associated with a higher degree of periodontal inflammation (described by Periodontal Status Index) in asthmatics. Obstructive sleep apnoea (OSA), presenting as upper airways collapse during sleep, leads to intermittent hypoxia. Therefore, oropharyngeal inflammation is associated with increased levels of proinflammatory cytokines and reactive oxygen species (ROS) [54,55][31][32]. During inflammation involving both upper and lower airways, the release of neutrophilic enzymes, such as MPO, MMPs, and neutrophil elastase, is elevated [56][33]. Moreover, MPO is considered as a mutual contributor to the higher incidence of OSA and cardiovascular diseases [57][34]. In the study by Akpinar et al. [17][35], patients with OSA demonstrated significantly higher levels of MPO in saliva compared to healthy controls. Serum differences were at the borderline of statistical significance. Salivary MPO levels positively correlated with the Apnoea-Hypopnea Index (AHI), the oxygen desaturation index, and sleep efficiency. The authors suggest that salivary MPO could be a useful oropharyngeal inflammatory marker in OSA patients. However, in the study by Nizam et al. [33][36], patients with mild-moderate and severe obstructive sleep apnoea syndrome demonstrated lower levels of MPO in saliva and serum compared with the healthy controls, but these differences were not significant.

4. Gastrointestinal Diseases

In active inflammatory bowel diseases, the mucosal barrier is injured by intestinal inflammatory and oxidative processes caused by enhanced neutrophil infiltration [58,59][37][38]. The increased production of proinflammatory cytokines and ROS is modulated by neutrophil recruitment and accumulation in the gastrointestinal wall [60][39]. The intestinal mucosal integrity is ensured by maintaining a balance between ROS and antioxidants, including MPO, which is responsible for the formation of neutrophil extracellular traps [61,62][40][41]. Importantly, MPO seems to be a therapeutic target for protecting colon mucosa from inflammatory damage [63][42]. In ourthe previous study, patients with inflammatory bowel diseases eligible for biologic therapy had significantly reduced MPO levels in the saliva of patients with ulcerative colitis (UC) compared to patients with Crohn’s disease (CD) and healthy controls. Based on the ROC analysis, the lower salivary MPO concentrations could be a significant predictor for the differential diagnosis between CD and UC [31][43]. Furthermore, as a result of an effective response to biologic treatment, only patients with UC demonstrated MPO levels significantly increased to those comparable to healthy subjects [32][44]. OurThe most recent cross-sectional study in Polish patients with IBD [64][45] found that lowered MPO concentrations in saliva could be a predictor for the non-invasive diagnosis of clinically active UC, and was significantly correlated with the endoscopic severity in this group. Also, salivary MPO in patients treated biologically and without steroid therapy demonstrated significant correlations with selected blood parameters, reflecting inflammatory status (such as CRP or white blood cells). OurThe findings suggest that MPO levels in saliva could be used to monitor IBD activity and treatment effectiveness. In contrast, Janšáková et al. [22][46] found only a slight increase in salivary MPO levels in patients with CD and orofacial granulomatosis (OFG) compared with the control group. In 2000, Lenander-Lumikari et al. [28][47] presented that salivary peroxidase and MPO activities were significantly elevated in patients with coeliac disease compared with healthy subjects. In turn, the gluten challenge resulted in a decrease in MPO activity in these patients. However, no differences in stimulated saliva flow rates were found. A non-gluten diet, including long-chain omega-3 fatty acids, flavonoids and carotenoids, can modulate the expression and production of oxidative and inflammatory mediators, preserving intestinal barrier integrity [65][48]. Inflammation caused by an imbalance between oxidant and antioxidant markers (including MPO) may stimulate DNA damage [66][49]. Chronic protein–energy malnutrition is associated with the permanent disruptions of salivary glands, which lead to decreased protein production [67][50]. In the study by Johansson et al. [23][51], no differences in MPO concentrations were observed between the saliva samples from Indian children with chronic protein–energy malnutrition and the control group.

5. Haematological Disorders

The suppression of salivary defence mechanisms appears after the chemotherapy introduction, not haematological disorders themselves [68][52]. The cytostatic treatment causes significant decreases in saliva secretion rates and the lack of peripheral blood granulocytes, leading to an extremely lowered count of neutrophils in saliva and, subsequently, decreased MPO activity [69,70][53][54]. However, the decreased MPO-dependent antimicrobial defence may be compensated by increased lactoferrin release in saliva [71][55]. The oral neutrophils reach normal counts in saliva even before peripheral blood [72][56]. Altered MPO activity can result in excessive accumulation of H2O2, which is responsible for oral tissue damage. Patients demonstrating oral mucositis with ulcerative lesions seem to favour the neutrophilic infiltration [73][57]. During oral mucositis, blood proteins pass into saliva due to leakage in the integrity of the oral mucosa [74][58]. In children with newly diagnosed acute leukaemia, Karolewska et al. [24][59] assessed the changes in the activity of salivary antibacterial factors in the course of leukaemia, depending on the oral clinical findings. Patients with aplasia demonstrated significantly lower levels of MPO and peroxidase in saliva. In addition, the significantly decreased salivary activities of MPO and peroxidase were presented in leukaemia children with mucositis compared to those without mucositis. In the study by van Leeuwen et al. [39][60], the salivary MPO demonstrated the fluctuating trends in multiple myeloma patients treated with high-dose melphalan and autologous haematopoietic stem cell transplantation (HSCT). In unstimulated saliva, the lowest MPO levels were measured one week after transplantation. Also, MPO concentrations were similarly low on the day of transplantation, with an increase on the fourth and eleventh postoperative days. For MPO in stimulated saliva, the changes did not show statistical significance. At the same time, decreases in the secretion of both resting and stimulated saliva were observed. Moreover, Salvador et al. [38][61] evaluated the effect of photobiomodulation (PBM) therapy on the reducing severity of oral mucositis in patients undergoing HSCT. In the study group, patients received PBM applications every day until the seventh post-transplant day, and in the control group, only the oral hygiene guidelines were applied. In both groups, salivary MPO levels significantly decreased one week after transplantation.

6. Infectious and Immunological Disorders

The study by Mellanen et al. [30][62] showed elevated levels of MPO in the saliva of HIV-seropositive patients. The authors speculated that this increase might be related to the severity of periodontal disease. In the study by Kirstilä et al. [25][63], patients with common variable immunodeficiency did not differ from the control subjects concerning MPO levels in saliva. However, total salivary peroxidase activity was significantly elevated in immunodeficient patients. Unexpectedly, MPO can also be present in human lymphocytes. The increased MPO in CD4(+) T lymphocytes from chronic HIV infection is found [75][64]. In chronic HIV, mitochondrial dysfunction can be induced by MPO, leading to the vicious cycle of mitochondrial damage [76][65]. Interestingly, Saheb Sharif-Askari et al. [37][66] determined that gene expression levels of MPO were significantly upregulated in saliva and blood from severe compared with asymptomatic COVID-19 patients. These findings suggest that the MPO expression in saliva could be used as a non-invasive marker for COVID-19 severity. Severe COVID-19 is strictly related to innate immune dysregulation, an elevated neutrophil-to-lymphocyte ratio, and cytokine storm [77,78][67][68]. These mechanisms associated with SARS-CoV-2 infection provoke oxidative stress, leading to lung tissue damage [79][69]. In severe COVID-19, increased MPO activity causes soluble endothelial glycocalyx (EG) shedding and its inhibition protects against EG degradation [80][70].

7. Autoimmunological Disorders

Based on immune complexome analysis, Yamane et al. [40][71] identified MPO as new IC-antigens that were frequently and specifically detected in the saliva of patients with Sjögren’s syndrome (SS). The authors suggest that MPO as a neutrophil intracellular protein indicates that repeated neutrophil destruction caused by altered autoimmunity could be involved in the pathogenesis of SS. In patients with ANCA-associated vasculitis in primary SS course, most cases present anti-MPO specificity [81,82][72][73]. In rheumatoid arthritis (RA), rheumatoid factor as an immune complex inappropriately activates neutrophils, affecting their longevity and function [83][74]. After release from degranulating neutrophils, MPO produces oxidants which activate proMMPs and inactivate tissue inhibitor of metalloproteinases 1, leading to inflammatory and oxidative damage in the joint tissues [84][75]. Moreover, MPO and neutrophil elastase, significantly increased in serum and synovial fluid in RA patients, can enhance the destructive MMP cascade [85,86][76][77]. The study by Yilmaz et al. [41][78] showed that only serum levels of MPO were significantly elevated in patients with RA compared with the healthy controls, regardless of periodontal status. In turn, salivary MPO concentrations were increased but without statistical significance. For saliva, MPO levels differ significantly between systemically healthy periodontitis patients and control subjects.

8. Other Disorders

Akcalı et al. [16][79] found no significant differences in salivary myeloperoxidase levels between patients with polycystic ovary syndrome (PCOS) and healthy subjects, regardless of gingival inflammation. Significantly higher serum myeloperoxidase levels were observed in PCOS patients with gingivitis than generally healthy individuals with gingivitis. Also, PCOS patients exhibited a positive correlation between salivary MPO levels and clinical periodontal parameters. Due to the low-grade chronic inflammation in PCOS, elevated local and systemic proinflammatory cytokines stimulate the production of MMP-9 and MPO, initiating the proteolytic cascades [87][80]. Also, oxidative imbalance plays a role in the pathogenesis of PCOS, e.g., the MPO G-463A variant is related to a higher risk of PCOS [88][81]. The co-presence of insulin resistance is associated with increased MPO activity and ROS production, potentiating leukocyte-endothelium interactions [89][82]. Increased MPO promotes the degradation of toxic lysosomal deposits. However, chronically elevated MPO activity causes lysosomal stress and cell death [90][83]. In the study by Drążewski et al. [19][84], patients with Pompe disease had significantly increased MPO levels compared to patients with mannosidosis. Patients with lysosomal storage diseases did not appear to differ significantly from healthy controls. Furthermore, Dodds et al. [18][85] showed that MPO concentrations in stimulated parotid saliva were nearly four-fold higher in patients with type 2 diabetes mellitus (T2DM) than in control subjects. In the pathogenesis of T2DM, a ROS flux is an independent factor modulated by MPO, regardless of metformin therapy and concomitant cardiovascular diseases [91][86]. Elevated MPO activity is responsible for endothelial dysfunction and atherosclerosis, leading to T2DM vascular complications [92][87]. The specific variant of MPO gene contributes to the higher predisposition for T2DM and its vascular complications, suggesting MPO as a probable therapeutic target for T2DM [93][88]. Interestingly, MPO is related to insulin resistance and inflammation in overweight individuals with first-degree relatives suffering from T2DM, increasing the risk of developing this disease in these subjects [94][89].

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