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 idiopathic 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-beta1), chemokines (MCP-1, MIP-1beta), 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.

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Cellular and molecular mechanisms of fibrosis.

The integrin family of cell adhesion receptors regulates a diverse array of cellular functions crucial to the initiation, progression and metastasis of solid tumours. The importance of integrins in several cell types that affect tumour progression has made them an appealing target for cancer therapy. Integrin antagonists, including the alphavbeta3 and alphavbeta5 inhibitor cilengitide, have shown encouraging activity in Phase II clinical trials and cilengitide is currently being tested in a Phase III trial in patients with glioblastoma. These exciting clinical developments emphasize the need to identify how integrin antagonists influence the tumour and its microenvironment.

/pdf/integrins-in-cancer-biological-implications-and-therapeutic-2ejzg8fop4.pdf

Integrins in cancer: biological implications and therapeutic opportunities

Fibrosis is a key aspect of many chronic inflammatory diseases and can affect almost every tissue in the body. This review discusses recent advances in our understanding of the mechanisms of fibrosis, focusing on the innate and adaptive immune responses. It also describes how some of these crucial pathogenic pathways are being therapeutically targeted in the clinic.

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Mechanisms of fibrosis: therapeutic translation for fibrotic disease

The cause of fibrotic diseases, pathologies characterized by excessive production, deposition, and contraction of extracellular matrix, is unknown. To understand the molecular basis of fibrotic disease, it is essential to appreciate how matrix deposition is normally controlled and how this process is dysregulated in fibrogenesis. This review discusses the current state of knowledge concerning interactions among the profibrotic proteins transforming growth factor-β (TGF-β), connective tissue growth factor (CTGF, CCN2), and ED-A fibronectin (ED-A FN) and the antifibrotic proteins tumor necrosis factor-α (TNF-α) and γ-interferon (IFN-γ).—Leask, A., Abraham, D. J. TGF-β signaling and the fibrotic response.

https://faseb.onlinelibrary.wiley.com/doi/pdf/10.1096/fj.03-1273rev

TGF-beta signaling and the fibrotic response.

Epithelial and hematopoietic cells have a high turnover and their progenitor cells divide continuously, making them prime targets for genetic and epigenetic changes that lead to cell transformation and tumorigenesis. The consequent changes in cell behavior and responsiveness result not only from genetic alterations such as activation of oncogenes or inactivation of tumor suppressor genes, but also from altered production of, or responsiveness to, stimulatory or inhibitory growth and differentiation factors. Among these, transforming growth factor β (TGF-β) and its signaling effectors act as key determinants of carcinoma cell behavior. The autocrine and paracrine effects of TGF-β on tumor cells and the tumor micro-environment exert both positive and negative influences on cancer development. Accordingly, the TGF-β signaling pathway has been considered as both a tumor suppressor pathway and a promoter of tumor progression and invasion. Here we evaluate the role of TGF-β in tumor development and attempt to reconcile the positive and negative effects of TGF-β in carcinogenesis.

TGF-beta signaling in tumor suppression and cancer progression.

The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis.

We have shown that the integrin alphavbeta6 activates latent TGF-beta in the lungs and skin. We show here that mice lacking this integrin are completely protected from pulmonary edema in a model of bleomycin-induced acute lung injury (ALI). Pharmacologic inhibition of TGF-beta also protected wild-type mice from pulmonary edema induced by bleomycin or Escherichia coli endotoxin. TGF-beta directly increased alveolar epithelial permeability in vitro by a mechanism that involved depletion of intracellular glutathione. These data suggest that integrin-mediated local activation of TGF-beta is critical to the development of pulmonary edema in ALI and that blocking TGF-beta or its activation could be effective treatments for this currently untreatable disorder.

/pdf/tgf-b-is-a-critical-mediator-of-acute-lung-injury-5bo5292sx0.pdf

TGF-β is a critical mediator of acute lung injury

Summary The mechanisms involved in activating latent TGFb are not fully understood, but recently there has been Transforming growth factor b (TGFb) family members important progress in this area. Plasmin can activate are secreted in inactive complexes with a latency- latent TGFb in cell-free systems (Lyons et al., 1990) and associated peptide (LAP), a protein derived from the in cell culture (Sato et al., 1990). However, plasminogen N-terminal region of the TGFb gene product. Extracel- knockout mice display none of the pathologic features lular activation of these complexes is a critical but of TGFb knockout mice, suggesting that plasmin is unincompletely understood step in regulation of TGFb likely to be the only molecule activating TGFb. Reactive function in vivo. We show that TGFb1 LAP is a ligand oxygen species can activate TGFb in vitro (Barcellosfor the integrin avb6 and that avb6-expressing cells Hoff and Dix, 1996), and radiation treatment appears induce spatially restricted activation of TGFb1. This able to activate TGFb in vivo via this mechanism (Barfinding explains why mice lacking this integrin develop cellos-Hoff et al., 1994). Thrombospondin (TSP) 1 can exaggerated inflammation and, as we show, are pro- activate TGFb by binding to a defined site on LAP and tected from pulmonary fibrosis. These data identify a inducing a conformational change in the latent complex; novel mechanism for locally regulating TGFb1 function TGFb is then bound to TSP1 in an active state (Schultzin vivo by regulating expression of the avb6 integrin. Cherry and Murphy-Ullrich, 1993; Schultz-Cherry et al.,

Stephen L. Dalton

Papers

The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis.

TGF-β is a critical mediator of acute lung injury

The Integrin avb6 Binds and Activates Latent TGFb1: A Mechanism for Regulating Pulmonary Inflammation and Fibrosis