| BackgroundAcute pancreatitis (AP) is an inflammatory disease that produces a complex systemic response. Clinically the overall mortality rate for AP is approximately 10%,but in its most severe form, characterized by pancreatic hemorrhage and necrosis, this increases to 20–30%. Morbidity and mortality are related to the systemic manifestations of the disease, which may include hepatic, renal, and respiratory failure. Although the pathophysiology of AP remains unclear, recent evidence suggests that activation of the polymorphonuclear leukocyte (PMN) is central to the evolution of remote organ injury and subsequent death .Excited with various cytokines, neutrophils release toxic free redicals and granules enzymes such as proteases , which make them play a key role in pancreatic local injury and remote organ failure. It is general believed that pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-a), interleukin-1 (IL-1), interleukin-6 (IL-6),IL-8, PAF ,some cell adhesion molecules, such as ICAM-1,integrins and free readicals are all responsible for pancreatic local injury and remote organs disfunction. Several experiments have been focused on antagonists of these molecules, but the kinds of these molecules are numerous. Recently, these molecules have been postulated to act locally, aggravating pancreatic injury, as well as systemically , to increase capillary permeability ,and promote leukocyte adherence , extravasation and ultimately through PMN activation. So, the timely clearance of activated neutrophils by macrophages will ameliorate prognosis of severe pancreatitis. In patients of severe pancreatitis , delayed neutrophils apoptosis have been demonstrated. This would suggest that activated neutrophils release more toxic agents and lead to persistence of inflammation. Neutrophils are short-lived, terminally differentiated blood cells that constitutively undergo apoptosis. Neutrophil apoptosis is believed critical to the resolution of acute inflammation and prevention of secondary tissue injury. Evidence suggests that apoptosis provides a mechanism for granulocyte deactivation. During apoptosis, PMNs lose the ability to adhere, phagocytose, degranulate, and secrete mediators in response to inflammatory stimuli. As cells die by means of apoptosis, they are cleared by macrophages. Throughout this process, neutrophil membranes remain intact, preventing leakage of proinflammatory intracellular contents. Furthermore, apoptotic PMNs do not stimulate cytokine secretion from ingesting macrophages, but can increase macrophages releasing agents such as TGF-? and PGE2 that have suppressive effects on the inflammatory response. In patients with burn injury, sepsis, systemic inflammatory response syndrome (SIRS) and reperfusion injury delayed neutrophil apoptosis have been found. Because neutrophils possess a variety of means of inducing tissue injury, delayed apoptosis of neutrophils may be implicated in the pathogenesis of persistent inflammatory states that might be implicated in multiple organ dysfunction syndrome and adult respiratory distress syndrome. Neutrophil express a number of the Bcl-2 family of proteins, but there are some discrepancies and ambiguities in the literature, largely because of the use of a variety of deferent methods to detect expression. It is now generally agreed that human neutrophils do not express the anti-apoptotic protein Bcl-2 but they constitutively express the pro-apoptotic proteins Bax, Bid, Bak and Bad. These proteins have a relatively long half life and hence their constitutive expression helps explain why bloodstream neutrophils have such a short survival time in the absence of Bcl-2 expression. Neutrophil also express anti-apoptotic protein, A1, Mcl-1, Bcl-xl, which have very short half lives . Hence, neutrophil apoptosis may be governed by the cellular levels of the relatively short-lived survival proteins, Bcl-xl, Mcl-1 and A1. In the absence of new synthesis of. Bcl-xl, Mcl-1 and A1, the activity of the longer lived pro-apoptotic proteins...
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