Tec酪氨酸蛋白激酶通路在重症急性胰腺炎肺损伤中作用的研究

Acute lung injury (ALI) is a major cause of mortality in severe acute pancreatitis.It has been proposed that the occurrence of ALI in severe acute pancreatitis is associated with the dysregulated inflammatory response, and neutrophils and macrophages are key immunocytes in this pathogenetic process. Tec, a member of the Tec family of non-receptor type protein tyrosine kinases, plays an important role in the regulation of immune function. We have found that Tec kinase is overexpressed in the lung tissue of acute pancreatitis mice model. Moreover, the overexpressed Tec kinase could inhibit the apoptosis of neutrophils and macrophages. However, the detailed mechanism of Tec kinase in the pathogenesis of ALI in severe acute pancreatitis is still unclear. In this study, the expressions of Tec kinase and related molecules are detected in the peripheral blood of severe acute pancreatitis patients with ALI, and the role of Tec kinase is initially established. Then the mice model of acute pancreatitis with ALI is established, and gene knockout, gene transfection, RNA interference and small molecular blockers will be applied to up or down regulate the expression of Tec kinase in neutrophils and macrophages. The expression of the molecules involved in the signal transduction pathway of Tec kinase, as well as the function of Tec kinase in cell migration, proliferation and apoptosis will be investigated to explore the possible molecular mechanism of Tec kinase in the pathogenesis of pulmonary damage. This study will provide a new target for the prevention and treatment of the acute lung injury in severe acute pancreatitis.

重症急性胰腺炎并发的急性肺损伤（ALI）是导致患者死亡的重要原因。目前认为失控的炎症反应参与了重症胰腺炎ALI的发生，且中性粒细胞和巨噬细胞是导致胰腺炎ALI的重要免疫细胞。Tec酪氨酸蛋白激酶是调节机体免疫功能的重要分子，我们前期工作证实Tec激酶在胰腺炎模型小鼠肺组织中高表达，且可减少中性粒细胞和巨噬细胞的凋亡，但Tec激酶参与胰腺炎ALI的具体机制尚不明确。本研究拟首先检测重症急性胰腺炎ALI患者外周血Tec激酶及相关信号分子的表达改变，初步确立Tec激酶参与胰腺炎ALI；建立胰腺炎肺损伤小鼠模型，采用基因敲除、基因转染、RNA干扰和小分子阻断剂等手段，增强或抑制Tec激酶在中性粒细胞、巨噬细胞中的表达，观察Tec激酶相关信号分子的表达改变及细胞迁移、增殖和凋亡等功能异常，并探讨与肺损伤的相关性，以明确Tec激酶参与胰腺炎ALI的分子机理，为预防和治疗胰腺炎ALI提供新的思路和靶点。