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Overview of wound repair and fibrosis.Epithelial and/or endothelial damage caused by various insults triggers complex interconnected wound-healing programs to quickly restore homeostasis. The coagulation pathway, which functions to stem blood loss, is triggered first, followed by acute inflammation and activation of innate immune mediators such as resident macrophages, neutrophils and dendritic cells. Epithelial and innate immune cell–derived cytokines subsequently influence the activation of the adaptive immune response. The tissue damage can also directly activate the adaptive immune response. Inflammatory and immune mediators (cytokines, chemokines and free radicals) attempt to eliminate the inciting factor while activating the resident quiescent fibroblasts into myofibroblasts that orchestrate angiogenesis and production of ECM components. Failure to adequately contain or eliminate the inciting factors can exacerbate the inflammatory response and lead to a chronic wound-healing response, with continued tissue damage, repair and regeneration, ultimately resulting in fibrosis. TSLP, thymic stromal lymphopoietin; Ab, antibody; PMN, polymorphonuclear leukocyte; EOS, eosinophil; Baso, basophil; Mast, mast cell.
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Fibrosis is a pathological feature of most chronic inflammatory diseases. Fibrosis, or scarring, is defined by the accumulation of excess extracellular matrix components. If highly progressive, the fibrotic process eventually leads to organ malfunction and death. Fibrosis affects nearly every tissue in the body. Here we discuss how key components o...
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The current research interest in the therapeutic management of wound healing is to attain a complete and rapid healing of chronic wounds with minimal scar. There is an urge to apply a novel approach to prompt the wound healing process because of the huge economic burden worldwide. Hence, the current article initially focuses on the management and c...
In this review we explore stem cell function in wounds that are resistant to healing, such as burn injuries and diabetes wounds. Diabetic ulcers are of interest due their remarkable resistance to heal; severe thermal burns are addressed due to critical need for effective therapies for the prevention shock and improvement in scarring. Cell-based the...
Citations
... Idiopathic Pulmonary Fibrosis (IPF) is a progressive, fatal disease, which has a median survival of 3.5 years and affects approximately 150,000 people in the United States (1,2). A defining feature of IPF is the Transforming Growth Factor-β (TGF-β)-dependent activation of lung fibroblasts, leading to the excessive secretion of extracellular matrix proteins, including collagen (3)(4)(5)(6). Activated fibroblasts are the primary cells responsible for the structural remodeling and impairment of lung function characteristic of IPF and thus represent a key therapeutic target for the treatment of the disease (6)(7)(8). ...
Idiopathic pulmonary fibrosis is a fatal disease characterized by the TGF-β-dependent activation of lung fibroblasts, leading to excessive deposition of collagen proteins and progressive replacement of healthy lung with scar tissue. We and others have shown that fibroblast activation is supported by metabolic reprogramming, including the upregulation of the de novo synthesis of glycine, the most abundant amino acid found in collagen protein. How fibroblast metabolic reprogramming is regulated downstream of TGF-β is incompletely understood. We and others have shown that TGF-β-mediated activation of the Mechanistic Target of Rapamycin Complex 1 (mTORC1) and downstream upregulation of Activating Transcription Factor 4 (ATF4) promote increased expression of the enzymes required for de novo glycine synthesis; however, whether mTOR and ATF4 regulate other metabolic pathways in lung fibroblasts has not been explored. Here, we used RNA sequencing to determine how both ATF4 and mTOR regulate gene expression in human lung fibroblasts following TGF-β. We found that ATF4 primarily regulates enzymes and transporters involved in amino acid homeostasis as well as aminoacyl-tRNA synthetases. mTOR inhibition resulted not only in the loss of ATF4 target gene expression, but also in the reduced expression of glycolytic enzymes and mitochondrial electron transport chain subunits. Analysis of TGF-β-induced changes in cellular metabolite levels confirmed that ATF4 regulates amino acid homeostasis in lung fibroblasts while mTOR also regulates glycolytic and TCA cycle metabolites. We further analyzed publicly available single cell RNAseq data sets and found increased expression of ATF4 and mTOR metabolic targets in pathologic fibroblast populations from the lungs of IPF patients. Our results provide insight into the mechanisms of metabolic reprogramming in lung fibroblasts and highlight novel ATF4 and mTOR-dependent pathways that may be targeted to inhibit fibrotic processes.
... Bundan tashqari, Wynn T. A. [8] tadqiqot xulosalariga ko'ra Th-17-limfositlarning yuqori konsentratsiyasi immun javobni kuchayishiga va orbital fibroz jarayonini tezlashishiga olib keladi. L.Barrett va R. L. Anderson boshchiligidagi tadqiqot guruhining ta'kidlashicha EOP patogenezida adipogenez kechroq yuzaga keladigan jarayon hisoblanadi, chunki EOP davomiyligi ortgan sari orbital yog' hajmi ortib boradi [9,10]. ...
Dolzarbligi. Butun jahon so‘g‘liqni saqlash tashkiloti (BJSST) statistik ma’lumotlariga ko‘ra dunyo aholisi orasida endokrin patologiya hisoblangan qalqonsimon bez kasalliklari tarqalishi jihatidan qandli diabetdan keyingi ikkinchi o‘rinda turadi. Tireotoksikoz butun dunyo bo‘ylab voyaga yetgan aholining 2,5 foizida, shuningdek ayollar o‘rtasida tireotoksikoz kasalligi erkaklarga nisbatan 10 baravar ko‘p kuzatiladi. Tadqiqot maqsadi. Keyingi 10–15 yil mobaynida tireotoksikoz kasalligida ko’rish a’zolarida kuzatiladigan o’zgarishlar to’g’risidagi ma’lumotlarni o’z ichiga olgan ilmiy adabiyotlar tahlilini o’tkazish. Material va usullar. Respublikamizda va chet ellardagi nufuzli nashrlarda chop etilgan ilmiy maqolalar hamda ilmiy axborot resurs manbalaridan foydalanilgan holda ularni o’rganish. Natijalar va xulosa. Endokrin oftalmopatiya tashxisli bemorlarda UTT, KT va MRT diagnostik tekshiruvlari ko‘z olmasi va orbita yumshoq to‘qimalarining morfologik xususiyatlarini o‘rgnish va mazkur patologiyani erta bosqichlarda aniqlash imkonini beradi. Tekshiruv turlari ichida UTT inson tanasiga salbiy ta’sirlarining yo‘qligi va informativ metod sifatida klinik amaliyotda keng foydalanishga tavsiya etilishi mumkin.
... Fibrotic scarring is a widespread phenomenon affecting virtually every tissue in the body. It often emerges as a common pathological consequence of various chronic diseases [2,3]. Dysfunctional healing through fibrotic scarring can lead to structural abnormalities within organs. ...
Tissue fibrosis represents a complex pathological condition characterized by the excessive accumulation of collagenous extracellular matrix (ECM) components, resulting in impaired organ function. Fibroblasts are central to the fibrotic process and crucially involved in producing and depositing collagen-rich ECM. Apart from their primary function in ECM synthesis, fibroblasts engage in diverse activities such as inflammation and shaping the tissue microenvironment, which significantly influence cellular and tissue functions. This review explores the role of Yes-associated protein (Yap) and Transcriptional co-activator with PDZ-binding motif (Taz) in fibroblast signaling and their impact on tissue fibrosis. Gaining a comprehensive understanding of the intricate molecular mechanisms of Yap/Taz signaling in fibroblasts may reveal novel therapeutic targets for fibrotic diseases.
... These ndings indicate that applying LiESWT to the pelvis may have affected the urethra rather than the bladder. Tissue brosis is caused by excessive deposition of extracellular matrix due to myo broblast proliferation associated with chronic in ammation [20] . In rabbits, extracorporeal shock wave therapy reduced the number of collagen bundles by suppressing myo broblast expression [21]. ...
Purpose
To investigate the effects of low-intensity extracorporeal shock wave therapy (LiESWT) on bladder and urethral dysfunction with detrusor overactivity and detrusor sphincter dyssynergia (DSD) resulting from spinal cord injury (SCI).
Methods
At 3 weeks after Th9 spinal cord transection, LiESWT was performed on the bladder and urethra of adult female Sprague Dawley rats with 300 shots of 2 Hz and an energy flux density of 0.12 mJ/mm², repeated four times every 3 days, totaling 1,200 shots. Six weeks postoperatively, a single cystometrogram (CMG) and an external urethral sphincter electromyogram (EUS-EMG) were simultaneously recorded in awake animals, followed by histological evaluation.
Results
Voiding efficiency significantly improved in the LiESWT group (71.2%) compared to that in the control group (51.8%). The reduced EUS activity ratio during voiding (duration of reduced EUS activity during voiding/ EUS contraction duration with voiding + duration of reduced EUS activity during voiding) was significantly higher in the LiESWT group (66.9%) compared to the control group (46.3%). Immunohistochemical examination revealed that fibrosis in the urethral muscle layer was reduced, and S-100 stained-positive area, a Schwann cell marker, was significantly increased in the urethra of the LiESWT group.
Conclusion
LiESWT targeting the urethra after SCI can restore the EUS-EMG tonic activity during voiding, thereby partially ameliorating DSD. Therefore, LiESWT is a promising approach for treating bladder and urethral dysfunction following SCI.
... Therefore, we conducted a study on a selected group of patients with paroxysmal TN with CCP, who exhibited arachnoiditis findings during surgery. Microscopic histopathological findings in the biopsies of the arachnoid membrane, such as chronic fibrosis, hyperplasia of neurothelial cells, and dystrophic calcifications, are alterations commonly associated with the chronic inflammatory response [20][21][22]. Additionally, immunostaining revealed the involvement of S100, proteins associated with neoplasms and inflammatory disorders, and CD20, a transmembrane phosphoprotein that plays a role in B lymphocyte activation and differentiation [23,24]. ...
... Several research studies indicated that incidents of foreign entities with cytopathic effects led to early pulmonary epithelial and endothelial injury that calls for various inflammatory and immune effector cells by releasing a network of inflammatory mediators, cytokines, chemokines, and growth factors resulting in the aid of alveolar damage. Further, the impairment in this healing process contributes to the non-reversible fibrosis [58,59]. Upon activation by inflammatory stimuli (either bacterial or viral infections), macrophages and monocytes are stimulated and secrets the major cytokines (such as TNF-α, interleukins, and chemokines (CCL2, CCL8, and CCL7) to fight against the pathogens [60][61][62][63]. ...
Introduction
Inflammation and oxidative stress are key factors in the development of pulmonary fibrosis (PF) by promoting the differentiation of fibroblasts through modulating various pathways including Wnt/β-catenin, TGF-β and mTOR signalling.
Objective and methods
This study aimed to evaluate the effects and elucidate the mechanisms of vistusertib (VSB) in treating pulmonary inflammation/fibrosis, specifically by targeting the mTOR pathway using various in vitro and in vivo models.
Results
Lipopolysaccharide (LPS)-induced inflammation model in macrophages (RAW 264.7), epithelial (BEAS-2B) and endothelial (HMVEC-L) cells revealed that treatment with VSB significantly reduced the IL-6, TNF-α, CCL2, and CCL7 expression. TGF-β induced differentiation was also significantly reduced upon VSB treatment in fibrotic cells (LL29 and DHLF). Further, bleomycin-induced inflammation and fibrosis models demonstrated that treatment with VSB significantly ameliorated the severe inflammation, and lung architectural distortion, by reducing the inflammatory markers expression/levels, inflammatory cells and oxidative stress indicators. Further, fibrosis model results exhibited that, VSB treatment significantly reduced the α-SMA, collagen and TGF-β expressions, improved the lung architecture and restored lung functions.
Conclusion
Overall, this study uncovers the anti-inflammatory/anti-fibrotic effects of VSB by modulating the mTOR activation. Although VSB was tested for lung fibrosis, it can be tested for other fibrotic disorders to improve the patient’s survival and quality of life.
... Fibrosis is the excessive accumulation of the extracellular matrix component proteins, such as collagens, fibronectins, and smooth muscle actins, ultimately leading to organ dysfunctions [95]. Bovine MEVs were uptaken by hepatic stellate cells (HSC), which are the cells that secrete pro-fibrotic bioactive molecules in liver injury and inhibit their proliferation via the overexpression of miR-148, in a mice model [96]. ...
Milk is a fundamental component of the human diet, owing to its substantial nutritional content. In addition, milk contains nanoparticles called extracellular vesicles (EVs), which have indicated their potential beneficial roles such as cell-to-cell communication, disease biomarkers, and therapeutics agents. Amidst other types of EVs, milk EVs (MEVs) have their significance due to their high abundance, easy access, and stability in harsh environmental conditions, such as low pH in the gut. There have been plenty of studies conducted to evaluate the therapeutic potential of bovine MEVs over the past few years, and attention has been given to their engineering for drug delivery and targeted therapy. However, there is a gap between the experimental findings available and clinical trials due to the many challenges related to EV isolation, cargo, and the uniformity of the material. This review aims to provide a comprehensive comparison of various techniques for the isolation of MEVs and offers a summary of the therapeutic potential of bovine MEVs described over the last decade, analyzing potential challenges and further applications. Although a number of aspects still need to be further elucidated, the available data point to the role of MEVs as a potential candidate with therapeutics potential, and the supplementation of MEVs would pave the way to understanding their in-depth effects.
... FGFR-2 and FGFR-4 greatly enhance endothelial cell production of urokinase-type plasminogen activator (uPa), facilitating new vasculature formation. FGF-2, FGF-8, and FGF-10 isoforms cause chemotaxis, endothelial cell migration, and proliferation [19]. bFGF induces corneal angiogenesis by regulating VEGF-A, VEGF-C, and VEGF-D expression [20,21]. ...
... Steroids are immunosuppressive agents that control this immune response and reduce tissue damage. This immunosuppressive effect is particularly relevant in fibrotic disorders with an autoimmune component, such as systemic sclerosis [17][18][19]30]. ...
... In most studies reviewed, ocular hypertension developed in children within 1 month of starting steroid treatment [39]. With prolonged steroid therapy, the prevalence of secondary fungal and viral eye infections increases, and central serous chorioretinopathy (CSR) might develop [19,40]. ...
Corneal neovascularization can impair vision and result in a poor quality of life. The pathogenesis involves a complex interplay of angiogenic factors, notably vascular endothelial growth factor (VEGF). This review provides a comprehensive overview of potential therapies for corneal neovascularization, covering tissue inhibitors of metalloproteinases (TIMPs), transforming growth factor beta (TGF-β) inhibitors, interleukin-1L receptor antagonist (IL-1 Ra), nitric oxide synthase (NOS) isoforms, galectin-3 inhibitors, retinal pigment epithelium-derived factor (PEDF), platelet-derived growth factor (PDGF) receptor inhibitors, and surgical treatments. Conventional treatments include anti-VEGF therapy and laser interventions, while emerging therapies such as immunosuppressive drugs (cyclosporine and rapamycin) have been explored. Losartan and decorin are potential antifibrotic agents that mitigate TGF-β-induced fibrosis. Ocular nanosystems are innovative drug-delivery platforms that facilitate the targeted release of therapeutic agents. Gene therapies, such as small interfering RNA and antisense oligonucleotides, are promising approaches for selectively inhibiting angiogenesis-related gene expression. Aganirsen is efficacious in reducing the corneal neovascularization area without significant adverse effects. These multifaceted approaches underscore the corneal neovascularization management complexity and highlight ideas for enhancing therapeutic outcomes. Furthermore, the importance of combination therapies and the need for further research to develop specific inhibitors while considering their therapeutic efficacy and potential adverse effects are discussed.
... Fibrotic tissue remodeling is characterized by excessive accumulation of extracellular matrix (ECM) components and uncontrolled proliferation of myofibroblasts, leading to epithelial death, loss of organ architecture, and functional decline. Fibrosis typically is a consequence of chronic disease such as hypertension, diabetes, and long-term inflammatory conditions [1,2]. Approximately 45% of deaths in the United States are attributable to fibrotic diseases [3]. ...
Fibrotic remodeling is the primary driver of functional loss in chronic kidney disease, with no specific anti-fibrotic agent available for clinical use. Transglutaminase 2 (TG2), a wound response enzyme that irreversibly crosslinks extracellular matrix proteins causing dysregulation of extracellular matrix turnover, is a well-characterized anti-fibrotic target in the kidney. We describe the humanization and characterization of two anti-TG2 monoclonal antibodies (zampilimab [hDC1/UCB7858] and BB7) that inhibit crosslinking by TG2 in human in vitro and rabbit/cynomolgus monkey in vivo models of chronic kidney disease. Determination of zampilimab half-maximal inhibitory concentration (IC50) against recombinant human TG2 was undertaken using the KxD assay and determination of dissociation constant (Kd) by surface plasmon resonance. Efficacy in vitro was established using a primary human renal epithelial cell model of tubulointerstitial fibrosis, to assess mature deposited extracellular matrix proteins. Proof of concept in vivo used a cynomolgus monkey unilateral ureteral obstruction model of chronic kidney disease. Zampilimab inhibited TG2 crosslinking transamidation activity with an IC50 of 0.25 nM and Kd of <50 pM. In cell culture, zampilimab inhibited extracellular TG2 activity (IC50 119 nM) and dramatically reduced transforming growth factor-β1-driven accumulation of multiple extracellular matrix proteins including collagens I, III, IV, V, and fibronectin. Intravenous administration of BB7 in rabbits resulted in a 68% reduction in fibrotic index at Day 25 post-unilateral ureteral obstruction. Weekly intravenous administration of zampilimab in cynomolgus monkeys with unilateral ureteral obstruction reduced fibrosis at 4 weeks by >50%, with no safety signals. Our data support the clinical investigation of zampilimab for the treatment of kidney fibrosis.
... Fibrosis is a pathological condition that can affect almost every tissue of the body, consisting of a delayed deposition and remodeling of the extracellular matrix (ECM) by fibroblasts. It is related to persistent infections, genetic disorders, repeated exposures to chemical substances and toxins, metabolic disorders (hypertension, hypercholesterolemia, diabetes, obesity), and minor human-leukocyte antigen mismatches in transplants [1][2][3][4]. Fibrosis, which often arises from a damage-repairing process, consists of two phases: a regenerative phase characterized by the replacement of injured cells with new ones of the same cytotype, and a fibroplasia phase characterized by the replacement of the normal parenchymal tissue with connective tissue [5,6]. Fibrosis is mainly triggered by a chronic stimulus mediated by pro-inflammatory cytokines. ...
Fibrosis is a pathological condition consisting of a delayed deposition and remodeling of the extracellular matrix (ECM) by fibroblasts. This deregulation is mostly triggered by a chronic stimulus mediated by pro-inflammatory cytokines, such as TNF-α and IL-1, which activate fibroblasts. Due to their anti-inflammatory and immunosuppressive potential, dental pulp stem cells (DPSCs) could affect fibrotic processes. This study aims to clarify if DPSCs can affect fibroblast activation and modulate collagen deposition. We set up a transwell co-culture system, where DPSCs were seeded above the monolayer of fibroblasts and stimulated with LPS or a combination of TNF-α and IL-1β and quantified a set of genes involved in inflammasome activation or ECM deposition. Cytokines-stimulated co-cultured fibroblasts, compared to unstimulated ones, showed a significant increase in the expression of IL-1β, IL-6, NAIP, AIM2, CASP1, FN1, and TGF-β genes. At the protein level, IL-1β and IL-6 release as well as FN1 were increased in stimulated, co-cultured fibroblasts. Moreover, we found a significant increase of MMP-9 production, suggesting a role of DPSCs in ECM remodeling. Our data seem to suggest a crosstalk between cultured fibroblasts and DPSCs, which seems to modulate genes involved in inflammasome activation, ECM deposition, wound healing, and fibrosis.
