JEAN-LOUIS FROSSARD, ANTOINE HADENGUE, and CATHERINE M. PASTOR
Am. J. Respir. Crit. Care Med., Volume 164, Number 1, July 2001, 162-170
The pathophysiology of acute pancreatitis includes the activation and release of pancreatic enzymes in the interstitium, the autodigestion of the pancreas, and the multiple organ dysfunction after their release in the systemic circulation. The initial phase of the disease originates from the activation of trypsinogen to trypsin within the acinar cells, which in turn activates various enzymes such as elastase and phospholipase A2 (PLA2), and the complement and kinin systems. Trypsinogen activation peptide (TAP), which is cleaved when trypsinogen is activated into trypsin, is found in pancreatic tissue during both experimental and human pancreatitis. The higher the peptide concentration is in plasma, urine, and ascites, the higher the severity of the disease. To prevent a premature activation, the harmful digestive enzymes are synthesized in acinar cells and released as inactive precursors. Moreover, when passing through the Golgi complex, these digestive enzymes are separated from other lysosomal enzymes which may activate trypsin from trypsinogen. Intra-acinar colocalization of digestive and lysosomal enzymes is one important feature of experimental pancreatic injury but the relevance of this colocalization in the pathology of human acute pancreatitis remains unclear. Another feature observed in experimental pancreatitis is the disruption of the paracellular barrier of acinar cells and intralobular pancreatic duct cells with extravasation of pancreatic enzymes into the interstitium.
The activation of pancreatic enzymes is not the only finding involved in the pathophysiology of the disease. After trypsinogen activation into trypsin, a local inflammation is initiated which results in the local production of inflammatory mediators. Experimental studies show that pancreatic injury is mediated by the release of proinflammatory mediators such as interleukin-1 (IL-1), IL-6, IL-8, as well as by the activation of inflammatory cells such as neutrophils, macrophages, and lymphocytes. Tumor necrosis factor- (TNF-), released by macrophages within pancreatic tissue, correlates with the severity of the experimental disease. In experimental protocols, treatment with IL-1 receptor antagonist, mediators blocking the generation of O2-derived free radicals, and treatment with platelet-activating factor (PAF) receptor antagonist improve the outcome of the disease. Interestingly, anti-inflammatory cytokines, such as IL-10, decrease the severity of experimental pancreatitis.
Activation of endothelial cells permits the transendothelial migration of neutrophils, monocytes, and lymphocytes in the pancreas and mediators released by these cells, such as neutrophil elastase, might be much more damaging than pancreatic enzymes. Decreased O2 delivery to the organ and generation of O2-derived free radicals also contribute to the injury. Moreover, proinflammatory mediators released by neutrophils and macrophages injure the vascular wall and increase the microvascular permeability, leading to intraparenchymal edema and O2 supply deficiency.
Thus, whatever the initial cause (alcohol, gallstone, etc.), the severity of acute pancreatitis is related to the injury of acinar cells and to the activation of various cells such as neutrophils, monocytes, lymphocytes, and endothelial cells. Local and systemic complications follow the release of numerous mediators by these activated cells. However, a full extrapolation of these experimental findings to humans should be cautious.
Tagler: Hiç etiket yok
Comments: 
(0)
Henüz yorum yapılmamış