br Hedgehog in chronic liver disease The liver responds to

Hedgehog in chronic liver disease The liver responds to different chronic insults with a highly conserved wound healing response during which different cell types must communicate to reconstruct fully functional, healthy liver parenchyma. The inter-cellular dialogue that orchestrates effective liver repair is accomplished by diverse factors (e.g. cytokines, growth factors, and morphogens, such as Hh ligands) that interact to appropriately modulate the fates of surviving liver cells. Cumulative data from humans and animal models indicates that Hh signalling is a pivotal regulator of the wound healing response in chronic liver disease. This discovery identifies the Hh pathway as a common target for therapeutic manipulation, regardless of the primary insult perpetuating liver injury (Table 1). Diverse insults (e.g. alcohol, toxic drugs, metabolically active fat, autoimmune attack, viral and parasitic infections) induce stress and cell death in liver epithelial Epigenetics Compound Library (hepatocytes or cholangiocytes). The injured/dying cells generate signals to recruit help and promote healing, including alarmins, damage-associated pattern molecules (DAMPs), cytokines, and morphogens. Because mortally-wounded liver epithelial cells cannot replicate, their alarm signals are configured to elicit a proliferative response in residual cells that survive, including less mature epithelial cells that can be incited to differentiate into replacements for the dead mature epithelia once the microenvironment becomes less noxious. The cellular source(s) of such immature liver epithelial cells has become a matter for debate, but morphologically the process is identified as a ductular reaction, i.e. the accumulation of immature-appearing ductal cells that aggregate to form nascent duct-like structures embedded in variable amounts of fibrous matrix with accompanying stromal cells (e.g. small oval-shaped cells with a high nuclear:cytoplasmic ratio, immune cells, activated endothelial cells and myofibroblasts).[83], [106] The cells in the ductular reaction have multiple duties that are essential for effective tissue repair, including nurturing progenitors to replace the dying epithelia, clearing dead cell debris, pathogen defense, vasculogenesis to optimise blood flow, and matrix remodelling to provide an appropriate scaffold for tissue reconstruction. Thus, it is intriguing that the ductular reaction and active scar tissue have many features in common, given that the former is believed to be a potentially beneficial response, while the latter is thought to reflect failed regeneration. This apparent paradox might be reconciled if future research confirms our hypothesis that the microenvironment of the ductular reaction is dynamic and when optimally regulated, engenders an incubator-like niche that initially promotes the generation and expansion of epithelial precursors and then gradually morphs to instruct their appropriate differentiation into mature epithelial replacements. Viewed from this perspective, progressive scarring that leads to cirrhosis might simply reflect futile/stalled regeneration, i.e. inability to move beyond the initial phases of the wound healing response. Arrest during early wound healing might be appropriate if the liver is repetitively re-challenged with noxious insults (as occurs during metabolic liver disease or chronic viral infection). Alternatively, it could occur despite resolution of the initial insult if key mechanisms that control the normal evolution of the ductular reaction become dysregulated because of inherited traits or environmental factors. Dysregulated wound healing itself promotes progressive tissue damage: persistent accumulation of myofibroblasts causes progressive liver fibrosis, ultimately resulting in cirrhosis; persistent accumulation of inflammatory immune cells perpetuates liver injury, leading to chronic hepatitis; and persistent expansion of progenitor cells and their arrest in immature forms favours carcinogenesis. The inability to shut down the wound healing response appropriately seems to be related more to patient characteristics (e.g. inheritance, age, gender, environmental exposures) that convey susceptibility to defective tissue repair than to the specific aetiology of the liver disease itself given that very different insults (e.g. alcoholic and non-alcoholic fatty liver disease,[108], [109] chronic viral hepatitis, schistosomiasis) result in progressive damage and end-organ failure in a similar proportion of afflicted individuals.