Mucosal Immunology, Massachusetts General Hospital, Charlestown, 02129, USA.
Am J Physiol Lung Cell Mol Physiol. 2011 Feb;300(2):L286-94. doi: 10.1152/ajplung.00147.2010. Epub 2010 Nov 19.
Airway neutrophil infiltration is a pathological hallmark observed in multiple lung diseases including pneumonia and cystic fibrosis. Bacterial pathogens such as Pseudomonas aeruginosa instigate neutrophil recruitment to the air space. Excessive accumulation of neutrophils in the lung often contributes to tissue destruction. Previous studies have unveiled hepoxilin A(3) as the key molecular signal driving neutrophils across epithelial barriers. The eicosanoid hepoxilin A(3) is a potent neutrophil chemoattractant produced by epithelial cells in response to infection with P. aeruginosa. The enzyme phospholipase A(2) liberates arachidonic acid from membrane phospholipids, the rate-limiting step in the synthesis of all eicosanoids, including hepoxilin A(3). Once generated, aracidonic acid is acted upon by multiple cyclooxygenases and lipoxygenases producing an array of functionally diverse eicosanoids. Although there are numerous phospholipase A(2) isoforms capable of generating arachidonic acid, the isoform most often associated with eicosanoid generation is cytoplasmic phospholipase A(2)α. In the current study, we observed that the cytoplasmic phospholipase A(2)α isoform is required for mediating P. aeruginosa-induced production of certain eicosanoids such as prostaglandin E(2). However, we found that neutrophil transepithelial migration induced by P. aeruginosa does not require cytoplasmic phospholipase A(2)α. Furthermore, P. aeruginosa-induced hepoxilin A(3) production persists despite cytoplasmic phospholipase A(2)α suppression and generation of the 12-lipoxygenase metabolite 12-HETE is actually enhanced in this context. These results suggest that alterative phospholipase A(2) isoforms are utilized to synthesize 12-lipoxygenase metabolites. The therapeutic implications of these findings are significant when considering anti-inflammatory therapies based on targeting eicosanoid synthesis pathways.
气道中性粒细胞浸润是多种肺部疾病（包括肺炎和囊性纤维化）的病理标志。细菌病原体如铜绿假单胞菌引发中性粒细胞向气道空间募集。肺内中性粒细胞的过度积聚常常导致组织破坏。先前的研究揭示了海魄啉 A(3)是驱动中性粒细胞穿过上皮屏障的关键分子信号。类二十烷酸海魄啉 A(3)是上皮细胞在感染铜绿假单胞菌时产生的一种强效中性粒细胞趋化因子。酶磷脂酶 A(2)从膜磷脂中释放出花生四烯酸，这是所有类二十烷酸（包括海魄啉 A(3)）合成的限速步骤。一旦生成，花生四烯酸就会被多种环氧化酶和脂氧合酶作用，产生一系列功能不同的类二十烷酸。虽然有许多能够产生花生四烯酸的磷脂酶 A(2)同工酶，但与类二十烷酸生成最相关的同工酶是细胞质磷脂酶 A(2)α。在本研究中，我们观察到细胞质磷脂酶 A(2)α同工酶对于介导铜绿假单胞菌诱导的某些类二十烷酸（如前列腺素 E(2)）的产生是必需的。然而，我们发现铜绿假单胞菌诱导的中性粒细胞跨上皮迁移并不需要细胞质磷脂酶 A(2)α。此外，尽管抑制细胞质磷脂酶 A(2)α后，铜绿假单胞菌诱导的海魄啉 A(3)产生仍持续存在，并且在此情况下，12-脂氧合酶代谢物 12-HETE 的生成实际上增强。这些结果表明，替代的磷脂酶 A(2)同工酶被用于合成 12-脂氧合酶代谢物。考虑到基于靶向类二十烷酸合成途径的抗炎治疗，这些发现具有重要的治疗意义。
