Alcohol, signaling, and ECM turnover.

Alcohol is recognized as a direct hepatotoxin, but the precise molecular pathways that are important for the initiation and progression of alcohol-induced tissue injury are not completely understood. The current understanding of alcohol toxicity to organs suggests that alcohol initiates injury by generation of oxidative and nonoxidative ethanol metabolites and via translocation of gut-derived endotoxin. These processes lead to cellular injury and stimulation of the inflammatory responses mediated through a variety of molecules. With continuing alcohol abuse, the injury progresses through impairment of tissue regeneration and extracellular matrix (ECM) turnover, leading to fibrogenesis and cirrhosis. Several cell types are involved in this process, the predominant being stellate cells, macrophages, and parenchymal cells. In response to alcohol, growth factors and cytokines activate many signaling cascades that regulate fibrogenesis. This mini-review brings together research focusing on the underlying mechanisms of alcohol-mediated injury in a number of organs. It highlights the various processes and molecules that are likely involved in inflammation, immune modulation, susceptibility to infection, ECM turnover and fibrogenesis in the liver, pancreas, and lung triggered by alcohol abuse.

The role of inflammatory and parenchymal cells in acute pancreatitis.

The infiltration of inflammatory cells into the pancreas is an early and central event in acute pancreatitis that promotes local injury and systemic complications of the disease. Recent research has yielded the important finding that resident cells of the pancreas (particularly acinar and pancreatic stellate cells) play a dynamic role in leukocyte attraction via secretion of chemokines and cytokines and expression of adhesion molecules. Significant progress has been made in recent years in our understanding of the role of leukocyte movement (adhesion to the blood vessel wall, transmigration through the blood vessel wall and infiltration into the parenchyma) in the pathophysiology of acute pancreatitis. This review discusses recent studies and describes the current state of knowledge in the field. It is clear that detailed elucidation of the numerous processes in the inflammatory cascade is an essential step towards the development of improved therapeutic strategies in acute pancreatitis. Studies to date suggest that combination therapy targeting different steps of the inflammatory cascade may be the treatment of choice for this disease.

Pancreatic endoscopic retrograde cholangiopancreatography (ERCP).

We review developments in five areas of therapeutic endoscopic retrograde cholangiopancreatography (ERCP) and management of pancreatic tumors during the period September 2005-August 2006. First, in the management of painful chronic pancreatitis, the use of multiple plastic stents for aggressive dilation of strictures located in the head of the pancreas has been put forward to resolve two significant issues associated with current techniques, i. e., the requirement for numerous ERCPs for stent exchange and the high relapse rate after stent removal. We then discuss the identification of protective factors against post-ERCP pancreatitis following pancreatic sphincterotomy. Next, bearing in mind the prospect of increasing use of neoadjuvant chemotherapy for resectable pancreatic ductal adenocarcinoma, new evidence supporting the systematic use of self-expandable metal biliary stents before cancer staging is presented and critically considered. A French study on the natural history of intraductal papillary mucinous neoplasms, which reinforces the current recommendation not to operate on all of these patients, is also discussed. Finally two centers with a high volume of cases have reported their experience with the drainage of pancreatic fluid collections with or without endosonography (EUS) guidance. It appears that EUS has extended the applicability of endoscopic drainage but, for collections amenable to conventional endoscopic techniques, it remains uncertain whether safety and effectiveness are improved when EUS guidance is used. Technical requisites for long-term success of drainage have been confirmed: multiple, double-pigtail stents should be inserted for a minimum of 6 weeks. It has also become evident that training in this technique is insufficient at many centers.

The role of junctional adhesion molecule C (JAM-C) in acute pancreatitis.

The recruitment of inflammatory cells contributes significantly to tissue injury in acute pancreatitis. This process implies several molecular interactions between circulating and endothelial cells. The adhesion molecule junctional adhesion molecule C (JAM-C) is involved in leukocyte transendothelial migration and it can form homophilic (JAM-C/JAM-C) and heterophilic interactions with the leukocyte integrin alpha(M)beta(2). In this study, the effect of early administration of monoclonal antibodies directed against JAM-C in cerulein-induced acute pancreatitis was assessed. This reagent significantly blocked influx of leukocytes, release of serum amylase, secretion of inflammatory cytokines, and acinar cell necrosis. These effects were rapid and protected against tissue injury throughout the duration of the model. Conversely, cerulein-induced acute pancreatitis was more severe in transgenic mice overexpressing JAM-C on endothelial cells under the control of the Tie2 promoter. It is proposed that JAM-C expressed by endothelial cells contributes to the pathophysiology of acute pancreatitis and could be considered a target for clinical applications.

Integrin alpha(v)beta(3) expression in colon carcinoma correlates with survival.

Integrin alpha(v)beta(3) is expressed by newly formed blood vessels in diseased and neoplastic tissue and can therefore be used as a marker for angiogenesis. We investigated its expression on the vasculature of 40 colon carcinomas using the anti-alpha(v)beta(3)-specific monoclonal antibody LM609. The average relapse-free interval and overall survival in patients suffering from colon carcinomas with high vascular expression of alpha(v)beta(3) integrin was significantly reduced compared with that in patients with low alpha(v)beta(3) integrin expressing tumor vasculature. Moreover, the expression level of alpha(v)beta(3) integrin correlated with the presence of liver metastases. In conclusion, we propose vascular expression of alpha(v)beta(3) integrin as a prognostic indicator for colon carcinoma.