Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1 -- 3509 2023-08-10 05:55:08 |
2 format correct Meta information modification 3509 2023-08-11 08:28:19 |

Video Upload Options

Do you have a full video?

Confirm

Are you sure to Delete?
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Tai, Y.; Woods, E.L.; Dally, J.; Deling, K.; Steadman, R.; Moseley, R.; Midgley, A.C. Strategies to Target Myofibroblasts for Scarless Skin Healing. Encyclopedia. Available online: https://encyclopedia.pub/entry/47872 (accessed on 15 October 2024).
Tai Y, Woods EL, Dally J, Deling K, Steadman R, Moseley R, et al. Strategies to Target Myofibroblasts for Scarless Skin Healing. Encyclopedia. Available at: https://encyclopedia.pub/entry/47872. Accessed October 15, 2024.
Tai, Yifan, Emma L. Woods, Jordanna Dally, Kong Deling, Robert Steadman, Ryan Moseley, Adam C Midgley. "Strategies to Target Myofibroblasts for Scarless Skin Healing" Encyclopedia, https://encyclopedia.pub/entry/47872 (accessed October 15, 2024).
Tai, Y., Woods, E.L., Dally, J., Deling, K., Steadman, R., Moseley, R., & Midgley, A.C. (2023, August 10). Strategies to Target Myofibroblasts for Scarless Skin Healing. In Encyclopedia. https://encyclopedia.pub/entry/47872
Tai, Yifan, et al. "Strategies to Target Myofibroblasts for Scarless Skin Healing." Encyclopedia. Web. 10 August, 2023.
Strategies to Target Myofibroblasts for Scarless Skin Healing
Edit

Myofibroblasts have drawn much attention among scientific research communities from multiple disciplines and specialisations. As further research uncovers the characterisations of myofibroblast formation, function, and regulation, the realisation of novel interventional routes for myofibroblasts within pathologies has emerged. The research community is approaching the means to finally target these cells, to prevent fibrosis, accelerate scarless wound healing, and attenuate associated disease-processes in clinical settings.

myofibroblast fibrosis wound healing immunomodulation antioxidants molecular therapy

1. Interventional Strategies to Target Myofibroblasts for Scarless Skin Healing

There are currently no clinically approved anti-scarring therapies specifically designed to limit or prevent dermal fibrosis. Several wound management strategies completed phase II trials, but did not advance to phase III trials in recent years. The clinical studies database, https://clinicaltrials.gov (‘Fibrosis, Skin’ searched 25 June 2021), showed 10 registered clinical trials that have either completed phase III or are currently in progress (Table 1). The proposed therapies include a range of treatment modes, including antibody and drug therapies, scar resection or reduction, and tissue-engineering strategies.
Table 1. Recent clinical trials for attenuated scar skin repair (completed phase III or ongoing).
Rituximab is a mouse/human chimeric antibody that binds CD20 on the surface of B-lymphocytes and initiates cell apoptosis, complement activation, and cell-mediated cytotoxicity. B-cell depletion by rituximab was shown to reduce fibrosis serum markers and myofibroblast activation in IgG4-related inflammatory diseases [1]. The results from the phase II/III trial are yet to be released; however, rituximab was shown to reduce B-cell presence in autoimmune scleroderma skin tissues, but had no discernible benefits to skin scar tissue histology after 6 months of treatment [2], which suggests that rituximab may be more effective as a pre-emptive measure. The anti-fibrotic effect of kynurenic acid was also proposed to occur via the induction of apoptosis in leukocytes and a reduction in inflammation, but with the additional regulation of the fibroblast production of MMPs and collagens [3]. Pirfenidone has received extensive attention for its efficacious action in the treatment of IPF [4][5]. Recently, Chen et al. used in situ self-assembling HA lattice nanostructure spray-on dressings loaded with pirfenidone to treat deep partial-thickness burn injuries in mouse models. The addition of pirfenidone to the wound dressing reduced collagen accumulation and myofibroblast presence within wound sites [6]. Multiple ongoing clinical trials focus on the management of established scars, with the aim to reduce scar appearance or to induce physiological healing after scar resection. The combinatory treatment of radiation-induced fibrosis with pentoxifylline (a hemorheological agent) and vitamin E was suggested to exhibit synergistic improvement in scar appearance and ECM remodelling, through actions of increased tissue perfusion and free radical scavenging [7]. Carbon dioxide (CO2) ablative fractional laser therapy has emerged as a promising low-invasiveness therapy for the induction of collagen remodelling, resulting in scar revision and reduced hypertrophic scar appearance after multiple sessions [8]. Integra is a biosynthetic dermal substitute wound dressing widely used in acute wound management; the ongoing clinical trial aims to perform scar resection and uses Integra to encourage attenuated scar healing, in a similar manner to previously shown outcomes of Integra-treated post-burn scar resections [9]. Autologous skin cells were harvested at the point of graft surgery, using ReCell technology [10]. The cells were applied to chronic wounds prior to the grafting of autologous donor skin, which resulted in remarkable healing results [11]. The ongoing clinical trial will attempt to recapitulate this improved healing response following scar resection in patients with hypertrophic scars.
There are numerous records of clinical trials aimed at one or more of the multifaceted aspects of skin fibrosis. However, progression to phase III trials appears to be rarely achieved, perhaps owing to the limited experimental evidence of myofibroblast-specific targets.

2. Experimental and Pre-Clinical Interventions for Myofibroblast Differentiation

Popularised pre-clinical strategies for preventing myofibroblast formation focus on inhibition of the canonical TGF-β1/Smad signalling pathway using cytokines, antibodies, and regulators of gene expression. Demonstrating the clinical efficacy of anti-TGF-β1 therapies has been hindered by the cytokine’s pleiotropism and ubiquitous presence, as well as the heterogenous processes of healing and fibrosis. Consequently, therapeutic targeting of TGF-β and its specific isoforms has proved challenging. Available clinical data are limited to early phase trials and studies with conflicting outcomes [12]. Recombinant human TGF-β3 (Avotermin, Juvista) was developed by Renovo and hailed as a potential novel inhibitor of dermal scar formation, based on its elevated presence and roles in non-scarring tissues compared to TGF-β1, such as early gestational foetal skin and the oral mucosa [13][14][15][16]. Phase I/II clinical trials concluded that the intradermal application of Juvista yielded both short- and long-term improvements in scar appearance, compared to placebo and standard wound care management [17][18]. Unfortunately, Juvista did not meet the necessary primary or secondary endpoints required by phase III trials, failing to demonstrate reduced scarring after excisional surgery. Fresolimumab is a neutralising antibody that targets all TGF-β isoforms; the effects of Fresolimumab on cutaneous SSc revealed reduced expression of fibrotic biomarkers and diminished myofibroblasts [19]. This suggested that a shotgun approach to TGF-β inhibition had anti-fibrotic effects, whilst neutralising TGF-β1 alone in SSc failed to demonstrate clinical efficacy [20]. An apparent trend has emerged, wherein anti-scarring interventions that target an individual aspect or factor of fibrotic conditions generally fail to realise clinical benefit. Moreover, the efficacious index of growth factors is limited by their low stability, short half-life in vivo, adverse effects arising from elevated local and/or systemic concentrations, and their non-specific nature (multiple protein-binding partners) [21].
MicroRNAs (miRNA) are short non-coding RNAs (18–25 nucleotides) that bind the 3′ untranslated region of mRNA, thereby inhibiting mRNA translation or promoting mRNA degradation. Multiple studies have shown the regulatory roles of miRNA in pathological wound healing and skin fibrosis. Notable miRNA targets upregulated in skin fibrosis include miRNA (miR)-21 [22] and miR-130b [23], whereas miR-29 [24], miR-129-5p [25], and miR-7 [26][27] were shown to be negative regulators of myofibroblast activity and fibrosis. The miRNAs, miR-21 and miR-17-5p, have been shown to be directly implicated in TGF-β1/Smad pathway promotion. Smad2 activity was potentiated by these miRNAs through their inhibition of Smad7 [28][29]. Thus, inhibiting the activity of these miRNAs has arisen as a potential avenue in gene therapies to mitigate TGF-β1/Smad pathway activity and myofibroblast differentiation.
Bone morphogenetic protein-7 (BMP7) exerted potent anti-fibrotic actions in vitro [30], and in pre-clinical fibrosis models [31][32][33][34]. BMP7 activation of Smad1/5/8 results in the competitive binding of Smad4, thereby inhibiting the TGF-β1/Smad2/3 pathway’s transcriptional activities [34]. Early reports indicated that BMP7 failed to prevent bleomycin-induced skin fibrosis [35]. However, a later study showed that BMP7 treatment at the point of thermal injury prevented hypertrophic scar formation [34]. Thus, BMP7 therapies require further optimization and testing to determine their effectiveness in the prevention of dermal fibrosis. Interferon (IFN)-γ induced the expression of Smad7, which antagonised interactions between Smad2/3 and TGFβRI/II [36]. The effects of IFN-γ on fibroblasts in vitro are conflicting; exogenous IFN-γ was suggested to abrogate TGF-β1-induced proliferation, migration, and differentiation to myofibroblasts [37]; but T-cell secretion of IFN-γ, found to be prominent in SSc, aggravated fibrosis by promoting fibroblast proliferation and collagen synthesis [38]. Early pre-clinical and small clinical studies suggested that IFN-γ was effective in the attenuation of lung, renal, and liver fibrosis [39][40][41], and oral submucosal fibrosis [39][40][41][42]. There is a current lack of studies describing definitive IFN-γ mechanisms involved in the regulation of myofibroblasts. Thus, whether IFN-γ delivery would be effective in attenuating dermal fibrosis remains unclear.
Alternative approaches include molecular inhibitors of non-canonical and mechanotransduction pathways to regulate ECM composition and disrupt the myofibroblast phenotype. Hepatocyte growth factor (HGF) was first implicated in liver regeneration [43], but has since been shown to prevent fibrosis initiation and progression in animal models [44][45]. HGF treatment was shown to attenuate collagen production by fibroblasts in multiple tissues [46][47][48]. Elevated HGF expression in fibrosis [49][50][51][52], but also in differentiation-resistant fibroblasts [53][54], suggests a duality of HGF actions which may be a consequence of truncated isoforms possessing a variable number of kringle domains (HGF/NK1-4) with differential signalling activities. Indeed, human oral mucosal fibroblast resistance to TGF-β1-induced differentiation was dependent on heightened HGF and HGF/NK1 expression, whereas HGF/NK2 was preferentially expressed by dermal fibroblasts [55]. Recently, HGF/NK1 gene therapy was shown to exert potent anti-fibrotic effects through attenuated collagen types I, III, and IV deposition in mouse models of renal fibrosis [32]. In addition, the HGF inhibition of collagen synthesis and promotion of MMP production has shown promise for therapeutic applications in reducing the pro-fibrotic activity of keloid fibroblasts in vitro and in a keloid heterograft mouse model [56][57][58]. Small molecule inhibitors of DDR1 have shown promise in reducing collagen types I and IV deposition in bleomycin-induced renal and lung fibrosis [59][60][61]. Ongoing research into DDR1-specific inhibitors have yielded promising results in models of renal fibrosis [60].
HA bioactivity is dependent on its molecular weight, enzymatic synthesis, and endogenous versus exogenous application [62][63][64]. The disruption or prevention of HA pericellular coat synthesis using hyaluronidase enzymes [65], HAS inhibitors [66][67] or exogenous HA oligosaccharides [68] results in the failure of TGF-β1-stimulated myofibroblast phenotypic acquisition. The inhibition of HAS2 activity [69] or global HAS synthesis of HA [66][67] have demonstrated preventative effects in various models of fibrosis. However, given the ubiquitous role of HAS-synthesised HA in tissues, and the lack of specific HAS isoenzyme inhibitors, it is unclear at present whether the inhibition of HA synthesis would be beneficial in a clinical setting. An additional action of BMP7 involved the induction of the nuclear translocation of HYAL2 and the subsequent splicing of CD44 mRNA, which resulted in the upregulated expression of the variant isoform, CD44v7/8. Fibroblasts with upregulated expression of CD44v7/8 exhibited ‘HA-phage’ activity, wherein the HA pericellular coat was rapidly internalised and broken down, resulting in the destabilization of the myofibroblast and phenotypic reversion to fibroblasts [30][70]. Whether CD44v7/8-dependent actions convey anti-fibrotic effects in dermal fibrosis is currently unknown.
The most promising integrin targets that have demonstrated roles in the pathogenesis of fibrosis are α4-containing integrins (α4β1/7) [71][72] and αv-containing integrins (αvβ1/3/5/6) [73][74][75]. Mechanotransduction by integrin αvβ6 promoted traction from proliferating liver cholangiocytes to FN/LAP, which subsequently released active TGF-β1 and initiated the differentiation of surrounding hepatic stellate cells to myofibroblasts [73][76]. A small peptidomimetic, EMD527040, mimics the RGD-binding sites of αvβ6 and αvβ1; orally administered EMD527040 attenuated biliary and non-biliary fibrogenesis [73]. The expression of integrin αvβ6 was elevated in keratinocytes during wound healing and fibrosis [77], but the detailed mechanistic roles of integrin αvβ6 and epithelial–mesenchymal crosstalk during dermal fibrosis have yet to be elucidated. Research has identified that integrin interactions with the EDGIHEL motif of EDA–FN was causative of downstream profibrotic responses [72][78][79]. The IST-9 [78][80], F8 [81][82], and vaccine-generated [83] antibodies that target EDA–FN or integrin α4 have demonstrated prevention of fibroblast–myofibroblast differentiation [78][80]. Therapeutic applications of antibodies can be limited by the cost and complexity of production, off-target immune activation or unspecific protein masking of critical protein–protein interactions. To address these issues, Zhang et al. developed a small blocking polypeptide to bind and block EDA–FN interactions with the α4β1 binding cleft, with high specificity [84]. The polypeptide, AF38Pep, was designed to mimic the integrin α4β1 receptor site for the EDGIHEL motif of EDA–FN and was shown to interfere with TGF-β1-stimulated fibroblast–myofibroblast formation by the specific blockade of integrin α4β1 signalling, the inhibition of FAK activation, and the prevention of profibrotic gene transcription [84]. The aforementioned first generation of small blocking polypeptides have revealed the renewed promise of the specific interruption of integrin-mediated mechanotransduction and myofibroblast formation. The implementation of integrin receptor peptidomimetics for the prevention of skin fibrosis will become more apparent in the coming years when the in vitro research progresses into pre-clinical models.
Another potential peptide therapy is the N-terminal amino acid sequence of α-SMA, Ac-EEED, which is important for the tropomyosin-1.6/7-stabilized incorporation of α-SMA into cytoplasmic stress fibres [85]. Interestingly, the cytoplasmic delivery of the Ac-EEED peptide resulted in the loss of α-SMA from β-cytoplasmic actin stress fibres and inhibited G-actin polymerization into F-actin [86][87], thereby reducing myofibroblast contraction in wound healing [88]. Ac-EEED peptide therapy has yet to be evaluated in skin fibrosis models, which may be related to the current lack of available dermal myofibroblast-specific targeting moieties that operate by endosomal uptake and the cytoplasmic release of payloads.

3. Immunomodulating Biomolecules for Fibrosis Attenuation

Immunoregulatory interventions aim to control the inflammatory phase in postnatal skin healing to attenuate scar formation [89][90]. Studies in transgenic mice provided early indicators that the absence of neutrophils and macrophages led to scar-free healing [91]. Targeted repression of the gap junction and inflammatory mediator protein, connexin-43, supported these findings [90][92]. Additionally, connexin-43 was shown to mediate cardiac fibroblast–myofibroblast differentiation [93] and promote aberrant cardiomyocyte–myofibroblast functional coupling [94]. Certain interleukin (IL) cytokines are implicated in the activation of inflammatory cascades. IL-8 production is a chemoattractant to neutrophils, whereas IL-6 secretion by fibroblasts activates macrophages and monocyte chemotaxis. Both IL-6 and IL-8 exhibit the rapid induction of expression following tissue injury, resulting in the recruitment of circulating inflammatory cells. The expression levels of IL-6 and IL-8 are elevated and maintained for longer in adult skin, compared to scarless scar-free foetal repair. The inhibition of phosphodiesterase 4 (PDE4) reduced scar formation in skin fibrosis models by interfering with the release of IL-6 from M2 macrophages [95]. Thus, IL-6 and IL-8 are considered pro-fibrotic mediators, whereas IL-10 antagonised their activity [89][96]. IL-10 gene therapy resulted in reduced inflammation and the promotion of scarless healing in mouse wound healing studies [97]. The exogenous addition and macrophage paracrine production of IL-10 were shown to induce myofibroblast reversal to fibroblastic phenotypes in vitro [98][99]. More recently, IL-10 induced myofibroblast–fibroblast dedifferentiation was shown to alter dynamic interactions with the surrounding fibrillar matrix with a demonstratable loss of contractility in IL-10 treated myofibroblasts [100]. Research into inflammation-induced fibrosis has revealed additional potential candidate ILs that may be targetable in skin fibrosis, including IL-11 [101], IL-16 [102], and IL-33 [103]. Keratinocytes have suggested roles in the regulation of the myofibroblast phenotype and profibrotic ECM during wound healing [104][105][106]. More recently, the keratinocyte secretion of IL-1α was demonstrated to restrain the myofibroblast phenotype, dependent on fibroblast integrin α4β1 expression and Cox-2/Nrf2 signalling [107][108].
The importance and therapeutic potential of macrophages in the wound healing process has been highlighted in recent years [109][110][111]. Crosstalk between myofibroblasts and macrophages during skin repair was reported [112]. Growth factors secreted by CD301b+ M2-type macrophages were shown to selectively stimulate the proliferation of adipocyte precursor (AP)-derived myofibroblasts only. In aged mice wounds and experimentally induced mouse skin fibrosis, AP-derived myofibroblasts and CD301b+ macrophages were reduced, and a CD29+ myofibroblast pool was increased. In keloids, CD301b+ macrophages and AP-derived myofibroblasts were also increased [113]. In fibrotic lung tissues, cadherin-11 mediated the adhesion between macrophages and myofibroblasts, promoting pro-fibrotic myofibroblast activity via the paracrine release of TGF-β1 by the macrophages [114]. Experimental research has suggested roles of mast cells in scar formation [115]; reduced numbers of activated mast cells were reported to improve healing and minimize scarring [116][117][118], whereas mast cell hyperplasia was causally linked to myofibroblast hyperplasia [119][120][121]. Increased neuropeptide activity and the presence of substance-P (SP) were found in hypertrophic scar samples [122][123]. Mast cells were previously suggested to be a major source of neuropeptide SP-stimulated inflammation and increased myofibroblast activity [124]. These studies showed that myofibroblast activity could be mediated through regulated leukocyte–myofibroblast interactions and suggest that targeting certain leukocyte subpopulations may serve as anti-fibrotic strategies.
Targeting inflammatory meditators has shown promise in alleviating the magnitude of fibrosis in various animal models. Follistatin-like-1 (FSTL1) was found to be elevated in serum from patients with silicosis and in mouse lung fibrosis models. FSTL1-induced IL-1β production by macrophages and positively regulated TGF-β1 signalling in fibroblasts. The inhibition of FSTL1 expression or activity protected against lung injury and fibrosis [125][126]. Recently, FSTL1 neutralizing antibodies were shown to exhibit potent anti-inflammatory actions, attenuate bleomycin-induced IPF and dermal fibrosis in vivo, and downregulate TGF-β1-driven fibrosis in human skin ex vivo [127].
The transmembrane serine protease and collagenase, fibroblast activation protein (FAP) is prominently expressed by activated fibroblasts and myofibroblasts during tissue remodelling and fibrosis [128]. FAP-cleaved collagen binds to the scavenger receptor (SR)-A, recruiting SR-A+ macrophages to sites of collagen turnover [129]. The liver expression of FAP in cirrhosis was shown to correlate with the severity of fibrosis but was not exclusively expressed by α-SMA+ myofibroblasts, suggesting that FAP marks a differentially activated fibroblast state [130]. Lines of research have started to establish the mechanistic actions of FAP in fibroblast heterogeneity and governance over the pro-fibrotic ECM [131]. Treatment with anti-FAP antibody reduced collagen type I production by fibro-stenotic intestinal myofibroblasts [132]. The FAP and dipeptidyl peptidase IV inhibitor, talabostat mesylate (PT100), was used to treat bleomycin-induced IPF murine models. Treatment with PT100 showed anti-fibro-proliferative activity but increased macrophage activation, with no effect on collagen expression [133]. Therefore, the present scope for specific FAP inhibition in dermal fibrosis models remains unclear, until more mechanistic information is reported.

4. Targeted Myofibroblast Apoptosis

In physiological wound healing, myofibroblasts disappeared following wound closure and resolution [134][135], predominantly by apoptosis [136]. Despite the elevated production of reactive oxygen species (ROS) by myofibroblasts during fibrosis, the persistence of TGF-β1 expression, ECM deposition, and accumulative stress-induced FAK promotes pro-survival and anti-apoptotic myofibroblast phenotypes [137][138]. The susceptibility of myofibroblasts to nitric oxide (NO)-induced apoptosis has been reported in vitro [139]. Therefore, a combination of reduced profibrotic growth factor expression, increased ECM turnover, and increased NO generation may set the stage for triggering myofibroblast apoptosis during the resolution of tissue repair and remodelling [140][141].
A single chain antibody (C1-3) specifically targets synaptophysin+ liver myofibroblasts without co-localising with liver monocytes or macrophages [142], thus demonstrating that the identification of unique markers of myofibroblasts in fibrosis could serve as targeting devices. The researchers showed that C1-3-gliotoxin conjugates induced non-parenchymal cell apoptosis and depleted liver myofibroblasts without affecting monocytes or macrophages, resulting in the reduced severity of fibrosis [142]. The anticancer drug, Elesclomol, was found to selectively induce apoptosis in activated fibroblasts and myofibroblasts isolated from scar tissue samples. Elesclomol upregulated intracellular levels of ROS, caspase-3, and cytochrome-c proteins, resulting in reduced myofibroblast numbers and a lower scar elevation in vivo [143].
The mechanical tension-stimulated myofibroblast differentiation increased mitochondrial priming and death signalling proteins, such as the pro-apoptotic BH3-only protein BIM [144][145]. The anti-apoptotic protein BCL-XL sequesters BIM and ensures myofibroblast survival. Lagares et al. showed that myofibroblasts were susceptible to apoptosis induced by the BCL-2 inhibitor and the BH3 mimetic drug, ABT-263 (Navitoclax), which inhibited BCL-XL and allowed BIM to activate myofibroblast apoptosis in mouse models of scleroderma dermal fibrosis [146]. These results were recapitulated in rabbit ear hypertrophic scar models, wherein ABT-263 improved scar appearance and collagen arrangement [147]. Future studies into the physiological triggers for time-appropriate myofibroblast apoptosis could potentially lead to the identification of novel treatments with improved therapeutic indexes for scarless wound healing.

5. Antioxidant Therapeutics

Another proposed regulator of normal and pathological scarring in numerous tissues is oxidative stress, referring to the overproduction of ROS via such mechanisms as NADPH oxidases (NOXs) and the mitochondria, at the expense of cellular and tissue antioxidant defences [148][149][150][151][152]. The induction of the myofibroblast phenotype is accompanied by depleted cellular antioxidants, leading to ROS generation and the implication of ROS in multiple signalling pathways associated with myofibroblast differentiation. Thus, an emergent area of research is focusing on evaluating the efficacious index of antioxidants against fibrosis and in restoring cellular redox balance. The liposomal delivery of copper/zinc (Cu/Zn) superoxide dismutase (SOD)-attenuated TGF-β1, α-SMA and collagen type I expression in dermal fibroblasts, although myofibroblast apoptosis remained unaffected [153]. Similarly, SOD1-containing fusion proteins alleviated oxidative stress in cardiac myofibroblasts via the reduced expression of TGF-β1, α-SMA, and collagen types I and III—whilst restoring MMP-1 and attenuating MMP inhibitor (TIMP-1) secretion [154]. Small molecule inhibitors of NOXs, such as GKT136901 and GKT137831, also exhibited therapeutic potential by reducing murine liver fibrosis [155][156]. In addition to the progress made with such promising findings, the development of nanoparticles with inherent antioxidant activities, such as cerium oxide, fullerene, and mesoporous silica, have also been explored as potential therapeutic options for fibrosis, which may also be combined with payloads of pharmaceuticals, genes, or proteins [157].
Natural compounds have a long history of use in wound healing, and the cellular mechanisms of action are beginning to be delineated as active components are extracted and assessed [158][159][160]. The exploitation of the aromatic nature and antioxidant capabilities of various naturally sourced polyphenolic compounds and their extracts have been demonstrated in numerous in vitro and in vivo systems, with desirable biocompatible and anti-fibrotic effects in models of pulmonary [161][162][163]; renal [164][165]; myocardial [166][167]; and skin fibrosis [168][169]. The clinical potential of natural compound-based therapies is often restricted by the lack of clarity in their multifaceted bioactivities. Hence, delineating cellular responses to the more specific and potent actions of natural compound extracts has become a popularised concept towards their clinical translation.

References

  1. Della-Torre, E.; Feeney, E.; Deshpande, V.; Mattoo, H.; Mahajan, V.; Kulikova, M.; Wallace, Z.S.; Carruthers, M.; Chung, R.T.; Pillai, S.; et al. B-cell depletion attenuates serological biomarkers of fibrosis and myofibroblast activation in IgG4-related disease. Ann. Rheum. Dis. 2015, 74, 2236–2243.
  2. Lafyatis, R.; Kissin, E.; York, M.; Farina, G.; Viger, K.; Fritzler, M.J.; Merkel, P.A.; Simms, R.W. B cell depletion with rituximab in patients with diffuse cutaneous systemic sclerosis. Arthritis Rheum. 2009, 60, 578–583.
  3. Dolivo, D.M.; Larson, S.A.; Dominko, T. Tryptophan metabolites kynurenine and serotonin regulate fibroblast activation and fibrosis. Cell. Mol. Life Sci. 2018, 75, 3663–3681.
  4. Fang, C.; Huang, H.; Guo, J.; Ferianc, M.; Xu, Z. Real-world experiences: Efficacy and tolerability of pirfenidone in clinical practice. PLoS ONE 2020, 15, e0228390.
  5. Feng, H.; Zhao, Y.; Li, Z.; Kang, J. Real-life experiences in a single center: Efficacy of pirfenidone in idiopathic pulmonary fibrosis and fibrotic idiopathic non-specific interstitial pneumonia patients. Adv. Respir. Dis. 2020, 14.
  6. Chen, J.; Wang, H.; Mei, L.; Wang, B.; Huang, Y.; Quan, G.; Lu, C.; Peng, T.; Pan, X.; Wu, C. A pirfenidone loaded spray dressing based on lyotropic liquid crystals for deep partial thickness burn treatment: Healing promotion and scar prophylaxis. J. Mater. Chem. B 2020, 8, 2573–2588.
  7. Kaidar-Person, O.; Marks, L.B.; Jones, E.L. Pentoxifylline and vitamin E for treatment or prevention of radiation-induced fibrosis in patients with breast cancer. Breast J. 2018, 24, 816–819.
  8. Patel, S.P.; Nguyen, H.V.; Mannschreck, D.; Redett, R.J.; Puttgen, K.B.; Stewart, F.D. Fractional CO2 Laser Treatment Outcomes for Pediatric Hypertrophic Burn Scars. J. Burn Care Res. 2019, 40, 386–391.
  9. Stiefel, D.; Schiestl, C.; Meuli, M. Integra Artificial Skin for burn scar revision in adolescents and children. Burns 2010, 36, 114–120.
  10. Wood, F.M.; Giles, N.; Stevenson, A.; Rea, S.; Fear, M. Characterisation of the cell suspension harvested from the dermal epidermal junction using a ReCell(R) kit. Burns 2012, 38, 44–51.
  11. Hu, Z.C.; Chen, D.; Guo, D.; Liang, Y.Y.; Zhang, J.; Zhu, J.Y.; Tang, B. Randomized clinical trial of autologous skin cell suspension combined with skin grafting for chronic wounds. Br. J. Surg. 2015, 102, e117–e123.
  12. Frangogiannis, N. Transforming growth factor-beta in tissue fibrosis. J. Exp. Med. 2020, 217, e20190103.
  13. Shah, M.; Foreman, D.M.; Ferguson, M.W. Neutralisation of TGF-beta 1 and TGF-beta 2 or exogenous addition of TGF-beta 3 to cutaneous rat wounds reduces scarring. J. Cell Sci. 1995, 108, 985–1002.
  14. Occleston, N.L.; O’Kane, S.; Laverty, H.G.; Cooper, M.; Fairlamb, D.; Mason, T.; Bush, J.A.; Ferguson, M.W. Discovery and development of avotermin (recombinant human transforming growth factor beta 3): A new class of prophylactic therapeutic for the improvement of scarring. Wound Repair Regen. 2011, 19 (Suppl. 1), s38–s48.
  15. Ferguson, M.W.; O’Kane, S. Scar-free healing: From embryonic mechanisms to adult therapeutic intervention. Philos. Trans. R. Soc. Lond. B Biol. Sci. 2004, 359, 839–850.
  16. Eslami, A.; Gallant-Behm, C.L.; Hart, D.A.; Wiebe, C.; Honardoust, D.; Gardner, H.; Hakkinen, L.; Larjava, H.S. Expression of integrin alphavbeta6 and TGF-beta in scarless vs. scar-forming wound healing. J. Histochem. Cytochem. 2009, 57, 543–557.
  17. Durani, P.; Occleston, N.; O’Kane, S.; Ferguson, M.W. Avotermin: A novel antiscarring agent. Int. J. Low Extrem. Wounds 2008, 7, 160–168.
  18. Ferguson, M.W.; Duncan, J.; Bond, J.; Bush, J.; Durani, P.; So, K.; Taylor, L.; Chantrey, J.; Mason, T.; James, G.; et al. Prophylactic administration of avotermin for improvement of skin scarring: Three double-blind, placebo-controlled, phase I/II studies. Lancet 2009, 373, 1264–1274.
  19. Rice, L.M.; Padilla, C.M.; McLaughlin, S.R.; Mathes, A.; Ziemek, J.; Goummih, S.; Nakerakanti, S.; York, M.; Farina, G.; Whitfield, M.L.; et al. Fresolimumab treatment decreases biomarkers and improves clinical symptoms in systemic sclerosis patients. J. Clin. Investig. 2015, 125, 2795–2807.
  20. Denton, C.P.; Merkel, P.A.; Furst, D.E.; Khanna, D.; Emery, P.; Hsu, V.M.; Silliman, N.; Streisand, J.; Powell, J.; Akesson, A.; et al. Recombinant human anti-transforming growth factor beta1 antibody therapy in systemic sclerosis: A multicenter, randomized, placebo-controlled phase I/II trial of CAT-192. Arthritis Rheum. 2007, 56, 323–333.
  21. Park, J.W.; Hwang, S.R.; Yoon, I.S. Advanced Growth Factor Delivery Systems in Wound Management and Skin Regeneration. Molecules 2017, 22, 1259.
  22. Li, Y.; Zhang, J.; Lei, Y.; Lyu, L.; Zuo, R.; Chen, T. MicroRNA-21 in Skin Fibrosis: Potential for Diagnosis and Treatment. Mol. Diagn. 2017, 21, 633–642.
  23. Luo, H.; Zhu, H.; Zhou, B.; Xiao, X.; Zuo, X. MicroRNA-130b regulates scleroderma fibrosis by targeting peroxisome proliferator-activated receptor gamma. Mod. Rheumatol. 2015, 25, 595–602.
  24. Gallant-Behm, C.L.; Piper, J.; Lynch, J.M.; Seto, A.G.; Hong, S.J.; Mustoe, T.A.; Maari, C.; Pestano, L.A.; Dalby, C.M.; Jackson, A.L.; et al. A MicroRNA-29 Mimic (Remlarsen) Represses Extracellular Matrix Expression and Fibroplasia in the Skin. J. Investig. Dermatol. 2019, 139, 1073–1081.
  25. Nakashima, T.; Jinnin, M.; Yamane, K.; Honda, N.; Kajihara, I.; Makino, T.; Masuguchi, S.; Fukushima, S.; Okamoto, Y.; Hasegawa, M.; et al. Impaired IL-17 signaling pathway contributes to the increased collagen expression in scleroderma fibroblasts. J. Immunol. 2012, 188, 3573–3583.
  26. Midgley, A.C.; Bowen, T.; Phillips, A.O.; Steadman, R. MicroRNA-7 inhibition rescues age-associated loss of epidermal growth factor receptor and hyaluronan-dependent differentiation in fibroblasts. Aging Cell 2014, 13, 235–244.
  27. Midgley, A.C.; Morris, G.; Phillips, A.O.; Steadman, R. 17beta-estradiol ameliorates age-associated loss of fibroblast function by attenuating IFN-gamma/STAT1-dependent miR-7 upregulation. Aging Cell 2016, 15, 531–541.
  28. Yuan, J.; Chen, H.; Ge, D.; Xu, Y.; Xu, H.; Yang, Y.; Gu, M.; Zhou, Y.; Zhu, J.; Ge, T.; et al. Mir-21 Promotes Cardiac Fibrosis After Myocardial Infarction Via Targeting Smad7. Cell Physiol. Biochem. 2017, 42, 2207–2219.
  29. Yu, F.; Guo, Y.; Chen, B.; Dong, P.; Zheng, J. MicroRNA-17-5p activates hepatic stellate cells through targeting of Smad7. Lab. Investig. 2015, 95, 781–789.
  30. Midgley, A.C.; Duggal, L.; Jenkins, R.; Hascall, V.; Steadman, R.; Phillips, A.O.; Meran, S. Hyaluronan regulates bone morphogenetic protein-7-dependent prevention and reversal of myofibroblast phenotype. J. Biol. Chem. 2015, 290, 11218–11234.
  31. Higgins, D.F.; Ewart, L.M.; Masterson, E.; Tennant, S.; Grebnev, G.; Prunotto, M.; Pomposiello, S.; Conde-Knape, K.; Martin, F.M.; Godson, C. BMP7-induced-Pten inhibits Akt and prevents renal fibrosis. Biochim. Biophys. Acta Mol. Basis Dis. 2017, 1863, 3095–3104.
  32. Midgley, A.C.; Wei, Y.; Zhu, D.; Gao, F.; Yan, H.; Khalique, A.; Luo, W.; Jiang, H.; Liu, X.; Guo, J.; et al. Multifunctional Natural Polymer Nanoparticles as Antifibrotic Gene Carriers for CKD Therapy. J. Am. Soc. Nephrol. 2020, 31, 2292–2311.
  33. Tsujimura, T.; Idei, M.; Yoshikawa, M.; Takase, O.; Hishikawa, K. Roles and regulation of bone morphogenetic protein-7 in kidney development and diseases. World J. Stem Cells 2016, 8, 288–296.
  34. Guo, J.; Lin, Q.; Shao, Y.; Rong, L.; Zhang, D. BMP7 suppresses excessive scar formation by activating the BMP7/Smad1/5/8 signaling pathway. Mol. Med. Rep. 2017, 16, 1957–1963.
  35. Murray, L.A.; Hackett, T.L.; Warner, S.M.; Shaheen, F.; Argentieri, R.L.; Dudas, P.; Farrell, F.X.; Knight, D.A. BMP-7 does not protect against bleomycin-induced lung or skin fibrosis. PLoS ONE 2008, 3, e4039.
  36. Ulloa, L.; Doody, J.; Massague, J. Inhibition of transforming growth factor-beta/SMAD signalling by the interferon-gamma/STAT pathway. Nature 1999, 397, 710–713.
  37. Vu, T.N.; Chen, X.; Foda, H.D.; Smaldone, G.C.; Hasaneen, N.A. Interferon-gamma enhances the antifibrotic effects of pirfenidone by attenuating IPF lung fibroblast activation and differentiation. Respir. Res. 2019, 20, 206.
  38. Xing, X.; Li, A.; Tan, H.; Zhou, Y. IFN-gamma(+) IL-17(+) Th17 cells regulate fibrosis through secreting IL-21 in systemic scleroderma. J. Cell Mol. Med. 2020, 24, 13600–13608.
  39. Oldroyd, S.D.; Thomas, G.L.; Gabbiani, G.; El Nahas, A.M. Interferon-gamma inhibits experimental renal fibrosis. Kidney Int. 1999, 56, 2116–2127.
  40. Weng, H.L.; Feng, D.C.; Radaeva, S.; Kong, X.N.; Wang, L.; Liu, Y.; Li, Q.; Shen, H.; Gao, Y.P.; Mullenbach, R.; et al. IFN-gamma inhibits liver progenitor cell proliferation in HBV-infected patients and in 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet-fed mice. J. Hepatol. 2013, 59, 738–745.
  41. Fusiak, T.; Smaldone, G.C.; Condos, R. Pulmonary Fibrosis Treated with Inhaled Interferon-gamma (IFN-gamma). J. Aerosol Med. Pulm. Drug Deliv. 2015, 28, 406–410.
  42. Haque, M.F.; Meghji, S.; Nazir, R.; Harris, M. Interferon gamma (IFN-gamma) may reverse oral submucous fibrosis. J. Oral Pathol. Med. 2001, 30, 12–21.
  43. Nakamura, T.; Nishizawa, T.; Hagiya, M.; Seki, T.; Shimonishi, M.; Sugimura, A.; Tashiro, K.; Shimizu, S. Molecular cloning and expression of human hepatocyte growth factor. Nature 1989, 342, 440–443.
  44. Liu, Y. Hepatocyte growth factor in kidney fibrosis: Therapeutic potential and mechanisms of action. Am. J. Physiol. Ren. Physiol. 2004, 287, F7–F16.
  45. Okayama, K.; Azuma, J.; Dosaka, N.; Iekushi, K.; Sanada, F.; Kusunoki, H.; Iwabayashi, M.; Rakugi, H.; Taniyama, Y.; Morishita, R. Hepatocyte growth factor reduces cardiac fibrosis by inhibiting endothelial-mesenchymal transition. Hypertension 2012, 59, 958–965.
  46. Mou, S.; Wang, Q.; Shi, B.; Gu, L.; Ni, Z. Hepatocyte growth factor suppresses transforming growth factor-beta-1 and type III collagen in human primary renal fibroblasts. Kaohsiung J. Med. Sci. 2009, 25, 577–587.
  47. Cui, Q.; Wang, Z.; Jiang, D.; Qu, L.; Guo, J.; Li, Z. HGF inhibits TGF-beta1-induced myofibroblast differentiation and ECM deposition via MMP-2 in Achilles tendon in rat. Eur. J. Appl. Physiol. 2011, 111, 1457–1463.
  48. Jiang, D.; Jiang, Z.; Han, F.; Zhang, Y.; Li, Z. HGF suppresses the production of collagen type III and alpha-SMA induced by TGF-beta1 in healing fibroblasts. Eur. J. Appl. Physiol. 2008, 103, 489–493.
  49. De Wever, O.; Nguyen, Q.D.; Van Hoorde, L.; Bracke, M.; Bruyneel, E.; Gespach, C.; Mareel, M. Tenascin-C and SF/HGF produced by myofibroblasts in vitro provide convergent pro-invasive signals to human colon cancer cells through RhoA and Rac. FASEB J. 2004, 18, 1016–1018.
  50. Atta, H.; El-Rehany, M.; Hammam, O.; Abdel-Ghany, H.; Ramzy, M.; Roderfeld, M.; Roeb, E.; Al-Hendy, A.; Raheim, S.A.; Allam, H.; et al. Mutant MMP-9 and HGF gene transfer enhance resolution of CCl4-induced liver fibrosis in rats: Role of ASH1 and EZH2 methyltransferases repression. PLoS ONE 2014, 9, e112384.
  51. Shao, J.; Sheng, G.G.; Mifflin, R.C.; Powell, D.W.; Sheng, H. Roles of myofibroblasts in prostaglandin E2-stimulated intestinal epithelial proliferation and angiogenesis. Cancer Res. 2006, 66, 846–855.
  52. Kajihara, I.; Jinnin, M.; Makino, T.; Masuguchi, S.; Sakai, K.; Fukushima, S.; Maruo, K.; Inoue, Y.; Ihn, H. Overexpression of hepatocyte growth factor receptor in scleroderma dermal fibroblasts is caused by autocrine transforming growth factor beta signaling. Biosci. Trends 2012, 6, 136–142.
  53. Xiang, Y.; Qin, Z.; Yang, Y.; Fisher, G.J.; Quan, T. Age-related elevation of HGF is driven by the reduction of fibroblast size in a YAP/TAZ/CCN2 axis-dependent manner. J. Dermatol. Sci. 2021, 102, 36–46.
  54. Qin, Z.; Worthen, C.A.; Quan, T. Cell-size-dependent upregulation of HGF expression in dermal fibroblasts: Impact on human skin connective tissue aging. J. Dermatol. Sci. 2017, 88, 289–297.
  55. Dally, J.; Khan, J.S.; Voisey, A.; Charalambous, C.; John, H.L.; Woods, E.L.; Steadman, R.; Moseley, R.; Midgley, A.C. Hepatocyte Growth Factor Mediates Enhanced Wound Healing Responses and Resistance to Transforming Growth Factor-beta(1)-Driven Myofibroblast Differentiation in Oral Mucosal Fibroblasts. Int. J. Mol. Sci. 2017, 18, 1843.
  56. Lee, W.J.; Park, S.E.; Rah, D.K. Effects of hepatocyte growth factor on collagen synthesis and matrix metalloproteinase production in keloids. J. Korean Med. Sci. 2011, 26, 1081–1086.
  57. Eto, H.; Suga, H.; Aoi, N.; Kato, H.; Doi, K.; Kuno, S.; Tabata, Y.; Yoshimura, K. Therapeutic potential of fibroblast growth factor-2 for hypertrophic scars: Upregulation of MMP-1 and HGF expression. Lab. Investig. 2012, 92, 214–223.
  58. Jeon, Y.R.; Ahn, H.M.; Choi, I.K.; Yun, C.O.; Rah, D.K.; Lew, D.H.; Lee, W.J. Hepatocyte growth factor-expressing adenovirus upregulates matrix metalloproteinase-1 expression in keloid fibroblasts. Int. J. Dermatol. 2016, 55, 356–361.
  59. Guerrot, D.; Kerroch, M.; Placier, S.; Vandermeersch, S.; Trivin, C.; Mael-Ainin, M.; Chatziantoniou, C.; Dussaule, J.C. Discoidin domain receptor 1 is a major mediator of inflammation and fibrosis in obstructive nephropathy. Am. J. Pathol. 2011, 179, 83–91.
  60. Moll, S.; Desmouliere, A.; Moeller, M.J.; Pache, J.C.; Badi, L.; Arcadu, F.; Richter, H.; Satz, A.; Uhles, S.; Cavalli, A.; et al. DDR1 role in fibrosis and its pharmacological targeting. Biochim. Biophys. Acta Mol. Cell Res. 2019, 1866, 118474.
  61. Wang, Z.; Zhang, Y.; Bartual, S.G.; Luo, J.; Xu, T.; Du, W.; Xun, Q.; Tu, Z.; Brekken, R.A.; Ren, X.; et al. Tetrahydroisoquinoline-7-carboxamide Derivatives as New Selective Discoidin Domain Receptor 1 (DDR1) Inhibitors. ACS Med. Chem. Lett. 2017, 8, 327–332.
  62. Itano, N.; Sawai, T.; Yoshida, M.; Lenas, P.; Yamada, Y.; Imagawa, M.; Shinomura, T.; Hamaguchi, M.; Yoshida, Y.; Ohnuki, Y.; et al. Three Isoforms of Mammalian Hyaluronan Synthases Have Distinct Enzymatic Properties. J. Biol. Chem. 1999, 274, 25085–25092.
  63. Cyphert, J.M.; Trempus, C.S.; Garantziotis, S. Size Matters: Molecular Weight Specificity of Hyaluronan Effects in Cell Biology. Int. J. Cell Biol. 2015, 2015, 563818.
  64. Qin, K.; Wang, F.; Simpson, R.M.L.; Zheng, X.; Wang, H.; Hu, Y.; Gao, Z.; Xu, Q.; Zhao, Q. Hyaluronan promotes the regeneration of vascular smooth muscle with potent contractile function in rapidly biodegradable vascular grafts. Biomaterials 2020, 257, 120226.
  65. Skurikhin, E.G.; Pershina, O.V.; Reztsova, A.M.; Ermakova, N.N.; Khmelevskaya, E.S.; Krupin, V.A.; Stepanova, I.E.; Artamonov, A.V.; Bekarev, A.A.; Madonov, P.G.; et al. Modulation of bleomycin-induced lung fibrosis by pegylated hyaluronidase and dopamine receptor antagonist in mice. PLoS ONE 2015, 10, e0125065.
  66. Andreichenko, I.N.; Tsitrina, A.A.; Fokin, A.V.; Gabdulkhakova, A.I.; Maltsev, D.I.; Perelman, G.S.; Bulgakova, E.V.; Kulikov, A.M.; Mikaelyan, A.S.; Kotelevtsev, Y.V. 4-methylumbelliferone Prevents Liver Fibrosis by Affecting Hyaluronan Deposition, FSTL1 Expression and Cell Localization. Int. J. Mol. Sci. 2019, 20, 6301.
  67. Collum, S.D.; Chen, N.Y.; Hernandez, A.M.; Hanmandlu, A.; Sweeney, H.; Mertens, T.C.J.; Weng, T.; Luo, F.; Molina, J.G.; Davies, J.; et al. Inhibition of hyaluronan synthesis attenuates pulmonary hypertension associated with lung fibrosis. Br. J. Pharmacol. 2017, 174, 3284–3301.
  68. Webber, J.; Jenkins, R.H.; Meran, S.; Phillips, A.; Steadman, R. Modulation of TGF beta 1-Dependent Myofibroblast Differentiation by Hyaluronan. Am. J. Pathol. 2009, 175, 148–160.
  69. Li, Y.; Liang, J.; Yang, T.; Monterrosa Mena, J.; Huan, C.; Xie, T.; Kurkciyan, A.; Liu, N.; Jiang, D.; Noble, P.W. Hyaluronan synthase 2 regulates fibroblast senescence in pulmonary fibrosis. Matrix Biol. 2016, 55, 35–48.
  70. Midgley, A.C.; Oltean, S.; Hascall, V.; Woods, E.L.; Steadman, R.; Phillips, A.O.; Meran, S. Nuclear hyaluronidase 2 drives alternative splicing of CD44 pre-mRNA to determine profibrotic or antifibrotic cell phenotype. Sci. Signal. 2017, 10.
  71. Kohan, M.; Muro, A.F.; White, E.S.; Berkman, N. EDA-containing cellular fibronectin induces fibroblast differentiation through binding to alpha4beta7 integrin receptor and MAPK/Erk 1/2-dependent signaling. FASEB J. 2010, 24, 4503–4512.
  72. Shinde, A.V.; Kelsh, R.; Peters, J.H.; Sekiguchi, K.; Van De Water, L.; McKeown-Longo, P.J. The alpha4beta1 integrin and the EDA domain of fibronectin regulate a profibrotic phenotype in dermal fibroblasts. Matrix Biol. 2015, 41, 26–35.
  73. Patsenker, E.; Popov, Y.; Stickel, F.; Jonczyk, A.; Goodman, S.L.; Schuppan, D. Inhibition of integrin alphavbeta6 on cholangiocytes blocks transforming growth factor-beta activation and retards biliary fibrosis progression. Gastroenterology 2008, 135, 660–670.
  74. Bagnato, G.L.; Irrera, N.; Pizzino, G.; Santoro, D.; Roberts, W.N.; Bagnato, G.; Pallio, G.; Vaccaro, M.; Squadrito, F.; Saitta, A.; et al. Dual alphavbeta3 and alphavbeta5 blockade attenuates fibrotic and vascular alterations in a murine model of systemic sclerosis. Clin. Sci. 2018, 132, 231–242.
  75. Henderson, N.C.; Arnold, T.D.; Katamura, Y.; Giacomini, M.M.; Rodriguez, J.D.; McCarty, J.H.; Pellicoro, A.; Raschperger, E.; Betsholtz, C.; Ruminski, P.G.; et al. Targeting of alphav integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nat. Med. 2013, 19, 1617–1624.
  76. Peng, Z.W.; Ikenaga, N.; Liu, S.B.; Sverdlov, D.Y.; Vaid, K.A.; Dixit, R.; Weinreb, P.H.; Violette, S.; Sheppard, D.; Schuppan, D.; et al. Integrin alphavbeta6 critically regulates hepatic progenitor cell function and promotes ductular reaction, fibrosis, and tumorigenesis. Hepatology 2016, 63, 217–232.
  77. Koivisto, L.; Bi, J.; Hakkinen, L.; Larjava, H. Integrin alphavbeta6: Structure, function and role in health and disease. Int. J. Biochem. Cell Biol. 2018, 99, 186–196.
  78. Serini, G.; Bochaton-Piallat, M.L.; Ropraz, P.; Geinoz, A.; Borsi, L.; Zardi, L.; Gabbiani, G. The fibronectin domain ED-A is crucial for myofibroblastic phenotype induction by transforming growth factor-beta1. J. Cell Biol. 1998, 142, 873–881.
  79. Shinde, A.V.; Bystroff, C.; Wang, C.; Vogelezang, M.G.; Vincent, P.A.; Hynes, R.O.; Van De Water, L. Identification of the peptide sequences within the EIIIA (EDA) segment of fibronectin that mediate integrin alpha9beta1-dependent cellular activities. J. Biol. Chem. 2008, 283, 2858–2870.
  80. Hinz, B.; Mastrangelo, D.; Iselin, C.E.; Chaponnier, C.; Gabbiani, G. Mechanical tension controls granulation tissue contractile activity and myofibroblast differentiation. Am. J. Pathol. 2001, 159, 1009–1020.
  81. Villa, A.; Trachsel, E.; Kaspar, M.; Schliemann, C.; Sommavilla, R.; Rybak, J.N.; Rosli, C.; Borsi, L.; Neri, D. A high-affinity human monoclonal antibody specific to the alternatively spliced EDA domain of fibronectin efficiently targets tumor neo-vasculature in vivo. Int. J. Cancer 2008, 122, 2405–2413.
  82. Ziffels, B.; Grotsch, A.; Al-Bayati, L.; Neri, D. Targeted delivery of calreticulin to ED-A fibronectin leads to tumor-growth retardation. J. Biotechnol. 2019, 290, 53–58.
  83. Femel, J.; Huijbers, E.J.; Saupe, F.; Cedervall, J.; Zhang, L.; Roswall, P.; Larsson, E.; Olofsson, H.; Pietras, K.; Dimberg, A.; et al. Therapeutic vaccination against fibronectin ED-A attenuates progression of metastatic breast cancer. Oncotarget 2014, 5, 12418–12427.
  84. Zhang, L.; Yan, H.; Tai, Y.; Xue, Y.; Wei, Y.; Wang, K.; Zhao, Q.; Wang, S.; Kong, D.; Midgley, A.C. Design and Evaluation of a Polypeptide that Mimics the Integrin Binding Site for EDA Fibronectin to Block Profibrotic Cell Activity. Int. J. Mol. Sci. 2021, 22, 1575.
  85. Prunotto, M.; Bruschi, M.; Gunning, P.; Gabbiani, G.; Weibel, F.; Ghiggeri, G.M.; Petretto, A.; Scaloni, A.; Bonello, T.; Schevzov, G.; et al. Stable incorporation of alpha-smooth muscle actin into stress fibers is dependent on specific tropomyosin isoforms. Cytoskeleton 2015, 72, 257–267.
  86. Caballero, S.; Yang, R.; Grant, M.B.; Chaqour, B. Selective blockade of cytoskeletal actin remodeling reduces experimental choroidal neovascularization. Investig. Ophthalmol. Vis. Sci. 2011, 52, 2490–2496.
  87. Clement, S.; Hinz, B.; Dugina, V.; Gabbiani, G.; Chaponnier, C. The N-terminal Ac-EEED sequence plays a role in alpha-smooth-muscle actin incorporation into stress fibers. J. Cell Sci. 2005, 118, 1395–1404.
  88. Hinz, B.; Gabbiani, G.; Chaponnier, C. The NH2-terminal peptide of alpha-smooth muscle actin inhibits force generation by the myofibroblast in vitro and in vivo. J. Cell Biol. 2002, 157, 657–663.
  89. Liechty, K.W.; Crombleholme, T.M.; Cass, D.L.; Martin, B.; Adzick, N.S. Diminished interleukin-8 (IL-8) production in the fetal wound healing response. J. Surg. Res. 1998, 77, 80–84.
  90. Gawronska-Kozak, B.; Bogacki, M.; Rim, J.S.; Monroe, W.T.; Manuel, J.A. Scarless skin repair in immunodeficient mice. Wound Repair Regen. 2006, 14, 265–276.
  91. Redd, M.J.; Cooper, L.; Wood, W.; Stramer, B.; Martin, P. Wound healing and inflammation: Embryos reveal the way to perfect repair. Philos. Trans. R. Soc. Lond. B Biol. Sci. 2004, 359, 777–784.
  92. Qiu, C.; Coutinho, P.; Frank, S.; Franke, S.; Law, L.Y.; Martin, P.; Green, C.R.; Becker, D.L. Targeting connexin43 expression accelerates the rate of wound repair. Curr. Biol. 2003, 13, 1697–1703.
  93. Cao, L.; Chen, Y.; Lu, L.; Liu, Y.; Wang, Y.; Fan, J.; Yin, Y. Angiotensin II upregulates fibroblast-myofibroblast transition through Cx43-dependent CaMKII and TGF-beta1 signaling in neonatal rat cardiac fibroblasts. Acta Biochim. Biophys. Sin. 2018, 50, 843–852.
  94. Schultz, F.; Swiatlowska, P.; Alvarez-Laviada, A.; Sanchez-Alonso, J.L.; Song, Q.; de Vries, A.A.F.; Pijnappels, D.A.; Ongstad, E.; Braga, V.M.M.; Entcheva, E.; et al. Cardiomyocyte-myofibroblast contact dynamism is modulated by connexin-43. FASEB J. 2019, 33, 10453–10468.
  95. Maier, C.; Ramming, A.; Bergmann, C.; Weinkam, R.; Kittan, N.; Schett, G.; Distler, J.H.W.; Beyer, C. Inhibition of phosphodiesterase 4 (PDE4) reduces dermal fibrosis by interfering with the release of interleukin-6 from M2 macrophages. Ann. Rheum. Dis. 2017, 76, 1133–1141.
  96. Liechty, K.W.; Kim, H.B.; Adzick, N.S.; Crombleholme, T.M. Fetal wound repair results in scar formation in interleukin-10-deficient mice in a syngeneic murine model of scarless fetal wound repair. J. Pediatr. Surg. 2000, 35, 866–872.
  97. Gordon, A.; Kozin, E.D.; Keswani, S.G.; Vaikunth, S.S.; Katz, A.B.; Zoltick, P.W.; Favata, M.; Radu, A.P.; Soslowsky, L.J.; Herlyn, M.; et al. Permissive environment in postnatal wounds induced by adenoviral-mediated overexpression of the anti-inflammatory cytokine interleukin-10 prevents scar formation. Wound Repair Regen. 2008, 16, 70–79.
  98. Sapudom, J.; Wu, X.; Chkolnikov, M.; Ansorge, M.; Anderegg, U.; Pompe, T. Fibroblast fate regulation by time dependent TGF-beta1 and IL-10 stimulation in biomimetic 3D matrices. Biomater. Sci. 2017, 5, 1858–1867.
  99. Ullm, F.; Riedl, P.; Machado de Amorim, A.; Patzschke, A.; Weiss, R.; Hauschildt, S.; Franke, K.; Anderegg, U.; Pompe, T. 3D Scaffold-Based Macrophage Fibroblast Coculture Model Reveals IL-10 Dependence of Wound Resolution Phase. Adv. Biosyst. 2020, 4, e1900220.
  100. Riedl, P.; Pompe, T. Functional label-free assessment of fibroblast differentiation in 3D collagen-I-matrices using particle image velocimetry. Biomater. Sci. 2021.
  101. Schafer, S.; Viswanathan, S.; Widjaja, A.A.; Lim, W.W.; Moreno-Moral, A.; DeLaughter, D.M.; Ng, B.; Patone, G.; Chow, K.; Khin, E.; et al. IL-11 is a crucial determinant of cardiovascular fibrosis. Nature 2017, 552, 110–115.
  102. Tamaki, S.; Mano, T.; Sakata, Y.; Ohtani, T.; Takeda, Y.; Kamimura, D.; Omori, Y.; Tsukamoto, Y.; Ikeya, Y.; Kawai, M.; et al. Interleukin-16 promotes cardiac fibrosis and myocardial stiffening in heart failure with preserved ejection fraction. PLoS ONE 2013, 8, e68893.
  103. Kotsiou, O.S.; Gourgoulianis, K.I.; Zarogiannis, S.G. IL-33/ST2 Axis in Organ Fibrosis. Front. Immunol. 2018, 9, 2432.
  104. Russo, B.; Brembilla, N.C.; Chizzolini, C. Interplay between Keratinocytes and Fibroblasts: A Systematic Review Providing a New Angle for Understanding Skin Fibrotic Disorders. Front. Immunol. 2020, 11, 648.
  105. Koskela, A.; Engstrom, K.; Hakelius, M.; Nowinski, D.; Ivarsson, M. Regulation of fibroblast gene expression by keratinocytes in organotypic skin culture provides possible mechanisms for the antifibrotic effect of reepithelialization. Wound Repair Regen. 2010, 18, 452–459.
  106. Ghahary, A.; Ghaffari, A. Role of keratinocyte-fibroblast cross-talk in development of hypertrophic scar. Wound Repair Regen 2007, 15 (Suppl. 1), S46–S53.
  107. Zheng, R.; Longmate, W.M.; DeFreest, L.; Varney, S.; Wu, L.; DiPersio, C.M.; Van De Water, L. Keratinocyte Integrin alpha3beta1 Promotes Secretion of IL-1alpha to Effect Paracrine Regulation of Fibroblast Gene Expression and Differentiation. J. Investig. Dermatol. 2019, 139, 2029–2038.
  108. Zheng, R.; Varney, S.D.; Wu, L.; DiPersio, C.M.; Van De Water, L. Integrin alpha4beta1 is required for IL-1alpha- and Nrf2-dependent, Cox-2 induction in fibroblasts, supporting a mechanism that suppresses alpha-SMA expression. Wound Repair Regen. 2021, 29, 597–601.
  109. Pakshir, P.; Hinz, B. The big five in fibrosis: Macrophages, myofibroblasts, matrix, mechanics, and miscommunication. Matrix Biol. 2018, 68–69, 81–93.
  110. Hesketh, M.; Sahin, K.B.; West, Z.E.; Murray, R.Z. Macrophage Phenotypes Regulate Scar Formation and Chronic Wound Healing. Int. J. Mol. Sci. 2017, 18, 1545.
  111. Rodrigues, M.; Kosaric, N.; Bonham, C.A.; Gurtner, G.C. Wound Healing: A Cellular Perspective. Physiol. Rev. 2019, 99, 665–706.
  112. Shook, B.A.; Wasko, R.R.; Rivera-Gonzalez, G.C.; Salazar-Gatzimas, E.; Lopez-Giraldez, F.; Dash, B.C.; Munoz-Rojas, A.R.; Aultman, K.D.; Zwick, R.K.; Lei, V.; et al. Myofibroblast proliferation and heterogeneity are supported by macrophages during skin repair. Science 2018, 362.
  113. Xin, Y.; Wang, X.; Zhu, M.; Qu, M.; Bogari, M.; Lin, L.; Mar Aung, Z.; Chen, W.; Chen, X.; Chai, G.; et al. Expansion of CD26 positive fibroblast population promotes keloid progression. Exp. Cell Res. 2017, 356, 104–113.
  114. Lodyga, M.; Cambridge, E.; Karvonen, H.M.; Pakshir, P.; Wu, B.; Boo, S.; Kiebalo, M.; Kaarteenaho, R.; Glogauer, M.; Kapoor, M.; et al. Cadherin-11-mediated adhesion of macrophages to myofibroblasts establishes a profibrotic niche of active TGF-beta. Sci. Signal. 2019, 12.
  115. Komi, D.E.A.; Khomtchouk, K.; Santa Maria, P.L. A Review of the Contribution of Mast Cells in Wound Healing: Involved Molecular and Cellular Mechanisms. Clin. Rev. Allergy Immunol. 2020, 58, 298–312.
  116. Wulff, B.C.; Parent, A.E.; Meleski, M.A.; DiPietro, L.A.; Schrementi, M.E.; Wilgus, T.A. Mast cells contribute to scar formation during fetal wound healing. J. Investig. Dermatol. 2012, 132, 458–465.
  117. Glim, J.E.; Beelen, R.H.; Niessen, F.B.; Everts, V.; Ulrich, M.M. The number of immune cells is lower in healthy oral mucosa compared to skin and does not increase after scarring. Arch. Oral Biol. 2015, 60, 272–281.
  118. Tellechea, A.; Bai, S.; Dangwal, S.; Theocharidis, G.; Nagai, M.; Koerner, S.; Cheong, J.E.; Bhasin, S.; Shih, T.Y.; Zheng, Y.; et al. Topical Application of a Mast Cell Stabilizer Improves Impaired Diabetic Wound Healing. J. Investig. Dermatol. 2020, 140, 901–911.
  119. Ozbilgin, M.K.; Inan, S. The roles of transforming growth factor type beta3 (TGF-beta3) and mast cells in the pathogenesis of scleroderma. Clin. Rheumatol. 2003, 22, 189–195.
  120. Irani, A.M.; Gruber, B.L.; Kaufman, L.D.; Kahaleh, M.B.; Schwartz, L.B. Mast cell changes in scleroderma. Presence of MCT cells in the skin and evidence of mast cell activation. Arthritis Rheum. 1992, 35, 933–939.
  121. Monument, M.J.; Hart, D.A.; Salo, P.T.; Befus, A.D.; Hildebrand, K.A. Neuroinflammatory Mechanisms of Connective Tissue Fibrosis: Targeting Neurogenic and Mast Cell Contributions. Adv. Wound Care 2015, 4, 137–151.
  122. Kwak, I.S.; Choi, Y.H.; Jang, Y.C.; Lee, Y.K. Immunohistochemical analysis of neuropeptides (protein gene product 9.5, substance P and calcitonin gene-related peptide) in hypertrophic burn scar with pain and itching. Burns 2014, 40, 1661–1667.
  123. Lebonvallet, N.; Laverdet, B.; Misery, L.; Desmouliere, A.; Girard, D. New insights into the roles of myofibroblasts and innervation during skin healing and innovative therapies to improve scar innervation. Exp. Dermatol. 2018, 27, 950–958.
  124. Hildebrand, K.A.; Zhang, M.; Befus, A.D.; Salo, P.T.; Hart, D.A. A myofibroblast-mast cell-neuropeptide axis of fibrosis in post-traumatic joint contractures: An in vitro analysis of mechanistic components. J. Orthop. Res. 2014, 32, 1290–1296.
  125. Fang, Y.; Zhang, S.; Li, X.; Jiang, F.; Ye, Q.; Ning, W. Follistatin like-1 aggravates silica-induced mouse lung injury. Sci. Rep. 2017, 7, 399.
  126. Chen, Z.; Fang, Y.; Zhang, S.; Li, L.; Wang, L.; Zhang, A.; Yuan, Z.; Wang, P.; Zhou, H.; Cui, W.; et al. Haplodeletion of Follistatin-Like 1 Attenuates Radiation-Induced Pulmonary Fibrosis in Mice. Int. J. Radiat. Oncol. Biol. Phys. 2019, 103, 208–216.
  127. Li, X.; Fang, Y.; Jiang, D.; Dong, Y.; Liu, Y.; Zhang, S.; Guo, J.; Qi, C.; Zhao, C.; Jiang, F.; et al. Targeting FSTL1 for Multiple Fibrotic and Systemic Autoimmune Diseases. Mol. Ther. 2021, 29, 347–364.
  128. Fitzgerald, A.A.; Weiner, L.M. The role of fibroblast activation protein in health and malignancy. Cancer Metastasis Rev. 2020, 39, 783–803.
  129. Mazur, A.; Holthoff, E.; Vadali, S.; Kelly, T.; Post, S.R. Cleavage of Type I Collagen by Fibroblast Activation Protein-alpha Enhances Class A Scavenger Receptor Mediated Macrophage Adhesion. PLoS ONE 2016, 11, e0150287.
  130. Levy, M.T.; McCaughan, G.W.; Abbott, C.A.; Park, J.E.; Cunningham, A.M.; Muller, E.; Rettig, W.J.; Gorrell, M.D. Fibroblast activation protein: A cell surface dipeptidyl peptidase and gelatinase expressed by stellate cells at the tissue remodelling interface in human cirrhosis. Hepatology 1999, 29, 1768–1778.
  131. Avery, D.; Govindaraju, P.; Jacob, M.; Todd, L.; Monslow, J.; Pure, E. Extracellular matrix directs phenotypic heterogeneity of activated fibroblasts. Matrix Biol. 2018, 67, 90–106.
  132. Truffi, M.; Sorrentino, L.; Monieri, M.; Fociani, P.; Mazzucchelli, S.; Bonzini, M.; Zerbi, P.; Sampietro, G.M.; Di Sabatino, A.; Corsi, F. Inhibition of Fibroblast Activation Protein Restores a Balanced Extracellular Matrix and Reduces Fibrosis in Crohn’s Disease Strictures Ex Vivo. Inflamm. Bowel Dis. 2018, 24, 332–345.
  133. Egger, C.; Cannet, C.; Gerard, C.; Suply, T.; Ksiazek, I.; Jarman, E.; Beckmann, N. Effects of the fibroblast activation protein inhibitor, PT100, in a murine model of pulmonary fibrosis. Eur. J. Pharmacol. 2017, 809, 64–72.
  134. Jun, J.I.; Lau, L.F. The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing. Nat. Cell Biol. 2010, 12, 676–685.
  135. Kisseleva, T.; Cong, M.; Paik, Y.; Scholten, D.; Jiang, C.; Benner, C.; Iwaisako, K.; Moore-Morris, T.; Scott, B.; Tsukamoto, H.; et al. Myofibroblasts revert to an inactive phenotype during regression of liver fibrosis. Proc. Natl. Acad. Sci. USA 2012, 109, 9448–9453.
  136. Desmouliere, A.; Redard, M.; Darby, I.; Gabbiani, G. Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar. Am. J. Pathol. 1995, 146, 56–66.
  137. Hinz, B.; Lagares, D. Evasion of apoptosis by myofibroblasts: A hallmark of fibrotic diseases. Nat. Rev. Rheumatol. 2020, 16, 11–31.
  138. Varney, S.D.; Betts, C.B.; Zheng, R.; Wu, L.; Hinz, B.; Zhou, J.; Van De Water, L. Hic-5 is required for myofibroblast differentiation by regulating mechanically dependent MRTF-A nuclear accumulation. J. Cell Sci. 2016, 129, 774–787.
  139. Bae, H.; Kim, T.; Lim, I. Effects of nitric oxide on apoptosis and voltage-gated calcium channels in human cardiac myofibroblasts. Clin. Exp. Pharmacol. Physiol. 2020, 47, 16–26.
  140. Forte, A.; Della Corte, A.; De Feo, M.; Cerasuolo, F.; Cipollaro, M. Role of myofibroblasts in vascular remodelling: Focus on restenosis and aneurysm. Cardiovasc. Res. 2010, 88, 395–405.
  141. Midgley, A.C.; Wei, Y.; Li, Z.; Kong, D.; Zhao, Q. Nitric-Oxide-Releasing Biomaterial Regulation of the Stem Cell Microenvironment in Regenerative Medicine. Adv. Mater. 2020, 32, e1805818.
  142. Douglass, A.; Wallace, K.; Parr, R.; Park, J.; Durward, E.; Broadbent, I.; Barelle, C.; Porter, A.J.; Wright, M.C. Antibody-targeted myofibroblast apoptosis reduces fibrosis during sustained liver injury. J. Hepatol. 2008, 49, 88–98.
  143. Feng, Y.; Wu, J.J.; Sun, Z.L.; Liu, S.Y.; Zou, M.L.; Yuan, Z.D.; Yu, S.; Lv, G.Z.; Yuan, F.L. Targeted apoptosis of myofibroblasts by elesclomol inhibits hypertrophic scar formation. EBioMedicine 2020, 54, 102715.
  144. Certo, M.; Del Gaizo Moore, V.; Nishino, M.; Wei, G.; Korsmeyer, S.; Armstrong, S.A.; Letai, A. Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer Cell 2006, 9, 351–365.
  145. Zhou, Y.; Huang, X.; Hecker, L.; Kurundkar, D.; Kurundkar, A.; Liu, H.; Jin, T.H.; Desai, L.; Bernard, K.; Thannickal, V.J. Inhibition of mechanosensitive signaling in myofibroblasts ameliorates experimental pulmonary fibrosis. J. Clin. Investig. 2013, 123, 1096–1108.
  146. Lagares, D.; Santos, A.; Grasberger, P.E.; Liu, F.; Probst, C.K.; Rahimi, R.A.; Sakai, N.; Kuehl, T.; Ryan, J.; Bhola, P.; et al. Targeted apoptosis of myofibroblasts with the BH3 mimetic ABT-263 reverses established fibrosis. Sci. Transl. Med. 2017, 9.
  147. Yang, X.; Xiao, Y.; Zhong, C.; Shu, F.; Xiao, S.; Zheng, Y.; Xia, Z. ABT-263 Reduces Hypertrophic Scars by Targeting Apoptosis of Myofibroblasts. Front. Pharmacol. 2020, 11, 615505.
  148. Shroff, A.; Mamalis, A.; Jagdeo, J. Oxidative Stress and Skin Fibrosis. Curr. Pathobiol. Rep. 2014, 2, 257–267.
  149. Siani, A.; Tirelli, N. Myofibroblast differentiation: Main features, biomedical relevance, and the role of reactive oxygen species. Antioxid. Redox. Signal. 2014, 21, 768–785.
  150. Gonzalez-Gonzalez, F.J.; Chandel, N.S.; Jain, M.; Budinger, G.R.S. Reactive oxygen species as signaling molecules in the development of lung fibrosis. Transl. Res. 2017, 190, 61–68.
  151. Su, H.; Wan, C.; Song, A.; Qiu, Y.; Xiong, W.; Zhang, C. Oxidative Stress and Renal Fibrosis: Mechanisms and Therapies. Adv. Exp. Med. Biol. 2019, 1165, 585–604.
  152. Ramos-Tovar, E.; Muriel, P. Molecular Mechanisms That Link Oxidative Stress, Inflammation, and Fibrosis in the Liver. Antioxidants 2020, 9, 1279.
  153. Vozenin-Brotons, M.C.; Sivan, V.; Gault, N.; Renard, C.; Geffrotin, C.; Delanian, S.; Lefaix, J.L.; Martin, M. Antifibrotic action of Cu/Zn SOD is mediated by TGF-beta1 repression and phenotypic reversion of myofibroblasts. Free Radic. Biol. Med. 2001, 30, 30–42.
  154. Tan, L.G.; Xiao, J.H.; Yu, D.L.; Zhang, L.; Zheng, F.; Guo, L.Y.; Yang, J.Y.; Tang, J.M.; Chen, S.Y.; Wang, J.N. PEP-1-SOD1 fusion proteins block cardiac myofibroblast activation and angiotensin II-induced collagen production. BMC Cardiovasc. Disord. 2015, 15, 116.
  155. Lan, T.; Kisseleva, T.; Brenner, D.A. Deficiency of NOX1 or NOX4 Prevents Liver Inflammation and Fibrosis in Mice through Inhibition of Hepatic Stellate Cell Activation. PLoS ONE 2015, 10, e0129743.
  156. Nishio, T.; Hu, R.; Koyama, Y.; Liang, S.; Rosenthal, S.B.; Yamamoto, G.; Karin, D.; Baglieri, J.; Ma, H.Y.; Xu, J.; et al. Activated hepatic stellate cells and portal fibroblasts contribute to cholestatic liver fibrosis in MDR2 knockout mice. J. Hepatol. 2019, 71, 573–585.
  157. Morry, J.; Ngamcherdtrakul, W.; Yantasee, W. Oxidative stress in cancer and fibrosis: Opportunity for therapeutic intervention with antioxidant compounds, enzymes, and nanoparticles. Redox Biol. 2017, 11, 240–253.
  158. Celiksoy, V.; Moses, R.L.; Sloan, A.J.; Moseley, R.; Heard, C.M. Evaluation of the In Vitro Oral Wound Healing Effects of Pomegranate (Punica granatum) Rind Extract and Punicalagin, in Combination with Zn (II). Biomolecules 2020, 10, 1234.
  159. Moses, R.L.; Dally, J.; Lundy, F.T.; Langat, M.; Kiapranis, R.; Tsolaki, A.G.; Moseley, R.; Prescott, T.A.K. Lepiniopsis ternatensis sap stimulates fibroblast proliferation and down regulates macrophage TNF-alpha secretion. Fitoterapia 2020, 141, 104478.
  160. Moses, R.L.; Fang, R.; Dally, J.; Briggs, M.; Lundy, F.T.; Kiapranis, R.; Moseley, R.; Prescott, T.A.K. Evaluation of Cypholophus macrocephalus sap as a treatment for infected cutaneous ulcers in Papua New Guinea. Fitoterapia 2020, 143, 104554.
  161. Liu, M.; Xu, H.; Zhang, L.; Zhang, C.; Yang, L.; Ma, E.; Liu, L.; Li, Y. Salvianolic acid B inhibits myofibroblast transdifferentiation in experimental pulmonary fibrosis via the up-regulation of Nrf2. Biochem. Biophys. Res. Commun. 2018, 495, 325–331.
  162. Zhang, Y.; Du, H.; Yu, X.; Zhu, J. Fucoidan attenuates hyperoxia-induced lung injury in newborn rats by mediating lung fibroblasts differentiate into myofibroblasts. Ann. Transl. Med. 2020, 8, 1501.
  163. Tavares, L.A.; Rezende, A.A.; Santos, J.L.; Estevam, C.S.; Silva, A.M.O.; Schneider, J.K.; Cunha, J.L.S.; Droppa-Almeida, D.; Correia-Neto, I.J.; Cardoso, J.C.; et al. Cymbopogon winterianus Essential Oil Attenuates Bleomycin-Induced Pulmonary Fibrosis in a Murine Model. Pharmaceutics 2021, 13, 679.
  164. Wang, W.; Ma, B.L.; Xu, C.G.; Zhou, X.J. Dihydroquercetin protects against renal fibrosis by activating the Nrf2 pathway. Phytomedicine 2020, 69, 153185.
  165. Veeren, B.; Bringart, M.; Turpin, C.; Rondeau, P.; Planesse, C.; Ait-Arsa, I.; Gimie, F.; Marodon, C.; Meilhac, O.; Gonthier, M.P.; et al. Caffeic Acid, One of the Major Phenolic Acids of the Medicinal Plant Antirhea borbonica, Reduces Renal Tubulointerstitial Fibrosis. Biomedicines 2021, 9, 358.
  166. Wu, H.; Li, G.N.; Xie, J.; Li, R.; Chen, Q.H.; Chen, J.Z.; Wei, Z.H.; Kang, L.N.; Xu, B. Resveratrol ameliorates myocardial fibrosis by inhibiting ROS/ERK/TGF-beta/periostin pathway in STZ-induced diabetic mice. BMC Cardiovasc. Disord. 2016, 16, 5.
  167. Lyu, L.; Chen, J.; Wang, W.; Yan, T.; Lin, J.; Gao, H.; Li, H.; Lv, R.; Xu, F.; Fang, L.; et al. Scoparone alleviates Ang II-induced pathological myocardial hypertrophy in mice by inhibiting oxidative stress. J. Cell Mol. Med. 2021, 25, 3136–3148.
  168. Sekiguchi, A.; Motegi, S.I.; Fujiwara, C.; Yamazaki, S.; Inoue, Y.; Uchiyama, A.; Akai, R.; Iwawaki, T.; Ishikawa, O. Inhibitory effect of kaempferol on skin fibrosis in systemic sclerosis by the suppression of oxidative stress. J. Dermatol. Sci. 2019, 96, 8–17.
  169. Jiang, L.; Deng, Y.; Li, W.; Lu, Y. Arctigenin suppresses fibroblast activity and extracellular matrix deposition in hypertrophic scarring by reducing inflammation and oxidative stress. Mol. Med. Rep. 2020, 22, 4783–4791.
More
Information
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register : , , , , , ,
View Times: 312
Revisions: 2 times (View History)
Update Date: 11 Aug 2023
1000/1000
ScholarVision Creations