Complex cytokine regulation of tissue fibrosis

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.

Science Translational Medicine, 2013

Fibrosis, or the accumulation of extracellular matrix molecules that make up scar tissue, is a common feature of chronic tissue injury. Pulmonary fibrosis, renal fibrosis, and hepatic cirrhosis are among the more common fibrotic diseases, which in aggregate represent a huge unmet clinical need. New appreciation of the common features of fibrosis that are conserved among tissues has led to a clearer understanding of how epithelial injury provokes dysregulation of cell differentiation, signaling, and protein secretion. At the same time, discovery of tissue-specific features of fibrogenesis, combined with insights about genetic regulation of fibrosis, has laid the groundwork for biomarker discovery and validation, and the rational identification of mechanism-based antifibrotic drugs. Together, these advances herald an era of sustained focus on translating the biology of fibrosis into meaningful improvements in quality and length of life in patients with chronic fibrosing diseases.

Frontiers in pharmacology, 2017

Current Research in Pharmacology and Drug Discovery, 2021

Fibrosis is a common condition that can affect all body tissues, driven by unresolved tissue inflammation and resulting in tissue dysfunction and organ failure that could ultimately lead to death. A myriad of factors are thought to contribute to fibrosis and, although it is relatively common, treatments focusing on reversing fibrosis are few and far between. The process of fibrosis involves a variety of cell types, including epithelial, endothelial, and mesenchymal cells, as well as immune cells, which have been shown to produce pro-fibrotic cytokines. Advances in our understanding of the molecular mechanisms of inflammation-driven tissue fibrosis and scar formation have led to the development of targeted therapeutics aiming to prevent, delay, or even reverse tissue fibrosis. In this review, we describe promising targets and agents in development, with a specific focus on cytokines that have been well-described to play a role in fibrosis: IL-1, TNF-α, IL-6, and TGF-β. An array of small molecule inhibitors, natural compounds, and biologics have been assessed in vivo, in vivo, and in the clinic, demonstrating the capacity to either directly interfere with pro-fibrotic pathways or to block intracellular enzymes that control fibrosis-related signaling pathways. Targeting pro-fibrotic cytokines, potentially via a multipronged approach, holds promise for the treatment of inflammation-driven fibrotic diseases in numerous organs. Despite the complexity of the interplay of cytokines in fibrotic tissues, the breadth of the currently ongoing research targeting cytokines suggests that these may hold the key to mitigating tissue fibrosis and reducing organ damage in the future.

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2013

The fibrotic diseases encompass a wide spectrum of entities including such multisystemic diseases as systemic sclerosis, nephrogenic systemic fibrosis and sclerodermatous graft versus host disease, as well as organ-specific disorders such as pulmonary, liver, and kidney fibrosis. Collectively, given the wide variety of affected organs, the chronic nature of the fibrotic processes, and the large number of individuals suffering their devastating effects, these diseases pose one of the most serious health problems in current medicine and a serious economic burden to society. Despite these considerations there is currently no accepted effective treatment. However, remarkable progress has been achieved in the elucidation of their pathogenesis including the identification of the critical role of myofibroblasts and the determination of molecular mechanisms that result in the transcriptional activation of the genes responsible for the fibrotic process. Here we review the origin of the myofibroblast and discuss the crucial regulatory pathways involving multiple growth factors and cytokines that participate in the pathogenesis of the fibrotic process. Potentially effective therapeutic strategies based upon this new information are considered in detail and the major challenges that remain and their possible solutions are presented. It is expected that translational efforts devoted to convert this new knowledge into novel and effective anti-fibrotic drugs will be forthcoming in the near future. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.

2000

Seminars in Liver Disease, 2010

Macrophages are found in close proximity with collagen-producing myofibroblasts and indisputably play a key role in fibrosis. They produce profibrotic mediators that directly activate fibroblasts, including transforming growth factor-β1 and platelet-derived growth factor, and control extracellular matrix turnover by regulating the balance of various matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases. Macrophages also regulate fibrogenesis by secreting chemokines that recruit fibroblasts and other inflammatory cells. With their potential to act in both a pro-and antifibrotic capacity, as well as their ability to regulate the activation of resident and recruited myofibroblasts, macrophages and the factors they express are integrated into all stages of the fibrotic process. These various, and sometimes opposing, functions may be performed by distinct macrophage subpopulations, the identification of which is a growing focus of fibrosis research. Although collagen-secreting myofibroblasts once were thought of as the master "producers" of fibrosis, this review will illustrate how macrophages function as the master "regulators" of fibrosis. Keywords Fibrosis; inflammation; collagen; wound healing; stellate cell; myofibroblasts; interleukin-13; transforming growth factor beta; tumor necrosis factor; interleukin-1; interleukin-17; arginase; Relm-alpha; chitinase Fibrosis results when normal wound-healing responses persist or are not regulated properly, usually in response to some type of repeated injury. For example, the primary causes of liver fibrosis include persistent hepatitis C virus infection, chronic infections with the helminth parasites Schistosoma mansoni and Schistosoma japonicum, alcohol abuse, and nonalcoholic steatohepatitis. Following acute liver injury, a beneficial wound-healing mechanism regenerates damaged parenchymal cells, including hepatocytes, to replace necrotic tissue and apoptotic cells. But, when the cause of injury persists, extracellular matrix (ECM) components like fibrillar collagens accumulate to high levels, ultimately leading to advanced fibrosis or cirrhosis and hepatocellular dysfunction, as well as hepatic insufficiency and portal hypertension caused by increased intrahepatic resistance to blood flow. In diseased liver, most ECM components are produced by hepatic stellate cells (HSCs), also known as lipocytes, Ito cells, or perisinusoidal cells. HSCs respond to injury by differentiating into myofibroblast-like cells with contractile, proinflammatory, and potent fibrogenic activities. In addition, several groups have identified important roles for bone marrow-derived stem

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.

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

Matrix Biology, 2013

Collagen deposition is a key process during idiopathic pulmonary fibrosis; however, little is known about the dynamics of collagen formation during disease development. Tissue samples of early stages of human disease are not readily available and it is difficult to identify changes in collagen content, since standard collagen analyses do not distinguish between 'old' and 'new' collagen. Therefore, the current study aimed to (i) investigate the dynamics of new collagen formation in mice using bleomycin-induced lung fibrosis in which newly synthesized collagen was labeled with deuterated water and (ii) use this information to identify genes and processes correlated to new collagen formation. Lung fibrosis was induced in female C57Bl/6 mice by bleomycin instillation. Animals were sacrificed at 1 to 5 weeks after fibrosis induction. Collagen synthesized during the week before sacrifice was labeled with deuterium by providing mice with deuterated drinking water. After sacrifice, we collected lung tissue for microarray analysis, determination of new collagen formation, and histology. Furthermore, we measured in vitro the expression of selected genes after transforming growth factor (TGF) β 1 -induced myofibroblast differentiation. Deuterated water labeling showed a strong increase in new collagen formation already during the first week after fibrosis induction and a complete return to baseline at five weeks. Correlation of new collagen formation data with gene expression data allowed us to create a gene expression signature of fibrosis within the lung and revealed fibrosis-specific processes, among which proliferation. This was confirmed by measuring cell proliferation and collagen synthesis simultaneously using deuterated water incorporation in a separate experiment. Furthermore, new collagen formation strongly correlated with gene expression of e.g. elastin, Wnt-1 inducible signaling pathway protein 1, tenascin C, lysyl oxidase, and type V collagen. Gene expression of these genes was upregulated in vitro in fibroblasts stimulated with TGFβ 1 . Together, these data demonstrate, using a novel combination of technologies, that the core process of fibrosis, i.e. the formation of new collagen, correlates not only with a wide range of genes involved in general extracellular matrix production and modification but also with cell proliferation. The observation that the large majority of the genes which correlated with new collagen formation also were upregulated during TGFβ 1induced myofibroblast differentiation provides further evidence for their involvement in fibrosis.