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Outcomes of wound healing: tissue regeneration or fibrosis. Following tissue injury, epithelial and/or endothelial cells release inflammatory mediators that initiate an antifibrinolytic-coagulation cascade, which triggers blood clot formation. This is followed by an inflammatory and pro- liferative phase, when leukocytes are recruited and then activated and induced to proliferate by chemokines and growth factors. The activated leukocytes secrete profibrotic cytokines such as IL-13 and TGF- b . Stimulated epithelial cells, endothelial cells, and myofibroblasts also produce MMPs, which disrupt the basement membrane, and additional cytokines and chemokines that recruit and activate neutrophils, macrophages, T cells, B cells, and eosinophils, important components of reparative tissue. The activated macrophages and neutrophils clean up tissue debris, dead cells, and invading organisms. Shortly after the initial inflammatory phase, myofibroblasts produce ECM components, and endothelial cells form new blood vessels. The myofibroblasts can be derived from local mesenchymal cells, recruited from the bone marrow (where they are known as fibrocytes), or derived by EMT. In the subsequent remodeling and maturation phase, the activated myofibroblasts stimulate wound contraction. Collagen fibers also become more organized, blood vessels are restored to normal, scar tissue is eliminated, and epithelial and/or endothelial cells divide and migrate over the basal layers to regenerate the epithelium or endothelium, respectively, restoring the damaged tissue to its normal appearance. However, in the case of chronic wounds, the normal healing process is disrupted. Persistent inflammation, tissue necrosis, and infection lead to chronic myofibroblast activation and excessive accumulation of ECM components, which promotes the formation of a permanent fibrotic scar.
Source publication
Fibroproliferative diseases, including the pulmonary fibroses, systemic sclerosis, liver cirrhosis, cardiovascular disease, progressive kidney disease, and macular degeneration, are a leading cause of morbidity and mortality and can affect all tissues and organ systems. Fibrotic tissue remodeling can also influence cancer metastasis and accelerate...
Contexts in source publication
Context 1
... is often defined as a wound-healing response that has gone out of control. Repair of damaged tissues is a fundamental biological process that allows the ordered replacement of dead or damaged cells after injury, a mechanism that is critically important for survival. Damage to tissues can result from various acute or chronic stimuli, including infections, autoimmune reactions, and mechanical injury. The repair process typically involves two distinct stages: a regenerative phase, where injured cells are replaced by cells of the same type, leaving no lasting evidence of damage; and a phase known as fibroplasia, or fibrosis, where connective tissue replaces normal parenchymal tissue. Although initially beneficial, the healing process becomes pathogenic if it continues unchecked, resulting in substantial remodeling of the ECM and formation of permanent scar tissue (Figure 1). In some cases, it might ultimately lead to organ failure and death. In contrast to acute inflammatory reactions, which are characterized by rapidly resolving vascular changes, edema, and neutrophil- ic infiltration, pathogenic fibrosis typically results from chronic inflammatory reactions — defined as responses that persist for sev- eral weeks or months and in which inflammation, tissue destruction, and repair processes occur simultaneously. Despite having obvious etiological and clinical distinctions, most chronic fibrotic disorders have in common a persistent irritant that sustains the production of growth factors, proteolytic enzymes, angiogenic factors, and fibrogenic cytokines, which together stimulate the deposition of connective tissue elements that progressively remodel and destroy normal tissue architecture (1, 2). When injuries occur, damaged epithelial and/or endothelial cells release inflammatory mediators that initiate an antifibrinolytic- coagulation cascade (3), which triggers formation of both blood clots and a provisional ECM (Figure 1). Platelets are exposed to ECM components, triggering aggregation, clot formation, ...
Context 2
... is often defined as a wound-healing response that has gone out of control. Repair of damaged tissues is a fundamental biological process that allows the ordered replacement of dead or damaged cells after injury, a mechanism that is critically important for survival. Damage to tissues can result from various acute or chronic stimuli, including infections, autoimmune reactions, and mechanical injury. The repair process typically involves two distinct stages: a regenerative phase, where injured cells are replaced by cells of the same type, leaving no lasting evidence of damage; and a phase known as fibroplasia, or fibrosis, where connective tissue replaces normal parenchymal tissue. Although initially beneficial, the healing process becomes pathogenic if it continues unchecked, resulting in substantial remodeling of the ECM and formation of permanent scar tissue (Figure 1). In some cases, it might ultimately lead to organ failure and death. In contrast to acute inflammatory reactions, which are characterized by rapidly resolving vascular changes, edema, and neutrophil- ic infiltration, pathogenic fibrosis typically results from chronic inflammatory reactions — defined as responses that persist for sev- eral weeks or months and in which inflammation, tissue destruction, and repair processes occur simultaneously. Despite having obvious etiological and clinical distinctions, most chronic fibrotic disorders have in common a persistent irritant that sustains the production of growth factors, proteolytic enzymes, angiogenic factors, and fibrogenic cytokines, which together stimulate the deposition of connective tissue elements that progressively remodel and destroy normal tissue architecture (1, 2). When injuries occur, damaged epithelial and/or endothelial cells release inflammatory mediators that initiate an antifibrinolytic- coagulation cascade (3), which triggers formation of both blood clots and a provisional ECM (Figure 1). Platelets are exposed to ECM components, triggering aggregation, clot formation, ...
Context 3
... Next, platelet degranulation promotes vasodilation and increased blood vessel permeability, while stimulated myofibroblasts (collagen-secreting a -SMA + fibroblasts) and epithelial and/or endothelial cells produce MMPs, which disrupt the basement membrane, allowing the efficient recruitment of inflammatory cells to the site of injury. Epithelial and endothelial cells also secrete growth factors, cytokines, and chemokines, which stimulate the proliferation and recruitment of leukocytes across the provisional ECM. Neutrophils are the most abundant inflammatory cell at the early stages of wound healing. When they degranulate and die, macrophages are recruited. During this initial leukocyte migration phase, the activated macrophages and neutrophils eliminate tissue debris, dead cells, and any invading organisms. They also produce cytokines and chemokines, which amplify the wound-healing response. These factors are also mitogenic and chemotactic for endothelial cells, which surround the injury and form new blood vessels as they migrate toward its center. Subse- quently, T cells become activated and secrete profibrotic cytokines such as IL-13 and TGF- b (4, 5), which in turn further activate the macrophages and fibroblasts. Activated fibroblasts transform into a -SMA–expressing myofibroblasts as they migrate along the fibrin lattice into the wound. Myofibroblasts are derived from local mesenchymal cells or recruited from the bone marrow (where they are known as fibrocytes) ( Figure 1). Epithelial cells can also undergo epithelial-mesenchymal transition (EMT), providing a rich renewable source of myofibroblasts (6). Following activation, myofibroblasts promote wound contraction, the process in which the edges of the wound migrate toward the center. Finally, epithelial and/or endothelial cells divide and migrate over the basal layers to regenerate the damaged tissue, which completes the normal healing process. However, when repeated injury occurs, chronic inflammation and repair cause an excessive accumulation of ECM components (such as hyaluronic acid, fibronectin, proteoglycans, and interstitial collagens), which contribute to the formation of a permanent fibrotic scar. The net amount of collagen deposited by fibroblasts is regulated continuously by collagen synthesis and collagen catabolism. The turnover of collagen and other ECM proteins is controlled by various MMPs and their inhibitors (tissue inhibitors of metalloproteinases [TIMPs]), which are produced by granulocytes, macrophages, epidermal cells, and myofibroblasts. Shifts in these opposing mechanisms (synthesis versus catabolism) regulate the net increase or decrease of collagen within a wound (7). The expanding pool of mesenchymal cells further exacerbates the response. In the remodeling phase, the synthesis of new collagen by fibroblasts exceeds the rate at which it is degraded such that the total amount of collagen continues to increase. Although inflammation typically precedes fibrosis, results from experimental models of this process have demonstrated that fibrosis is not necessarily driven by inflammation at all times, suggesting that the mechanisms that regulate fibrogenesis are, to a certain extent, distinct from those regulating inflammation (8). This might explain the general lack of efficacy of antiinflammatory mediators in the treatment of fibrotic disease and the need to identify targeted antifibrotic therapies. The spectrum of diseases that result from chronic tissue damage or out-of-control wound-healing responses are too numerous to list. However, the goal of this Review series on fibrotic diseases is to highlight some of the major fibrotic diseases and to identify common and unique mechanisms of fibrogenesis in the various organ systems affected by these ...
Similar publications
Fibrosis plays a role in a wide number of diseases and organs, including pulmonary fibrosis, liver cirrhosis, pancreatic cancer, cardiovascular and kidney diseases, macular degeneration, cancer metastasis, and chronic organ transplant rejection. Despite many efforts to develop effective and accurate noninvasive diagnostic and prognostic techniques,...
Citations
... Instead of replacing injured tissue with functional native cellular components and an appropriate microstructure, this chronic condition is characterized by transdifferentiation of resident connective tissue fibroblasts or other progenitor cells into highly synthetic and contractile α-SMA + myofibroblasts [2,3], which produce excessive amounts of acellular, primarily collagen I-based, extracellular matrix (ECM) that lacks functional properties of the uninjured tissue. As fibrosis develops in myriad organs in response to many different types of tissue stress and damage, common estimates suggest that nearly half of all deaths in the developed world are consequent to the development of tissue fibrosis [4], while fibrotic conditions that do not result in mortality may still confer substantial morbidity. Although our understanding of the basic science of fibrosis has progressed significantly over the past several decades, the development of clinically successful therapeutics has lagged greatly behind the elucidation of key mechanisms underlying the development, progression, and maintenance of tissue fibrosis (reviewed by Henderson et al., 2020 [5]), underlying a dire need for the discovery of novel anti-fibrotic therapeutics. ...
Fibrosis is a ubiquitous pathology, and prior studies have indicated that various artemisinin (ART) derivatives (including artesunate (AS), artemether (AM), and dihydroartemisinin (DHA)) can reduce fibrosis in vitro and in vivo. The medicinal plant Artemisia annua L. is the natural source of ART and is widely used, especially in underdeveloped countries, to treat a variety of diseases including malaria. A. afra contains no ART but is also antimalarial. Using human dermal fibroblasts (CRL-2097), we compared the effects of A. annua and A. afra tea infusions, ART, AS, AM, DHA, and a liver metabolite of ART, deoxyART (dART), on fibroblast viability and expression of key fibrotic marker genes after 1 and 4 days of treatment. AS, DHA, and Artemisia teas reduced fibroblast viability 4 d post-treatment in up to 80% of their respective controls. After 4 d of treatment, AS DHA and Artemisia teas downregulated ACTA2 up to 10 fold while ART had no significant effect, and AM increased viability by 10%. MMP1 and MMP3 were upregulated by AS, 17.5 and 32.6 fold, respectively, and by DHA, 8 and 51.8 fold, respectively. ART had no effect, but A. annua and A. afra teas increased MMP3 5 and 16-fold, respectively. Although A. afra tea increased COL3A1 5 fold, MMP1 decreased >7 fold with no change in either transcript by A. annua tea. Although A. annua contains ART, it had a significantly greater anti-fibrotic effect than ART alone but was less effective than A. afra. Immunofluorescent staining for smooth-muscle α-actin (α-SMA) correlated well with the transcriptional responses of drug-treated fibroblasts. Together, proliferation, qPCR, and immunofluorescence results show that treatment with ART, AS, DHA, and the two Artemisia teas yield differing responses, including those related to fibrosis, in human dermal fibroblasts, with evidence also of remodeling of fibrotic ECM.
... TGF-β is one of the most studied cytokines in the literature [7][8][9][10][11][12]15]. In fibrosis, activated myofibroblasts contribute to the production of an excessive ECM [24]. IL-1β induces myofibroblast activation via TGF-β1 and is also a potent proinflammatory mediator that exacerbates parenchymal-cell damage [25]. ...
Purpose
To create a reproducible and standardized urethral stricture model in rats, evaluating both histomorphologic findings and gene expression data. In studies involving experimental animals, more standardization is needed for the creation of a urethral stricture model.
Methods
Sixteen male rats were randomized into two groups. The Sham group (n:8) underwent only a penoscrotal incision, while the stricture group (n:8) had their urethras exposed through a penoscrotal incision, followed by electrocauterization to the corpus spongiosum. On the 15th day, blood and urethral tissues were harvested for histologic and molecular analyses. Histomorphologic, immunohistochemical, and reverse transcription polymerase chain reaction analyses were performed.
Results
The stricture group exhibited more severe and intense spongiofibrosis, inflammation, epithelial desquamation, and congestion in vascular structures compared to the controls (p < 0.05). The urethral tissue in the stricture group showed an increased ratio of inflammation parameters, including Collagen 1A1, Collagen 3A1, elastin, Transforming growth factor β1, α Smooth muscle actin, Platelet-derived growth factor α, and Platelet-derived growth factor β. Transforming growth factor β1, Platelet-derived growth factor α, and Platelet-derived growth factor β each correlated highly with the other six parameters (r > 0.60, p < 0.05).
Conclusion
Developing electrocoagulation-induced urethral stricture in rats is a simple, reliable, inexpensive, and reproducible. Reporting histologic data with qualitative and semi-quantitative scoring will enhance data standardization, aiding reader understanding and analysis. Transforming growth factor β and Platelet-derived growth factor play key roles in fibrosis during stricture development. Incorporating these cytokines in urethral stricture animal model studies can demonstrate successful stenosis creation.
... Following tissue injury, epithelial cells have a pivotal role in the recruitment and activation of inflammatory cells, endothelial cells and fibroblasts. Furthermore, epithelial cells undergo epithelial-mesenchymal transition (EMT), facilitating their transdifferentiation into myofibroblasts (127,128). These myofibroblasts are responsible for extracellular matrix (ECM) production, proliferation and migration across the basal layer, facilitating the coverage and regeneration of damaged tissue. ...
... Fibrosis is a healing process that occurs in response to tissue injury (128). During the healing phase, angiogenesis is triggered to facilitate tissue repair, enhance oxygen supply and facilitate the migration of inflammatory cells to the lesion area (143). ...
Macrophages form a crucial component of the innate immune system, and their activation is indispensable for various aspects of immune and inflammatory processes, tissue repair, and maintenance of the balance of the body's state. Macrophages are found in all ocular tissues, spanning from the front surface, including the cornea, to the posterior pole, represented by the choroid/sclera. The neural retina is also populated by specialised resident macrophages called microglia. The plasticity of microglia/macrophages allows them to adopt different activation states in response to changes in the tissue microenvironment. When exposed to various factors, microglia/macrophages polarise into distinct phenotypes, each exhibiting unique characteristics and roles. Furthermore, extensive research has indicated a close association between microglia/macrophage polarisation and the development and reversal of various intraocular diseases. The present article provides a review of the recent findings on the association between microglia/macrophage polarisation and ocular pathological processes (including autoimmune uveitis, optic neuritis, sympathetic ophthalmia, retinitis pigmentosa, glaucoma, proliferative vitreoretinopathy, subretinal fibrosis, uveal melanoma, ischaemic optic neuropathy, retinopathy of prematurity and choroidal neovascularization). The paradoxical role of microglia/macrophage polarisation in retinopathy of prematurity is also discussed. Several studies have shown that microglia/macrophages are involved in the pathology of ocular diseases. However, it is required to further explore the relevant mechanisms and regulatory processes. The relationship between the functional diversity displayed by microglia/macrophage polarisation and intraocular diseases may provide a new direction for the treatment of intraocular diseases.
... The diagnostic hallmark of EoE is an intense influx of eosinophils into the esophageal epithelium, defined as ≥ 15 eosinophils/high-power field (eos/hpf ). Prolonged eosinophilic inflammation can lead to lamina propria fibrosis (LPF), which is regarded as one of the key changes associated with fibrostenotic EoE and is a result of excessive deposition of extracellular matrix (ECM) components such as collagen (i.e., type I collagen) with increased fibroblast activation and proliferation [2,[6][7][8]. Currently, the assessment of LPF in biopsies collected from EoE patients relies on manual and subjective interpretation of lamina propria (LP) remodeling (e.g. ...
Eosinophilic esophagitis (EoE) is a chronic inflammatory condition characterized by an intense infiltration of eosinophils into the esophageal epithelium. When not adequately controlled, eosinophilic inflammation can lead to changes in components of the extracellular matrix (ECM) of the lamina propria. Particularly, alterations to the collagen fiber matrix can lead to lamina propria fibrosis (LPF), which plays an important role in the fibrostenotic complications of EoE. Current approaches to assess LPF in EoE are prone to inter-observer inconsistencies and provide limited insight into the structural remodeling of the ECM. An objective approach to quantify LPF can eliminate inter-observer inconsistencies and provide novel insights into the fibrotic transformation of the lamina propria in EoE. Second harmonic generation (SHG) microscopy is a powerful modality for objectively quantifying disease associated alterations in ECM collagen structure that is finding increasing use for clinical research. We used SHG with morphometric analysis (SHG-MA) to characterize lamina propria collagen fibers and ECM porosity in esophageal biopsies collected from children with active EoE (n = 11), inactive EoE (n = 11), and non-EoE (n = 11). The collagen fiber width quantified by SHG-MA correlated positively with peak eosinophil count (r = 0.65, p < 0.005) and histopathologist scoring of LPF (r = 0.52, p < 0.005) in the esophageal biopsies. Patients with active EoE had a significant enlargement of ECM pores compared to inactive EoE and non-EoE (p < 0.005), with the mean pore area correlating positively with EoE activity (r = 0.76, p < 0.005) and LPF severity (r = 0.65, p < 0.005). These results indicate that SHG-MA can be utilized to objectively characterize and provide novel insights into lamina propria ECM structural remodeling in children with EoE, which could aid in monitoring disease progression.
... Increases in profibrotic cytokines such as transforming growth factor beta-1 (TGFβ1), tumor necrosis factor alpha (TNFα), interleukin 6 (IL6), interleukin 1 beta (IL1β), cytokine-induced neutrophil chemoattractant 1 (CINC1), vascular endothelial growth factor (VEGF), WNT1-inducible-signaling pathway protein 1 (WISP1), and a tissue inhibitor of metalloproteinases 1 (TIMP1) have been reported by various investigators in the bleomycin rodent model. They are implicated in lung fibrosis by their involvement in one or more processes of myofibroblast activation and drive fibrosis pathology in rodents [15][16][17][18][19][20][21][22][23][24][25][26][27][28]. A growing number of preclinical studies have identified promising therapeutic options. ...
Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease characterized by the relentless deposition of extracellular matrix (ECM), causing lung distortions and dysfunction. Animal models of human IPF can provide great insight into the mechanistic pathways underlying disease progression and a means for evaluating novel therapeutic approaches. In this study, we describe the effect of bleomycin concentration on disease progression in the classical rat bleomycin model. In a dose–response study (1.5, 2, 2.5 U/kg i.t), we characterized lung fibrosis at day 14 after bleomycin challenge using endpoints including clinical signs, inflammatory cell infiltration, collagen content, and bronchoalveolar lavage fluid-soluble profibrotic mediators. Furthermore, we investigated fibrotic disease progression after 2 U/kg i.t. bleomycin administration at days 3, 7, and 14 by quantifying the expression of clinically relevant signaling molecules and pathways, epithelial mesenchymal transition (EMT) biomarkers, ECM components, and histopathology of the lung. A single bleomycin challenge resulted in a progressive fibrotic response in rat lung tissue over 14 days based on lung collagen content, histopathological changes, and modified Ashcroft score. The early fibrogenesis phase (days 3 to 7) is associated with an increase in profibrotic mediators including TGFβ1, IL6, TNFα, IL1β, CINC1, WISP1, VEGF, and TIMP1. In the mid and late fibrotic stages, the TGFβ/Smad and PDGF/AKT signaling pathways are involved, and clinically relevant proteins targeting galectin-3, LPA1, transglutaminase-2, and lysyl oxidase 2 are upregulated on days 7 and 14. Between days 7 and 14, the expressions of vimentin and α-SMA proteins increase, which is a sign of EMT activation. We confirmed ECM formation by increased expressions of procollagen-1Aα, procollagen-3Aα, fibronectin, and CTGF in the lung on days 7 and 14. Our data provide insights on a complex network of several soluble mediators, clinically relevant signaling pathways, and target proteins that contribute to drive the progressive fibrotic phenotype from the early to late phase (active) in the rat bleomycin model. The framework of endpoints of our study highlights the translational value for pharmacological interventions and mechanistic studies using this model.
... Collagen, a superfamily of extracellular matrix proteins with a triple helix structure, is vital for maintaining tissue structure and stability, and it plays a crucial role in mediating physiological processes such as tissue regeneration and wound healing [1][2][3][4][5]. The dysregulation of collagen remodeling has been widely recognized as a key underlying factor contributing to a variety of severe diseases such as tumors and fibrosis [6][7][8][9]. The aberrant synthesis and degradation of type I and type IV collagen have been closely implicated in the multifaceted processes of tumor progression, invasion, and metastasis [10][11][12][13]. ...
The accurate detection of multiplex collagen biomarkers is vital for diagnosing and treating various critical diseases such as tumors and fibrosis. Despite the attractive optical properties of quantum dots (QDs), it remains technically challenging to create stable and specific QDs-based probes for multiplex biological imaging. We report for the first time the construction of multi-color QDs-based peptide probes for the simultaneous fingerprinting of multiplex collagen biomarkers in connective tissues. A bipeptide system composed of a glutathione (GSH) host peptide and a collagen-targeting guest peptide (CTP) has been developed, yielding CTP-QDs probes that exhibit exceptional luminescence stability when exposed to ultraviolet irradiation and mildly acidic conditions. The versatile bipeptide system allows for facile one-pot synthesis of high-quality multicolor CTP-QDs probes, exhibiting superior selectivity in targeting critical collagen biomarkers including denatured collagen, type I collagen, type II collagen, and type IV collagen. The multicolor CTP-QDs probes have demonstrated remarkable efficacy in simultaneously fingerprinting multiple collagen types in diverse connective tissues, irrespective of their status, whether affected by injury, diseases, or undergoing remodeling processes. The innovative multicolor CTP-QDs probes offer a robust toolkit for the multiplex fingerprinting of the collagen suprafamily, demonstrating significant potential in the diagnosis and treatment of collagen-related diseases.
... Instead of replacing injured tissue with functional native cellular components and appropriate microstructure, this chronic condition is characterized by transdifferentiation of resident connective tissue fibroblasts or other progenitor cells into highly synthetic and contractile α-SMA + myofibroblasts [2,3], which produce excessive amounts of acellular, primarily collagen I-based extracellular matrix (ECM) that lacks functional properties of the uninjured tissue. We and others have shown that multifunctional members of the transforming growth factor β (TGF-β) family act as master regulators of fibrosis [4,5]. Several signaling pathways downstream of TGF-β (e.g., SMAD, MAPK, and PI3K/Akt-mediated signaling) engage in crosstalk with other upstream cytokines, leading to complex signaling paradigms involved in fibrotic healing [6][7][8]. ...
... (www.preprints.org) | NOT PEER-REVIEWED | Posted: 11 March 2024 doi:10.20944/preprints202403.0640.v15 ...
Fibrosis is a ubiquitous pathology, and prior studies have indicated that various artemisinin (ART) derivatives (including artesunate (AS), artemether (AM), and dihydroartemisinin (DHA)) can reduce fibrosis in vitro and in vivo. The medicinal plant, Artemisia annua L., is the natural source of ART and is widely used, especially in underdeveloped countries, to treat a variety of diseases including malaria, while A. afra contains no ART but is also antimalarial. Using human dermal fibroblasts (CRL-2097), we compared the effects of A. annua and A. afra tea infusions, ART, AS, AM, DHA, and a liver metabolite of ART, deoxyART (dART), on fibroblast viability and expression of key fibrotic marker genes after 1 and 4 days of treatment. AS, DHA, and Artemisia tea significantly reduced fibroblast viability at 1 and 4 d post-treatment. After 4 d post treatment, AS, DHA, and A. afra tea downregulated ACTA2, and upregulated MMP3, with other genes either being unaffected or differentially affected. ART and AM had no significant effect on either fibroblast viability or fibrotic gene expression. Although A. annua contains ART, it had a significantly greater anti-fibrotic effect than ART alone. Immunofluorescent staining for smooth muscle α-actin (α-SMA) correlated well with transcriptional responses of drug-treated fibroblasts. Together, proliferation, qPCR, and immunofluorescence results show that treatment with ART, AS, DHA, and the two Artemisia teas yield differing responses, including those related to fibrosis, in human dermal fibroblasts.
... Fibrotic diseases, such as idiopathic pulmonary fibrosis (IPF), are prevalent in the developed world and account for almost 50% of all deaths. IPF is the most common type of fibrotic interstitial lung disease (ILD) (Travis et al. 2013;Wynn 2007). IPF is a chronic and progressive lung disease that is characterized by the continuous reproduction of pulmonary fibroblasts and accumulation of extracellular matrix (ECM) causing respiratory system failure and eventually death (Chanda et al. 2019;Richeldi et al. 2017). ...
Fibrosis is a prevailing pathology in chronic diseases and accounts for 45% of deaths in developed countries. This condition is primarily identified by the transformation of fibroblasts into myofibroblasts and the overproduction of extracellular matrix (ECM) by myofibroblasts. Pterostilbene (PTS) is a natural analogue of resveratrol and is most commonly found in blueberries. Research has shown that PTS exerts a wide range of pharmacological effects, such as antioxidant, anti-inflammatory, and anticancer effects. As a result, PTS has the potential to prevent and cure numerous diseases. Emerging evidence has indicated that PTS can alleviate myocardial fibrosis, renal fibrosis, pulmonary fibrosis, hepatic fibrosis, and colon fibrosis via the inhibition of inflammation, oxidative stress, and fibrogenesis effects in vivo and in vitro, and the potential mechanisms are linked to various pathways, including transforming growth factor-β1 (TGF-β1)/small mother against decapentaplegic proteins (Smads) signalling, the reactive oxygen species (ROS)-driven Pitx2c/mir-15b pathway, nuclear factor kappa B (NF-κB) signalling, Kelch-like epichlorohydrin-associated protein-1 (Keap-1)/NF-E2-related factor-2 (Nrf2) cascade, the NLR family pyridine structure domain 3 (NLRP3) pathway, the Janus kinase-2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway, and the Src/STAT3 pathway. In this review, we comprehensively summarize the antifibrotic effects of PTS both in vivo and in vitro and the pharmacological mechanisms, pharmacokinetics, and toxicology of PTS and provide insights into and strategies for exploring promising agents for the treatment of fibrosis.
Graphical Abstract
... The fibrotic diseases comprise a highly heterogeneous group of pathologic conditions caused by multiple etiologic factors and involving numerous and complex molecular alterations that result in the excessive and disorganized accumulation of fibrotic tissue in various organs of the body causing abnormalities in their function and eventually leading to organ failure [1][2][3][4]. The fibrotic diseases are quite frequent and it has been estimated that, collectively, they may contribute to 40 to 45% of the overall mortality in the USA [1]. ...
... The fibrotic diseases comprise a highly heterogeneous group of pathologic conditions caused by multiple etiologic factors and involving numerous and complex molecular alterations that result in the excessive and disorganized accumulation of fibrotic tissue in various organs of the body causing abnormalities in their function and eventually leading to organ failure [1][2][3][4]. The fibrotic diseases are quite frequent and it has been estimated that, collectively, they may contribute to 40 to 45% of the overall mortality in the USA [1]. Despite their serious clinical consequences and high mortality, there is currently no effective therapy for these disorders and they remain among the most frequent causes of morbidity and mortality worldwide. ...
... In this regard, it has been shown that canonical Smad-mediated pathways are intimately involved in the potent stimulation of interstitial collagen gene expression and ECM protein production by TGF-β1 [11,38], however, non-Smad pathways (non-canonical) also participate in the regulation of expression of genes encoding these proteins by TGF-β1 [40]. Given the high mortality rates caused by the fibrotic diseases that have been estimated to be responsible for a much as 45% of the mortality in the Western developed countries [1] there is great interest in the identification of effective antifibrotic therapeutic interventions. In the present study, we demonstrated a potent inhibition of TGF-β1-induced stimulation of COL1A1 gene expression induced by in vitro treatment with the statin, Simvastatin and examined the molecular mechanisms responsible for these effects. ...
A potent stimulation of fibroblast collagen production is one of the crucial pleotropic effects of transforming growth factor β (TGF-β) and has been considered to play a crucial role in the pathogenesis of fibrotic diseases including Systemic Sclerosis and Pulmonary Fibrosis. This complex process involves numerous intracellular reactions mediated by canonical Smad-dependent or non-canonical pathways that transduce the extracellular stimuli into the nucleus. Here, we demonstrated that Simvastatin, a widely used statin, induces a potent inhibition of TGF-β1 profibrotic effects in cultured normal human dermal fibroblasts, and studied the molecular mechanisms involved in these effects. We also examined Simvastatin modulation of TGF-β1 induced fibroblast to myofibroblast transition. Normal human dermal fibroblasts were cultured with various concentrations of Simvastatin in the presence or absence of TGF-β1 (10ng/ml) for 24, 48, and 72 h. The effects of Simvastatin on TGF-β1 stimulation of COL1A1 expression and type 1 collagen production were examined. Assessment of Smad2/3 and Erk1/2 phosphorylation, chromatin immunoprecipitation assays for Sp1 transcription factor binding to the COL1A1 proximal promoter, siRNA-mediated RhoA knockdown, and F-actin immunofluorescence microscopy was performed to examine the molecular mechanisms involved.
... When epithelial and/or endothelial damage occurs, it triggers a series of intricate wound healing processes, facilitating a rapid restoration of homeostasis [3]. The increased endothelial permeability (i.e., vascular leak) and antifibrinolytic coagulation cascade (i.e., extravascular coagulation), which is responsible for the blood clot formation and preventing excessive blood loss, are primarily activated in response to inflammatory mediators that are released by damaged epithelial and/or endothelial cells [16]. Following this, an inflammation and immune activation phase ensues, wherein leukocytes such as macrophages, neutrophils, dendritic cells, and T/B cells are recruited, activated, and induced to proliferate by the chemokines and growth factors (GFs) that are produced by epithelial and/or endothelial cells, platelets, and early inflammatory cells [17,18]. ...
... Shortly after the initial inflammatory phase, myofibroblasts initiate the production of ECM components (collagen type I, fibronectin, elastin) and execute wound contracture. Meanwhile, endothelial cells actively facilitate the formation of new blood vessels [16]. And during the remodeling phase, the provisional deposited ECM is crosslinked and turned over by the action of lysyl oxidase (LOX) and becomes organized [25]. ...
... After the blood vessels have been restored, a gradual elimination of scar tissue occurs, creating a conducive environment for epithelial and endothelial cells to undergo division and migration and eventually restore the damaged tissue [25]. However, the presence of persistent inciting factors, such as chronic infection and inflammation, can trigger a prolonged wound healing response, including continuous activation of myofibroblasts and excessive accumulation of ECM components, culminating in the development of fibrosis [16]. ...
Fibrosis is a progressive pathological process participating in the progression of many diseases and can ultimately result in organ malfunction and failure. Around 45% of deaths in the United States are believed to be attributable to fibrotic disorders, and there are no favorable treatment regiments available to meet the need of blocking fibrogenesis, reversing established fibrosis, and curing diseases, especially in the terminal stage. Therefore, early detection and continuous monitoring provide valuable benefits for patients. Among all the advanced techniques developed in recent years for fibrosis evaluation, molecular imaging stands out with its distinct advantage of visualizing biochemical processes and patterns of target localization at the molecular and cellular level. In this review, we summarize the current state of the art in molecular imaging of benign fibrosis diseases. We will first introduce molecular pathways underlying fibrosis processes and potential targets. We will then elaborate on molecular probes that have been developed thus far, expounding on their mechanisms and current states of translational advancement. Finally, we will delineate the extant challenges impeding further progress in this area and the prospective benefits after overcoming these problems.
