Hepatic wound repair

BACKGROUND: Human chronic liver diseases (CLDs) with different aetiologies rely on chronic activation of wound healing that represents the driving force for fibrogenesis progression (throughout defined patterns of fibrosis) to the end stage of cirrhosis and liver failure. ISSUES: Fibrogenesis progression has a major worldwide clinical impact due to the high number of patients affected by CLDs, increasing mortality rate, incidence of hepatocellular carcinoma and shortage of organ donors for liver transplantation. BASIC SCIENCE ADVANCES: Liver fibrogenesis is sustained by a heterogeneous population of profibrogenic hepatic myofibroblasts (MFs), the majority being positive for alpha smooth muscle actin (alphaSMA), that may originate from hepatic stellate cells and portal fibroblasts following a process of activation or from bone marrow-derived cells recruited to damaged liver and, in a method still disputed, by a process of epithelial to mesenchymal transition (EMT) involving cholangiocytes and hepatocytes. Recent experimental and clinical data have identified, at tissue, cellular and molecular level major profibrogenic mechanisms: (a) chronic activation of the wound-healing reaction, (b) oxidative stress and related reactive intermediates, and (c) derangement of epithelial-mesenchymal interactions. CLINICAL CARE RELEVANCE: Liver fibrosis may regress following specific therapeutic interventions able to downstage or, at least, stabilise fibrosis. In cirrhotic patients, this would lead to a reduction of portal hypertension and of the consequent clinical complications and to an overall improvement of liver function, thus extending the complication-free patient survival time and reducing the need for liver transplantation. CONCLUSION: Emerging mechanisms and concepts related to liver fibrogenesis may significantly contribute to clinical management of patients affected by CLDs

Angiogenesis and liver fibrogenesis

Angiogenesis is a dynamic, hypoxiastimulated and growth factor-dependent process, eventually leading to the formation of new vessels from pre-existing blood vessels. In the last decade experimental and clinical studies have described the occurrence of hepatic angiogenesis in a number of different pathophysiological conditions, including those involving inflammatory, fibrotic and ischemic features. In particular, the literature evidence indicates that hepatic angiogenesis is strictly associated with, and may even favour fibrogenic progression of chronic inflammatory liver diseases of different aetiology. In this review, current “in vivo” and “in vitro” evidence supporting the potential pathogenetic role of angiogenesis in chronic liver diseases will be reviewed in an attempt to outline cellular and molecular mechanisms involved, with a specific emphasis on the crucial role of hypoxic conditions and hepatic stellate cells (HSCs), particularly when activated to the myofibroblast-like pro-fibrogenic phenotype

Liver fibrosis: a dynamic and potentially reversible process

In any chronic liver disease (CLDs), whatever the aetiology, reiteration of liver injury results in persisting inflammation and progressive fibrogenesis, with chronic activation of the wound healing response in CLDs, representing a major driving force for progressive accumulation of ECM components, eventually leading to liver cirrhosis. Cirrhosis is characterized by fibrous septa dividing the hepatic parenchyma into regenerative pseudo-lobules, as well as by extensive changes in vascular architecture, the development of portal hypertension and related complications. Liver fibrogenesis (i.e., the dynamic process leading to increased deposition of ECM and much more) can lead to different patterns of fibrosis and is sustained by myofibroblast-like cells (MFs) of different origin, with activated hepatic stellate cells (HSC/MFs) being the major cell type involved. Major pro-fibrogenic mechanisms also include oxidative stress, as well as derangement of epithelial-mesenchymal interactions and, as recently suggested, the process of epithelial to mesenchymal transition (EMT). Liver fibrosis has been considered traditionally as an irreversible process but experimental and clinical literature data published in the last decade have suggested that both the removal of the aetiological agent or condition, as well as an effective therapy, can result in significant regression of liver fibrosis. This is usually associated, particularly in animal models, with induction of apoptosis in MFs but, unfortunately, human HSC/MFs are much more resistant to apoptosis than murine MFs. However, clinical studies provided no unequivocal evidence for a complete reversal of cirrhosis or a significant reversal of vascular changes in conditions of established cirrhosis

Dose dependent and divergent effects of superoxide anion on cell death, proliferation, and migration of activated human hepatic stellate cells

BACKGROUND AND AIM: Activated myofibroblast‐like cells, originating from hepatic stellate cells (HSC/MFs) or other cellular sources, play a key profibrogenic role in chronic liver diseases (CLDs) that, as suggested by studies in animal models or rat HSC/MFs, may be modulated by reactive oxygen intermediates (ROI). In this study, human HSC/MFs, exposed to different levels of superoxide anion (O(2)(•−)) and, for comparison, hydrogen peroxide (H(2)O(2)), were analysed in terms of cytotoxicity, proliferative response, and migration. METHODS: Cultured human HSC/MFs were exposed to controlled O(2)(•−) generation by hypoxanthine/xanthine oxidase systems or to a range of H(2)O(2) concentrations. Induction of cell death, proliferation, and migration were investigated using morphology, molecular biology, and biochemical techniques. RESULTS: Human HSC/MFs were shown to be extremely resistant to induction of cell death by O(2)(•−) and only high rates of O(2)(•−) generation induced either necrotic or apoptotic cell death. Non‐cytotoxic low levels of O(2)(•−), able to upregulate procollagen type I expression (but not tissue inhibitor of metalloproteinase 1 and 2), stimulated migration of human HSC/MFs in a Ras/extracellular regulated kinase (ERK) dependent, antioxidant sensitive way, without affecting basal or platelet derived growth factor (PDGF) stimulated cell proliferation. Non‐cytotoxic levels of H(2)O(2) did not affect Ras/ERK or proliferative response. A high rate of O(2)(•−) generation or elevated levels of H(2)O(2 )induced cytoskeletal alterations, block in motility, and inhibition of PDGF dependent DNA synthesis. CONCLUSIONS: Low non‐cytotoxic levels of extracellularly generated O(2)(•−) may stimulate selected profibrogenic responses in human HSC/MFs without affecting proliferation