hif1α在ifnγ及tnfα协同引起肠上皮屏障功能损害中的作用-the role of hi f1 α in the intestinal epithelial barrier function damage caused by ifn γ and tnf α synergistically.docxVIP

第三军医大学硕士学位论文 第三军医大学硕士学位论文 PAGE PAGE 3 Role of HIF-1α in intestinal epithelial barrier dysfunction induced by synergy of interferon-γ and tumor necrosis factor-α Abstract Background Aims: Intestinal epithelial barrier dysfunction is one of the most important mechanisms in the pathophysiological disturbance occurred at the early stage of severe burn injury. Affected by postburn stress, ischemia, hypoxia and inflammation, the production of systemic and intestinal proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ) and interleukin 1 beta (IL-1β), was sharply increased. What the relationship between these proinflammatory cytokines and postburn intestinal epithelial barrier dysfunction is, and whether these proinflammatory cytokines participate in the pathogenesis of intestinal epithelial barrier dysfunction or not? If they do take part in it, what the mechanism is? The existing data can’t give us a satisfactory answer yet. Previous studies have demonstrated that some inflammatory cytokines, including IFN-γ, TNF-α, IL-1β, are capable of inducing intestinal epithelial barrier dysfunction individually or synergistically. It has been reported that some inflammatory cytokines disrupt intestinal epithelial barrier function by inducing the expression of myosin light chain kinase (MLCK), increasing myosin light chain (MLC) phosphorylation, causing the reorganization of tight junction proteins ZO-1, occludin and claudin-1, however，the precise mechanism by which inflammatory cytokines induce the upregulation of MLCK remains unclear. Hypoxia inducible factor-1 (HIF-1), a heterodimer of HIF-1α and HIF-1β, is a transcription factor believed to be the master regulator of oxygen homeostasis. The expression of HIF-1α subunit is regulated by oxygen concentration, while HIF-1β subunit expresses constitutively. It has been demonstrated that HIF-1α is also a key regulator in inflammation, and that oxygen is not the only factor regulating HIF-