Fibrosis—a lethal component of systemic sclerosis

Frontiers in Molecular Biosciences, 2024

Editorial on the Research Topic Volume II: fibrotic tissue remodeling as a driver of disease pathogenesis Organ failure occurs when the resident tissues are unable to meet their metabolic needs and fail to perform their designated function. Many pathophysiological conditions can cause organ failure. Among them, fibrosis is a major contributor as it significantly perturbs the elasticity of the cells and renders them inefficient . Initially, the research regarding organ pathophysiology was more focused towards deciphering the pathways leading to the death of the participating cells. However, in the last two decades, research on fibrotic tissue remodelling gained significant attention as it started to unravel subtle changes within the organ microenvironment during disease progression, not just in end-stage organ failure. Fibrosis is a slowly developing phenomenon that eventually causes tissue degeneration, leading to devastating consequences in organs like heart, kidney, lung and liver . It occurs due to excessive accumulation of fibrous connective tissue in the extracellular matrix (ECM) area of injured tissues resulting in a fibrotic scar. The basic components of this fibrotic scar are-a mixture of fibrotic cells and collagens, chiefly types I and III. If this fibrotic tissue accumulation occurs beyond a threshold level, eventually organ malfunction occurs . Several pro-fibrotic factors and cytokines have been proposed to be the major mediators of fibrosis in various tissues (Al-Hatt et al., 2022). With the rapid advancement of techniques like ECM proteomics, several novel molecules are also being reported as causal factors in this process . In this issue, the objective was to delineate minute nuances of renal and cardiac fibrosis and their potential therapeutic measures. In this issue, two reviews, two original research articles and one perspective article encompassed the different aspects of fibrosis. Wang et al. contributed with a comprehensive review on renal fibrosis. The review summarized how renal fibrosis is a common manifestation of any chronic kidney disease. Although this occurs as a self-repair process in response to kidney damage, it seriously affects the renal filtration function and has almost no specific treatments . Hence, exploring targeted therapeutic measures is the need of the hour. It has been reported by many researchers that Histone deacetylases (HDACs) are major causal players in promoting renal fibrosis through epigenetic modifications involving non-histone . In this review, the

Journal of Clinical Investigation, 2018

Fibrosis is defined by the overgrowth, hardening, and/or scarring of various tissues and is attributed to excess deposition of extracellular matrix components including collagen. Fibrosis is the end result of chronic inflammatory reactions induced by a variety of stimuli including persistent infections, autoimmune reactions, allergic responses, chemical insults, radiation, and tissue injury. Although current treatments for fibrotic diseases such as idio-pathic pulmonary fibrosis, liver cirrhosis, systemic sclerosis, progressive kidney disease, and cardiovascular fibrosis typically target the inflammatory response, there is accumulating evidence that the mechanisms driving fibrogenesis are distinct from those regulating inflammation. In fact, some studies have suggested that ongoing inflammation is needed to reverse established and progressive fibrosis. The key cellular mediator of fibrosis is the myofibroblast, which when activated serves as the primary collagen-producing cell. Myofibroblasts are generated from a variety of sources including resident mesenchymal cells, epithelial and endothelial cells in processes termed epithelial/endothelial-mesenchymal (EMT/EndMT) transition, as well as from circulating fibroblast-like cells called fibrocytes that are derived from bone-marrow stem cells. Myofibroblasts are activated by a variety of mechanisms, including paracrine signals derived from lymphocytes and macrophages, autocrine factors secreted by myofibroblasts, and pathogen-associated molecular patterns (PAMPS) produced by pathogenic organisms that interact with pattern recognition receptors (i.e. TLRs) on fibroblasts. Cytokines (IL-13, IL-21, TGF-β1), chemokines (MCP-1, MIP-1β), angiogenic factors (VEGF), growth factors (PDGF), peroxisome proliferator-activated receptors (PPARs), acute phase proteins (SAP), caspases, and components of the renin–angiotensin–aldosterone system (ANG II) have been identified as important regulators of fibrosis and are being investigated as potential targets of antifibrotic drugs. This review explores our current understanding of the cellular and molecular mechanisms of fibrogenesis.

Frontiers in pharmacology, 2017

Fibrogenesis & Tissue Repair, 2012

Fibrosis in systemic sclerosis (SSc), a complex polygenic disease associated with autoimmunity and proliferative/ obliterative vasculopathy, shares pathobiologic features in common with other fibrosing illnesses, but also has distinguishing characteristics. Fibroblast activation induced by transforming growth factor-β (TGF-β), Wnts and innate immune receptors, along with oxidative stress and reactive oxygen species (ROS) are implicated in pathogenesis. On the other hand, the roles of endothelial-mesenchymal differentiation and bone marrow-derived fibrocytes remain to be established. Fibrotic responses are modulated by transcriptional activators and cofactors, epigenetic factors, and microRNAs that can amplify or inhibit ligand-induced signaling. The nuclear orphan receptor PPAR-γ appears to be important in governing the duration and intensity of fibroblast activation and mesenchymal progenitor cell differentiation, and defects in PPAR-γ expression or function in SSc may underlie the uncontrolled progression of fibrosis. Identifying the perturbations in signaling pathways and cellular differentiation programs responsible for tissue damage and fibrosis in SSc allows their selective targeting using novel compounds, or by innovative uses of already-approved drugs (drug repurposing).

Arthritis Research & Therapy, 2007

Fibrosis, characterized by excessive extracellular matrix accumulation, is a common feature of many connective tissue diseases, notably scleroderma (systemic sclerosis). Experimental studies suggest that a complex network of intercellular interactions involving endothelial cells, epithelial cells, fibroblasts and immune cells, using an array of molecular mediators, drives the pathogenic events that lead to fibrosis. Transforming growth factor-β and endothelin-1, which are part of a cytokine hierarchy with connective tissue growth factor, are key mediators of fibrogenesis and are primarily responsible for the differentiation of fibroblasts toward a myofibroblast phenotype. The tight skin mouse (Tsk-1) model of cutaneous fibrosis suggests that numerous other genes may also be important. CTD = connective tissue disease; CTGF = connective tissue growth factor; ECM = extracellular matrix; ET = endothelin; MAGP = microfibrilassociated glycoprotein; SMA = smooth muscle actin; SSc = systemic sclerosis; TGF = transforming growth factor; Tsk = tight skin.

Pathobiol Review, 2014

2010

Fibrosis of the kidney is caused by the prolonged injury and deregulation of normal wound healing and repair processes, and by an excess deposition of extracellular matrices. Despite intensive research, our current understanding of the precise mechanism of fibrosis is limited. There is a connection between fibrotic events involving inflammatory and noninflammatory glomerulonephritis, inflammatory cell infiltration, and podocyte loss. The current review will discuss the inflammatory response after renal injury that leads to fibrosis in relation to non-inflammatory mechanisms.

Laboratory Investigation, 2012

Pulmonary fibrosis is a hallmark of several systemic diseases such as systemic sclerosis. Initiation and early development is not well characterized, as initiation usually is unnoticed in patients, yet fibrosis has been considered a late event, occurring after an inflammatory phase. By utilizing an animal model, the starting point can be defined and the initiation process and early development thoroughly investigated. To investigate these processes from a systemic perspective, we choose a systemic administration route, instead of the more commonly used local administration. The aim of this work was to study the initiation of pulmonary fibrosis in an animal model and to investigate early alterations in connective tissue, cell turnover and acute immune response in lung parenchyma. Animals were injected subcutaneously with bleomycin, three times a week (w) for 1-4w (controls received saline). Total collagen was histologically assessed by Picro Sirius Red and Masson's Trichrome, collagen production by antibodies directed against N-terminal of procollagens I and III, proliferation by labeling with proliferating cell nuclear antigen, apoptosis by TUNEL and innate immunity by detecting neutrophils and macrophages. Total collagen was significantly increased at 1, 2 and 4w compared with controls. Procollagen I, was increased at 1w and remained increased, whereas procollagen III-staining was increased at 2w, compared with controls. Myofibroblasts were increased at all times as were proliferation, whereas apoptosis was increased from 2w. Neutrophils peaked at 1w (2779±820 cells/mm 2 ) and gradually decreased, whereas macrophages peaked at 2w (135±29 cells/mm 2 ). Subcutaneously administered bleomycin induces rapid alterations in connective tissue and cell turnover, suggesting a plasticity of the connective tissue. A transient neutrophilia is detected and increased number of macrophages likely represents a clearance process of said neutrophils. The study suggests fibrosis initiation and acute inflammation to occur in parallel in this model. Laboratory Investigation (2012) 92, 917-925;

Modern rheumatology, 2018

Extracellular matrix (ECM) plays a crucial role in the regulation of both physiological and pathological angiogenesis. ECM homeostasis and function is ensuring by the tightly regulation of the different ECM components including, collagens, proteoglycans and a variety of different glycoproteins. An altered expression of the above ECM molecules as well as an imbalance between the action of matrix remodeling enzymes and their tissue inhibitors is known to be responsible for impaired angiogenesis and fibrosis. Systemic Sclerosis (SSc) is an autoimmune disease characterized by micro-angiopathy, failure of reparative angiogenesis and excessive fibrosis of the skin and various internal organs, dues to an increased production of ECM. A comprehensive search through Medline/PubMed and Scopus was performed for English-language original papers, using the keywords related to ECM components and SSc. This review will analyze the role played by ECM components in the deregulation of angiogenic mecha...