activin A and IL-1. The production of these factors indicates the presence of autocrine loops that perpetuate PaSC activation, promoting the development of fibrosis. Protein kinases such as MAPKs are primary mediators of activating signals initiated by the growth factors, angiotensin II and ethanol. Other signalling pathways regulating PaSC activation include PI3K, RHO kinase and TGF-β/SMAD-related pathways. Following activation, PaSCs migrate to areas of tissue damage and contract, phagocytose, and induce products that regulate the ECM through facilitating repair or by promoting fibrosis. The migration of PaSCs is modulated by Indian hedgehog (IHH), a peptide that is involved in pancreatic development, patterning and differentiation. Stellate cells express smoothened (Smo) and patched-1 (Ptch1) proteins, which are significant features of the hedgehog receptor system. Indian Hedgehog binding results in relocation of the transcriptional of transcription factor Gli-1 into the nucleus, inducing chemokinetic migration of PaSCs. Following activation, PaSCs have two fates. If there is sustained inflammation and injury, PaSC activation is perpetuated, resulting in the growth of pancreatic fibrosis. The activation of P2 receptors induces intracellular calcium signalling which mediates the fibrogenic function of activated stellate cells. However, if inflammation and injury is minor, PaSCs undergo an apoptotic fate and become quiescent, preventing the development of fibrosis. PaSCs also display ethanol inducible ADH activity. The possibility that pancreatic stellate cells may be exposed to ethanol and acetaldehyde during ethanol consumption is likely, as the pancreas metabolise ethanol to acetaldehyde through the oxidative pathway. PaSCs are activated upon exposure to ethanol and its metabolite acetaldehyde or to oxidant stress. Ethanol at clinically relevant concentrations causes α-SMA expression and collagen production in PaSCs but produce a minimal effect on cell proliferation. Increased α-SMA expression in stellate cells exposed to ethanol suggests activation and transformation of the cells to a myofibroblast phenotype. Incubation of PaSCs with ethanol in the presence of ADH inhibitor 4MP had inhibited the increase in collagen synthesis induced by ethanol. The conversion of ethanol to acetaldehyde via ADH is a significant step in the ethanol induced activation of pancreatic stellate cells. Clinical significance Pancreatitis Pancreatitis is generally classified into two forms, acute and chronic. In acute pancreatitis, necroinflammation of the organ occurs, while chronic pancreatitis is distinguished by the progressive loss of endocrine and exocrine function. After pancreatic damage occurs, pathologic events such as interstitial oedema, necrosis of parenchymal cells, activation and proliferation of PaSCs take place. Inflammation and parenchymal necrosis