BBA - Molecular Basis of Disease (v.1832, #7)
Editorial Board (i).
Preface to BBA issue devoted to fibrosis by Scott L. Friedman (865).
Molecular assembly and mechanical properties of the extracellular matrix: A fibrous protein perspective by Lisa D. Muiznieks; Fred W. Keeley (866-875).
The extracellular matrix is an integral and dynamic component of all tissues. Macromolecular compositions and structural architectures of the matrix are tissue-specific and typically are strongly influenced by the magnitude and direction of biomechanical forces experienced as part of normal tissue function. Fibrous extracellular networks of collagen and elastin provide the dominant response to tissue mechanical forces. These matrix proteins enable tissues to withstand high tensile and repetitive stresses without plastic deformation or rupture. Here we provide an overview of the hierarchical molecular and supramolecular assembly of collagens and elastic fibers, and review their capacity for mechanical behavior in response to force. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.► The extracellular matrix is rich in collagen and elastic fibers. ► Collagen provides tissues with tensile strength to resist deformation. ► Elastin provides tissues with elasticity to withstand repetitive stress. ► We review collagen and elastin assembly and mechanical properties.
Keywords: Extracellular matrix; Collagen; Elastin; Self-assembly; Tensile strength; Elastic modulus;
Extracellular matrix degradation in liver fibrosis: Biochemistry and regulation by John P. Iredale; Alexandra Thompson; Neil C. Henderson (876-883).
Fibrosis is a highly conserved wound healing response and represents the final common pathway of virtually all chronic inflammatory injuries. Over the past 3 decades detailed analysis of hepatic extracellular matrix synthesis and degradation using approaches incorporating human disease, experimental animal models and cell culture have highlighted the extraordinarily dynamic nature of tissue repair and remodelling in this solid organ. Furthermore emerging studies of fibrosis in other organs demonstrate that basic common mechanisms exist, suggesting that bidirectionality of the fibrotic process may not solely be the preserve of the liver. In this review we will examine the cellular and molecular mechanisms that govern extracellular matrix degradation and fibrosis resolution, and highlight how manipulation of these processes may result in the development of effective anti-fibrotic therapies. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.► Tissue fibrosis represents the final common pathway of virtually all chronic inflammatory injuries. ► Fibrosis is a highly dynamic process involving both matrix synthesis and degradation. ► Manipulation of matrix synthesis and degradation may result in the development of effective anti-fibrotic therapies.
Keywords: Fibrosis; Matrix; Metalloproteinase; Macrophage; Hepatic stellate cell;
Tissue mechanics and fibrosis by Rebecca G. Wells (884-890).
Mechanical forces are essential to the development and progression of fibrosis, and are likely to be as important as soluble factors. These forces regulate the phenotype and proliferation of myofibroblasts and other cells in damaged tissues, the activation of growth factors, the structure and mechanics of the matrix, and, potentially, tissue patterning. Better understanding of the variety and magnitude of forces, the characteristics of those forces in biological tissues, and their impact on fibrosis in multiple tissues is needed and may lead to identification of important new therapeutic targets. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.► Mechanical forces play a critical role in fibrosis. ► There are multiple forces acting on tissues. ► Matrix stiffness is the best appreciated mechanical stimulus in fibrosis. ► Mechanical forces determine the activation of myofibroblasts.
Keywords: Tissue stiffness; Myofibroblast; Tension; Stretch; Shear; Hydrostatic pressure;
Integrin-mediated regulation of TGFβ in fibrosis by Neil C. Henderson; Dean Sheppard (891-896).
Fibrosis is a major cause of morbidity and mortality worldwide. Currently, therapeutic options for tissue fibrosis are severely limited, and organ transplantation is the only effective treatment for end-stage fibrotic disease. However, demand for donor organs greatly outstrips supply, and so effective anti-fibrotic treatments are urgently required. In recent years, the integrin family of cell adhesion receptors has gained prominence as key regulators of chronic inflammation and fibrosis. Fibrosis models in multiple organs have demonstrated that integrins have profound effects on the fibrotic process. There is now abundant in vivo data demonstrating critical regulatory roles for integrins expressed on different cell types during tissue fibrogenesis. In this review, we will examine the ways in which integrins regulate these processes and discuss how the manipulation of integrins using function blocking antibodies and small molecule inhibitors may have clinical utility in the treatment of patients with a broad range of fibrotic diseases. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.► Tissue fibrosis is a major healthcare burden worldwide. ► Integrin-mediated activation of latent TGFβ is a major mechanism driving fibrosis. ► Pharmacologic manipulation of integrins may lead to new antifibrotic treatments.
Keywords: Integrin; Fibrosis; TGFβ;
Tyrosine kinase signaling in fibrotic disorders by Christian Beyer; Jörg H.W. Distler (897-904).
Tyrosine kinases regulate a broad variety of physiological cell processes, including metabolism, growth, differentiation and apoptosis. Abnormal tyrosine kinase activity disturbs the physiological cell homeostasis and can lead to cancer, vascular disease, and fibrosis. In regard to fibrosis, different tyrosine kinases have been identified as determinants of disease progression and potential targets for anti-fibrotic therapies. This includes both receptor tyrosine kinases (e.g., PDGF receptor, VEGF receptor, EGF receptor, and JAK kinases) as well as non-receptor tyrosine kinases (e.g., c-Abl, c-Kit, and Src kinases). Given their central role in the pathogenesis of fibrosis, researchers of our field study the anti-fibrotic effects of monoclonal antibodies or small-molecule inhibitors to block the aberrant tyrosine kinase activity and treat fibrosis in preclinical models of various fibrotic diseases (e.g., idiopathic pulmonary fibrosis, renal fibrosis, liver fibrosis, and dermal fibrosis). The results of these studies were promising and prompted clinical trials with different compounds in fibrotic diseases. So far, results from studies with intedanib in idiopathic pulmonary fibrosis and imatinib in idiopathic pulmonary fibrosis and systemic sclerosis have been reported. Although none of these studies reported a positive primary outcome, promising trends in anti-fibrotic efficacy awaken our hopes for a new class of effective anti-fibrotic targeted therapies. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.► Tyrosine kinases are key regulators of fibrotic tissue remodeling. ► Blockade of abnormal tyrosine kinase activity can inhibit experimental fibrosis. ► Trials with the tyrosine kinase inhibitor imatinib in IPF and SSc are inconclusive. ► A large RCT with the tyrosine kinase inhibitor intedanib in IPF is very promising.
Keywords: Tyrosine kinase; Fibrosis; Idiopathic pulmonary fibrosis; Systemic sclerosis; Imatinib; Intedanib;
Serotonin paracrine signaling in tissue fibrosis by Derek A. Mann; Fiona Oakley (905-910).
The molecule serotonin (5-hydroxytryptamine or 5-HT) is involved in numerous biological processes both inside and outside of the central nervous system. 5-HT signals through 5-HT receptors and it is the diversity of these receptors and their subtypes that give rise to the varied physiological responses. It is clear that platelet derived serotonin is critical for normal wound healing in multiple organs including, liver, lung heart and skin. 5-HT stimulates both vasoconstriction and vasodilation, influences inflammatory responses and promotes formation of a temporary scar which acts as a scaffold for normal tissue to be restored. However, in situations of chronic injury or damage 5-HT signaling can have deleterious effects and promote aberrant wound healing resulting in tissue fibrosis and impaired organ regeneration. This review highlights the diverse actions of serotonin signaling in the pathogenesis of fibrotic disease and explores how modulating the activity of specific 5-HT receptors, in particular the 5-HT2 subclass could have the potential to limit fibrosis and restore tissue regeneration. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.► Introduction, overview of serotonin signaling and biology ► The role of serotonin in wound healing, regeneration and fibrosis ► Future perspectives
Keywords: Fibrosis; Serotonin;
Fibrosis of two: Epithelial cell-fibroblast interactions in pulmonary fibrosis by Norihiko Sakai,; Andrew M. Tager (911-921).
Idiopathic pulmonary fibrosis (IPF) is characterized by the progressive and ultimately fatal accumulation of fibroblasts and extracellular matrix in the lung that distorts its architecture and compromises its function. IPF is now thought to result from wound-healing processes that, although initiated to protect the host from injurious environmental stimuli, lead to pathological fibrosis due to these processes becoming aberrant or over-exuberant. Although the environmental stimuli that trigger IPF remain to be identified, recent evidence suggests that they initially injure the alveolar epithelium. Repetitive cycles of epithelial injury and resultant alveolar epithelial cell death provoke the migration, proliferation, activation and myofibroblast differentiation of fibroblasts, causing the accumulation of these cells and the extracellular matrix that they synthesize. In turn, these activated fibroblasts induce further alveolar epithelial cell injury and death, thereby creating a vicious cycle of pro-fibrotic epithelial cell-fibroblast interactions. Though other cell types certainly make important contributions, we focus here on the “pas de deux” (steps of two), or perhaps more appropriate to IPF pathogenesis, the “folie à deux” (madness of two) of epithelial cells and fibroblasts that drives the progression of pulmonary fibrosis. We describe the signaling molecules that mediate the interactions of these cell types in their “fibrosis of two”, including transforming growth factor-β, connective tissue growth factor, sonic hedgehog, prostaglandin E2, angiotensin II and reactive oxygen species. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.
Keywords: Pulmonary fibrosis; Epithelial cells; Apoptosis; Fibroblasts; Myofibroblasts; Extracellular matrix;
Regenerative activity of the lung after epithelial injury by Andrew E. Vaughan; Harold A. Chapman (922-930).
Lung epithelial cells use remarkably adaptive sensing and signaling systems to maintain a physiological state supporting gas exchange and minimizing environmental insults. One facet of epithelial adaptability is the reversible acquisition of mesenchymal features, a process termed epithelial–mesenchymal transition (EMT). Although in the adult, permanent and complete EMT appears rare or non-existent, a growing body of evidence implicates a critical role for the activation of EMT signaling in tissue remodeling, including fibrotic lung disease. The specific phenotypes of cells undergoing EMT re-programming during epithelial responses to injury continue to be defined and are reviewed here. Several recent studies implicate epithelial expression of canonical EMT transcription factors, such as Snail and Twist1, with the acquisition of a less differentiated, more proliferative stem-like state, providing an additional link between activation of EMT signaling and tissue repair. In lung airways, proliferating variant clara cells rely upon Snail for effective epithelial repair, and in the breast, cells possessing the greatest regenerative capacity also express Snail2. The ongoing elucidation of signaling underlying epithelial stem/progenitor expansion coincides with recent discoveries implicating regenerative activity in the lung, possibly including de novo regeneration of airway and alveolar units. It remains largely unknown what signals drive organization of epithelial progenitor cells that expand after lung injury, to what degree such organization is ever functionally relevant, and whether the lung regenerative potential recently observed in mouse models extends to humans. Yet these unknowns with clinical potential bring future mechanistic studies of EMT and lung repair directly into the field of regenerative medicine. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.► Introduction of the epithelial–mesenchymal transition (EMT) concept derived from developmental and cancer biology ► EMT and associated signaling pathways in lung repair and fibrosis ► EMT phenotypes and their relationship to a pluripotent state or “stemness” ► Candidate airway and alveolar progenitor cells responsible for lung regeneration ► Newly appreciated injury models demonstrating regeneration of functional pulmonary structures
Keywords: Epithelial–mesenchymal transition; Stem/progenitor cell; Signaling;
Renal epithelial injury and fibrosis by Brigitte Kaissling; Michel LeHir; Wilhelm Kriz (931-939).
Chronic kidney disease at a certain advanced stage inevitably progresses to end stage renal failure characterized by the progressing loss of nephrons accompanied by the increasing appearance of fibrotic tissue, called renal fibrosis. The urgent question is whether renal fibrosis is a response to injury or if fibrosis acquires a self-sustaining progressive potential that actively contributes to the deterioration of the kidney. The present review distinguishes between renal fibrosis subsequent to a glomerular injury and fibrosis subsequent to a primary tubular injury. Glomerular diseases enter a progressing course after encroaching onto the tubule leading to what is generally called “tubulointerstitial fibrosis”. The progression of the injury at the level of the tubulointerstitium appears to be fully dependent on the progression of the disease in the corresponding glomerulus. Primary tubular injuries have a very good chance of recovery. If they develop a local fibrotic process, this seems to be supportive for recovery. Cases in which recovery fails appear to secondarily initiate a glomerular disease accounting for a glomerulus-dependent vicious cycle to progression. Even if most researchers think of renal fibrosis as a process promoting the progression of the disease this review points out that the available structural evidence speaks in favour of a protective role of fibrosis supporting recovery after acute tubular injury or, under progressing circumstances, providing a firm three-dimensional framework that permits still intact or partially damaged nephrons to survive. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.
Keywords: Tubulointerstitial fibrosis; Tubular injury; Glomerular injury; Progression to CKD;
Endoplasmic reticulum stress as a pro-fibrotic stimulus by Harikrishna Tanjore; William E. Lawson; Timothy S. Blackwell (940-947).
Current evidence suggests a prominent role for endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) in fibrotic conditions affecting a number of internal organs, including the lungs, liver, GI tract, kidney, and heart. ER stress enhances the susceptibility of structural cells, in most cases the epithelium, to pro-fibrotic stimuli. Studies suggest that ER stress facilitates fibrotic remodeling through activation of pro-apoptotic pathways, induction of epithelial–mesenchymal transition, and promotion of inflammatory responses. While genetic mutations that lead to ER stress underlie some cases of fibrosis, including lung fibrosis secondary to mutations in surfactant protein C (SFTPC), a variety of other factors can cause ER stress. These ER stress inducing factors include metabolic abnormalities, oxidative stress, viruses, and environmental exposures. Interestingly, the ability of the ER to maintain homeostasis under stress diminishes with age, potentially contributing to the fact that fibrotic disorders increase in incidence with aging. Taken together, underlying ER stress and UPR pathways are emerging as important determinants of fibrotic remodeling in different forms of tissue fibrosis. Further work is needed to better define the mechanisms by which ER stress facilitates progressive tissue fibrosis. In addition, it remains to be seen whether targeting ER stress and the UPR could have therapeutic benefit. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.► ER stress and the unfolded protein response contribute tofibrotic remodeling. ► ER stress enhances the susceptibility of epithelial cells to pro-fibrotic stimuli. ► ER stress facilitates fibrosis by promoting apoptosis, inflammation, and/or EMT. ► Genetic mutations, viruses, and environmental exposures may cause ER stress in vivo.
Keywords: Unfolded protein response; Fibrosis; Interstitial lung disease; Apoptosis; Epithelial–mesenchymal transition;
Origins and functions of liver myofibroblasts by Sara Lemoinne; Axelle Cadoret; Haquima El Mourabit; Dominique Thabut; Chantal Housset (948-954).
Myofibroblasts combine the matrix-producing functions of fibroblasts and the contractile properties of smooth muscle cells. They are the main effectors of fibrosis in all tissues and make a major contribution to other aspects of the wound healing response, including regeneration and angiogenesis. They display the de novo expression of α-smooth muscle actin. Myofibroblasts, which are absent from the normal liver, are derived from two major sources: hepatic stellate cells (HSCs) and portal mesenchymal cells in the injured liver. Reliable markers for distinguishing between the two subpopulations at the myofibroblast stage are currently lacking, but there is evidence to suggest that both myofibroblast cell types, each exposed to a particular microenvironment (e.g. hypoxia for HSC-MFs, ductular reaction for portal mesenchymal cell-derived myofibroblasts (PMFs)), expand and exert specialist functions, in scarring and inflammation for PMFs, and in vasoregulation and hepatocellular healing for HSC-MFs. Angiogenesis is a major mechanism by which myofibroblasts contribute to the progression of fibrosis in liver disease. It has been clearly demonstrated that liver fibrosis can regress, and this process involves a deactivation of myofibroblasts, although probably not to a fully quiescent phenotype. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.
Keywords: Myofibroblast; Liver fibrosis; Angiogenesis; Hepatic stellate cell; Portal fibroblast; Ductular reaction;
Bone marrow contributions to fibrosis by Alison Mackinnon; Stuart Forbes (955-961).
Bone marrow transplant experiments in mice using labelled donor bone marrow have indicated that following injury bone marrow derived cells can circulate and home to the injured organs. In particular fibrocytes and myofibroblasts are capable of contributing to the wound healing response, including collagen deposition. In chronic injury this can lead to a pathological degree of fibrosis. Experiments have shown that this can be a relatively insignificant contribution to the scar forming population in certain organs and that the majority of the scar forming cells are intrinsic to the organ. Conversely, in certain circumstances, the circulating cells become major players in the organs fibrotic response. Whilst cell tracking experiments are relatively simple to perform, to actually determine a functional contribution to a fibrotic response more sophisticated approaches are required. This can include the use of bone marrow transplantation from recipients with collagen reporter systems which gives a read out of bone marrow derived cells that are transcriptional active for collagen production in a damaged organ. Another technique is to use bone marrow transplants from donors that have a mutation in the collagen to demonstrate a functional difference in fibrosis when bone marrow transplants performed. Recent reports have identified factors mediating recruitment of circulating fibrocytes to injured organs, such as CXCL12 and CXCL16 and shown that blocking these factors reduced fibrocyte recruitment and subsequent fibrosis. The identification of such factors may enable the development of novel therapies to block further fibrocyte engraftment and fibrosis in situations of pathological scarring. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.► Circulating bone marrow derived cells can engraft damaged organs and contribute to fibrosis. ► Macrophages are key players in the progression and resolution of organ fibrosis. ► MSCs and macrophages are cells with potential cell therapy applications.
Keywords: Bone marrow; Fibrosis; Fibrocyte; Macrophage; Myofibroblast;
Resident mesenchymal cells and fibrosis by Nicol Hutchison; Cécile Fligny; Jeremy S. Duffield (962-971).
Fibrosis is a major clinical problem associated with as many as 45% of all natural deaths in developed nations.It can affect all organs and accumulating evidence indicates that fibrogenesis is not merely a bystander product of injury, but is a central pathological problem directly contributing to loss of organ function. In the majority of clinical cases, fibrogenesis is strongly associated with the recruitment of leukocytes, even in the absence of infection. Although chronic infections are a significant cause of fibrogenesis, in most cases fibrotic disease occurs in the context of sterile injury, such as microvascular disease, toxic epithelial injury or diabetes mellitus. Fibrogenesis is a direct consequence of the activation of extensive, and previously poorly appreciated, populations of mesenchymal cells in our organs which are either wrapped around capillaries and known as ‘pericytes’, or embedded in interstitial spaces between cell structures and known as resident ‘fibroblasts’. Recent fate-mapping and complementary studies in several organs indicate that these cells are the precursors of the scar-forming myofibroblasts that appear in our organs in response to injury. Here we will review the literature supporting a central role for these cells in fibrogenesis, and highlight some of the critical cell to cell interactions that are necessary for the initiation and continuation of the fibrogenic process. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.► Resident mesenchymal cells are the major source of myofibroblasts in fibrosis. ► Pericytes are resident mesenchymal cells located in the microvasculature. ► Targeting myofibroblast activation may lead to novel anti-fibrotic therapeutics.
Keywords: Fibrillar extracellular matrix; Fibrosis; Resident mesenchymal cell; Pericyte; Myofibroblast; Anti-fibrotic therapeutics;
Autophagy and mesenchymal cell fibrogenesis by Moira Hilscher; Virginia Hernandez-Gea; Scott L. Friedman (972-978).
Autophagy is a catabolic pathway essential for cellular energy homeostasis that involves the self-degradation of intracellular components in lysosomes. This process has been implicated in the pathophysiology of many human disorders, including infection, cancer, and fibrosis. Autophagy is also recognized as a mediator of survival and proliferation, and multiple pathways induce autophagy under conditions of cellular stress, including nutrient and energy depletion. High autophagic activity has been detected in fibrogenic cells from several tissues; however the role of autophagy in fibrogenesis and mesenchymal cells varies greatly in different tissues and settings, with contributions uncovered to energy metabolism and collagen turnover by fibrogenic cells. Because several chemical modulators of autophagy have already been identified, autophagy regulation constitutes a potential target for antifibrotic therapy. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.► Fibrotic diseases account for more than 45% of deaths in the industrialized world. ► Despite the progress made in elucidating its regulation, there are many gaps in our understanding of autophagy. ► Autophagy has recently been implicated in the pathophysiology of fibrosis.
Keywords: Fibrosis; Mesenchymal cells; Fibroblast and fibrotic diseases; Energy homeostasis;
Inflammasome biology in fibrogenesis by Xinshou Ouyang; Ayaz Ghani; Wajahat Z. Mehal (979-988).
Pathogens and sterile insults both result in an inflammatory response. A significant part of this response is mediated by cytosolic machinery termed as the inflammasome which results in the activation and secretion of the cytokines interleukin-1β (IL-1β) and IL-18. Both of these are known to result in the activation of an acute inflammatory response, resulting in the production of downstream inflammatory cytokines such as tumor necrosis factor (TNF-α), interferon-gamma (IFN-γ), chemotaxis of immune cells, and induction of tissue injury. Surprisingly this very acute inflammatory pathway is also vital for the development of a full fibrogenic response in a number of organs including the lung, liver, and skin. There is evidence for the inflammasome having a direct role on tissue specific matrix producing cells such as the liver stellate cell, and also indirectly through the activation of resident tissue macrophage populations. The inflammasome requires stimulation of two pathways for full activation, and initiating stimuli include Toll-like receptor (TLR) agonists, adenosine triphosphate (ATP), particulates, and oxidative stress. Such a role for an acute inflammatory pathway in fibrosis runs counter to the prevailing association of TGF-β driven anti-inflammatory and pro-fibrotic pathways. This identifies new therapeutic targets which have the potential to simultaneously decrease inflammation, tissue injury and fibrosis. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.
Keywords: Fibrosis; Inflammasome; IL-1b; Sterile; Inflammation;
Macrophages and fibrosis: How resident and infiltrating mononuclear phagocytes orchestrate all phases of tissue injury and repair by Maciej Lech; Hans-Joachim Anders (989-997).
Certain macrophage phenotypes contribute to tissue fibrosis, but why? Tissues host resident mononuclear phagocytes for their support to maintain homeostasis. Upon injury the changing tissue microenvironment alters their phenotype and primes infiltrating monocytes toward pro-inflammatory macrophages. Several mechanisms contribute to their deactivation and macrophage priming toward anti-inflammatory and pro-regenerative macrophages that produce multiple cytokines that display immunosuppressive as well as pro-regeneratory effects, such as IL-10 and TGF-beta1. Insufficient parenchymal repair creates a tissue microenvironment that becomes dominated by multiple growth factors that promote the pro-fibrotic macrophage phenotype that itself produces large amounts of such growth factors that further support fibrogenesis. However, the contribution of resident mononuclear phagocytes to physiological extracellular matrix turnover implies also their fibrolytic effects in the late stage of tissue scaring. Fibrolytic macrophages break down fibrous tissue, but their phenotypic characteristics remain to be described in more detail. Together, macrophages contribute to tissue fibrosis because the changing tissue environments prime them to assist and orchestrate all phases of tissue injury and repair. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.► Fibrosis was selected throughout evolution because of its life saving benefits. ► Macrophages contribute to fibrosis because they contribute to all phases of tissue injury and repair. ► Macrophages not only support fibrogenesis, but they also support fibrolysis. ► Suppressing sterile tissue inflammation and promoting tissue regeneration are the best way to prevent tissue fibrosis.
Keywords: Immunity; Regeneration; Polarization; Inflammation; Wound healing; Fibrosis;
Dendritic cells and liver fibrosis by Adeeb H. Rahman; Costica Aloman (998-1004).
Dendritic cells are a relative rare population of specialized antigen presenting cells that are distributed through most lymphoid and non-lymphoid tissues and play a critical role in linking the innate and adaptive arms of the immune system. The liver contains a heterogeneous population of dendritic cells that may contribute to liver inflammation and fibrosis through a number of mechanisms. This review summarizes current knowledge on the development and characterization of liver dendritic cells and their potential impact on liver fibrosis. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.► Mouse and human livers contain heterogeneous populations of dendritic cells (DCs). ► There is currently a lack of cell markers that can be used to unequivocally identify DCs. ► Studies of DC during fibrogenesis have focused on their role in inflammation. ► DC expansion promotes fibrosis regression.
Keywords: Dendritic cell; Liver fibrosis; Flt3 ligand; Hepatic inflammation; Fibrosis progression; Fibrosis regression;
Regulation of wound healing and organ fibrosis by toll-like receptors by Peter Huebener; Robert F. Schwabe (1005-1017).
Chronic injury often triggers maladaptive wound healing responses leading to the development of tissue fibrosis and subsequent organ malfunction. Inflammation is a key component of the wound healing process and promotes the development of organ fibrosis. Here, we review the contribution of Toll-like receptors (TLRs) to wound healing with a particular focus on their role in liver, lung, kidney, skin and myocardial fibrosis. We discuss the role of TLRs on distinct cell populations that participate in the repair process following tissue injury, and the contribution of exogenous and endogenous TLR ligands to the wound healing response. Systemic review of the literature shows that TLRs promote tissue repair and fibrosis in many settings, albeit with profound differences between organs. In particular, TLRs exert a pronounced effect on fibrosis in organs with higher exposure to bacterial TLR ligands, such as the liver. Targeting TLR signaling at the ligand or receptor level may represent a novel strategy for the prevention of maladaptive wound healing and fibrosis in chronically injured organs. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.► TLRs detect pathogen-associated molecular patterns. ► In tissue injury, TLRs may also detect endogenous molecular “danger” patterns. ► TLRs are expressed not only on immune cells but also on fibroblasts and epithelium. ► TLRs promote maladaptive wound healing responses such as fibrosis and carcinogenesis. ► The contribution of TLRs to wound healing is highly organ- and context-dependent.
Keywords: Toll-like receptor; Fibrosis; Wound healing;
Coagulation and coagulation signalling in fibrosis by Paul F. Mercer; Rachel C. Chambers (1018-1027).
Following tissue injury, a complex and coordinated wound healing response comprising coagulation, inflammation, fibroproliferation and tissue remodelling has evolved to nullify the impact of the original insult and reinstate the normal physiological function of the affected organ. Tissue fibrosis is thought to result from a dysregulated wound healing response as a result of continual local injury or impaired control mechanisms. Although the initial insult is highly variable for different organs, in most cases, uncontrolled or sustained activation of mesenchymal cells into highly synthetic myofibroblasts leads to the excessive deposition of extracellular matrix proteins and eventually loss of tissue function. Coagulation was originally thought to be an acute and transient response to tissue injury, responsible primarily for promoting haemostasis by initiating the formation of fibrin plugs to enmesh activated platelets within the walls of damaged blood vessels. However, the last 20 years has seen a major re-evaluation of the role of the coagulation cascade following tissue injury and there is now mounting evidence that coagulation plays a critical role in orchestrating subsequent inflammatory and fibroproliferative responses during normal wound healing, as well as in a range of pathological contexts across all major organ systems. This review summarises our current understanding of the role of coagulation and coagulation initiated signalling in the response to tissue injury, as well as the contribution of uncontrolled coagulation to fibrosis of the lung, liver, kidney and heart. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.► Introduce the key steps involved in the initiation of coagulation, coagulation signalling and fibrinolysis ► We review the evidence for the coagulation cascade in fibrosis of the lung, liver, kidney and heart. ► We summarise the opportunities and challenges of targeting the coagulation cascade in fibrosis.
Keywords: Fibrosis; Coagulation; Proteinase-activated receptor; Myofibroblast; Extracellular matrix;
Oxidative stress and pulmonary fibrosis by Paul Cheresh; Seok-Jo Kim; Sandhya Tulasiram; David W. Kamp (1028-1040).
Oxidative stress is implicated as an important molecular mechanism underlying fibrosis in a variety of organs, including the lungs. However, the causal role of reactive oxygen species (ROS) released from environmental exposures and inflammatory/interstitial cells in mediating fibrosis as well as how best to target an imbalance in ROS production in patients with fibrosis is not firmly established. We focus on the role of ROS in pulmonary fibrosis and, where possible, highlight overlapping molecular pathways in other organs. The key origins of oxidative stress in pulmonary fibrosis (e.g. environmental toxins, mitochondria/NADPH oxidase of inflammatory and lung target cells, and depletion of antioxidant defenses) are reviewed. The role of alveolar epithelial cell (AEC) apoptosis by mitochondria- and p53-regulated death pathways is examined. We emphasize an emerging role for the endoplasmic reticulum (ER) in pulmonary fibrosis. After briefly summarizing how ROS trigger a DNA damage response, we concentrate on recent studies implicating a role for mitochondrial DNA (mtDNA) damage and repair mechanisms focusing on 8-oxoguanine DNA glycosylase (Ogg1) as well as crosstalk between ROS production, mtDNA damage, p53, Ogg1, and mitochondrial aconitase (ACO2). Finally, the association between ROS and TGF-β1-induced fibrosis is discussed. Novel insights into the molecular basis of ROS-induced pulmonary diseases and, in particular, lung epithelial cell death may promote the development of unique therapeutic targets for managing pulmonary fibrosis as well as fibrosis in other organs and tumors, and in aging; diseases for which effective management is lacking. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.► Oxidative stress is an important mechanism underlying fibrosis. ► ROS derived from the mitochondria and NOX4 can promote fibrosis. ► AEC apoptosis in lung fibrosis is coupled with mitochondria, ER, and p53 activation. ► ROS-induced AEC apoptosis is blocked in cells overexpressing Ogg1 or ACO2. ► The interactive effects between oxidative stress and TGF-β augment fibrosis.
Keywords: Reactive oxygen species; Epithelium; Mitochondria; NADPH oxidase; Apoptosis;
Chemokines in tissue fibrosis by Hacer Sahin; Hermann E. Wasmuth (1041-1048).
Fibrosis or scarring of diverse organs and tissues is considered as a pathologic consequence of a chronically altered wound healing response which is tightly linked to inflammation and angiogenesis. The recruitment of immune cells, local proliferation of fibroblasts and the consecutive accumulation of extracellular matrix proteins are common pathophysiological hallmarks of tissue fibrosis, irrespective of the organ involved. Chemokines, a family of chemotactic cytokines, appear to be central mediators of the initiation as well as progression of these biological processes. Traditionally chemokines have only been considered to play a critical role in orchestrating the influx of immune cells to sites of tissue injury. However, within the last years, further aspects of chemokine biology including fibroblast activation and angiogenesis have been deciphered in tissue fibrosis of many different organs. Interestingly, certain chemokines appear to mediate common effects in liver, kidney, lung, and skin of various animal models, while others mediate tissue specific effects. These aspects have to be kept in mind when extrapolating data of animal studies to early human trials. Nevertheless, the further understanding of chemokine effects in tissue fibrosis might be an attractive approach for identifying novel therapeutic targets in chronic organ damage associated with high morbidity and mortality. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.► Chemokines are involved in all processes of a wound healing response. ► Chemokines display common and organ-specific effects during fibrogenesis. ► Chemokines display pro- or anti-fibrotic properties depending on the model used. ► Chemokine-antagonistic strategies are being actively developed for human trials.
Keywords: Chemokine; Tissue fibrosis; Liver; Lung; Kidney; Skin;
Cytokine mediated tissue fibrosis by Lee A. Borthwick; Thomas A. Wynn; Andrew J. Fisher (1049-1060).
Acute inflammation is a recognised part of normal wound healing. However, when inflammation fails to resolve and a chronic inflammatory response is established this process can become dysregulated resulting in pathological wound repair, accumulation of permanent fibrotic scar tissue at the site of injury and the failure to return the tissue to normal function. Fibrosis can affect any organ including the lung, skin, heart, kidney and liver and it is estimated that 45% of deaths in the western world can now be attributed to diseases where fibrosis plays a major aetiological role. In this review we examine the evidence that cytokines play a vital role in the acute and chronic inflammatory responses that drive fibrosis in injured tissues. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.► Fibrosis can affect any organ including the lung, skin, heart, kidney and liver. ► 45% of deaths can now be attributed to diseases where fibrosis plays a major role. ► Acute or chronic inflammatory responses are critical in driving fibrosis. ► Here we examine the evidence for cytokines driving fibrosis in injured tissue.
Keywords: Fibrosis; Cytokine; Macrophage; Fibroblast; Myofibroblast; Inflammation;
Natural killer and natural killer T cells in liver fibrosis by Bin Gao; Svetlana Radaeva (1061-1069).
The liver lymphocyte population is enriched with natural killer (NK) cells, which play a key role in host defense against viral infection and tumor transformation. Recent evidence from animal models suggests that NK cells also play an important role in inhibiting liver fibrosis by selectively killing early or senescence activated hepatic stellate cells (HSCs) and by producing the anti-fibrotic cytokine IFN-γ. Furthermore, clinical studies have revealed that human NK cells can kill primary human HSCs and that the ability of NK cells from HCV patients to kill HSCs is enhanced and correlates inversely with the stages of liver fibrosis. IFN-α treatment enhances, while other factors (e.g., alcohol, TGF-β) attenuate, the cytotoxicity of NK cells against HSCs, thereby differentially regulating liver fibrogenesis. In addition, the mouse liver lymphocyte population is also enriched for natural killer T (NKT) cells, whereas human liver lymphocytes have a much lower percentage of NKT cells. Many studies suggest that NKT cells promote liver fibrogenesis by producing pro-fibrotic cytokines such as IL-4, IL-13, hedgehog ligands, and osteopontin; however, NKT cells may also attenuate liver fibrosis under certain conditions by killing HSCs and by producing IFN-γ. Finally, the potential for NK and NKT cells to be used as therapeutic targets for anti-fibrotic therapy is discussed. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.► The liver lymphocyte population is enriched with NK and NKT cells. ► NK cells inhibit liver fibrosis by killing activated HSCs and by producing IFN-γ. ► IFN-α therapy enhances, while alcohol and TGF-β inhibit, NK cell killing of HSCs. ► NKT cells produce pro-fibrotic cytokines to promote liver fibrosis. ► NKT cells also produce anti-fibrotic cytokines to inhibit liver fibrosis.
Keywords: Viral hepatitis; Alcoholic liver disease; NKG2D; NAFLD; IFN-gamma;
Fibroblasts as architects of cancer pathogenesis by Timothy Marsh; Kristian Pietras; Sandra S. McAllister (1070-1078).
Studies of epithelial cancers (i.e., carcinomas) traditionally focused on transformation of the epithelium (i.e., the cancer cells) and how aberrant signaling within the cancer cells modulates the surrounding tissue of origin. In more recent decades, the normal cells, blood vessels, molecules, and extracellular components that surround the tumor cells, collectively known as the “tumor microenvironment” or “stroma”, have received increasing attention and are now thought to be key regulators of tumor initiation and progression. Of particular relevance to the work reviewed herein are the fibroblasts, which make up the major cell type within the microenvironment of most carcinomas. Due to their inherent heterogeneity, plasticity, and function, it is perhaps not surprising that fibroblasts are ideal modulators of normal and cancerous epithelium; however, these aspects also present challenges if we are to interrupt their tumor-supportive functions. Here, we review the current body of knowledge and the many questions that still remain about the special entity known as the cancer-associated fibroblast. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.► Form and function — normal, activated, and cancer-associated fibroblasts ► Cancer-associated fibroblasts — heterogeneity ► Fibroblasts in cancer pathophysiology ► Tracing the origins of CAFs ► Interactions in the tumor microenvironment and CAFs as a clinical entity
Keywords: Fibrosis; Cancer; Cancer-associated fibroblasts; Bone marrow cells; Heterogeneity;
Strategies for biomarker discovery in fibrotic disease by Richard P. Marshall; Juliet K. Simpson; Pauline T. Lukey (1079-1087).
The discovery and development of biomarkers for fibrotic diseases have potential utility in clinical decision-making as well as in pharmaceutical research and development. This review describes strategies for identifying diagnostic, prognostic and theranostic biomarkers. A range of technologies and platforms for biomarker discovery are highlighted, including several with specific relevance for fibrosis. Some challenges specific to fibrotic diseases are outlined including; benchmarking biomarkers against imperfect clinical measures of fibrosis, the complexity resulting from diverse aetiologies and target organs, and the availability of samples (including biopsy) from well-characterised patients with fibrotic disease. To overcome these challenges collaboration amongst clinical specialities as well as between academia and industry is essential. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.► Fibrosis is a core process in a number of chronic progressive diseases with a variety of aetiologies. ► The dynamic nature of extracellular matrix deposition lends itself to biomarker discovery. ► Diagnostic, prognostic and theranostic markers are required. ► Platform technologies as well as statistical approaches to biomarker discovery are discussed. ► Interdisciplinary as a well as public/private collaborations will be required for success.
Keywords: Fibrosis; Biomarker discovery; Drug discovery; Diagnostic; Prognostic; Theranostic;
Strategies for anti-fibrotic therapies by Joel Rosenbloom; Fabian A. Mendoza; Sergio A. Jimenez (1088-1103).
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.► Fibrotic diseases affect multiple organs, are progressive, and impair function. ► Exaggerated deposition of extracellular matrix characterizes fibrotic diseases. ► Currently there is no effective treatment for fibrotic diseases. ► New knowledge of cellular and molecular mechanisms of tissue fibrosis is discussed. ► Novel pathogenesis-based strategies will result in effective anti-fibrotic therapies.
Keywords: Fibrotic disease; Myofibroblast; Fibrosis; Tyrosine kinase; TGF-ß; Anti-fibrotic therapy;