Pancreatic MAP kinase pathways and acetaldehyde.
Alcohol abuse is a major cause of pancreatitis, a condition that can manifest as both acute necroinflammation and chronic damage (acinar atrophy and fibrosis). It is generally accepted that alcohol-induced pancreatic injury is a consequence of the metabolism of alcohol by the pancreas (via the oxidative and non-oxidative pathways) producing the toxic metabolites acetaldehyde and fatty acid ethyl esters (FAEEs) respectively. Ethanol oxidation within the pancreas also leads to oxidant stress within the gland. Acetaldehyde, oxidant stress and FAEEs cause numerous molecular changes in pancreatic acinar cells which predispose the gland to autodigestion and necroinflammation. An important recent development relates to the identification of pancreatic stellate cells (PSCs) as the key mediators of alcohol-induced pancreatic fibrosis, when activated by ethanol, acetaldehyde or oxidant stress. Recent studies implicate the mitogen activated protein kinase (MAPK) pathway, a major signalling pathway in mammalian cells, as a critical regulator of the effects of ethanol and acetaldehyde on acinar cells as well as PSCs. Particularly important are the modulatory effects of ethanol and its metabolites on downstream transcription factors NF-kappaB and AP-1 (which regulate inflammatory responses via cytokine production) in acinar cells. In PSCs, additional signalling molecules identified as important to the process of ethanol and acetaldehyde-induced PSC activation include protein kinase C (PKC), phosphatidylinositol-3-kinase (PI3K) and peroxisome proliferator-activated receptor gamma (PPARgamma). Interestingly, cross-talk has been demonstrated between PI3K and MAPK in acetaldehyde-treated PSCs. The above advances in the identification of relevant signalling molecules may enable therapeutic targeting of these pathways so as to prevent/reduce alcohol-induced acute as well as chronic injury of the pancreas.
Apte
M
M
Pancreatic Research Group, South Western Sydney Clinical School, Liverpool Hospital, the Universify of New South Wales, Sydney, Australia.
McCarroll
J
J
Pirola
R
R
Wilson
J
J
D000079:Acetaldehyde / Q000378:metabolism*; D000428:Alcohol Drinking / Q000009:adverse effects*; D000431:Ethanol / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology; D047495:PPAR gamma / Q000378:metabolism; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism*; D010182:Pancreatic Diseases / Q000139:chemically induced / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
D047495:PPAR gamma; D000431:Ethanol; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D000079:Acetaldehyde