Selective eicosanoid-generating capacity of cytoplasmic phospholipase A2 in Pseudomonas aeruginosa-infected epithelial cells
Selective eicosanoid-generating capacity of cytoplasmic phospholipase A2 in Pseudomonas aeruginosa-infected epithelial cells
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DOI：
10.1152/ajplung.00147.2010
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发表时间：
2011-02-01
影响因子：
4.9
通讯作者：
McCormick, Beth A.
中科院分区：
文献类型：
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作者：
Hurley, Bryan P.;Pirzai, Waheed;McCormick, Beth A.
Hurley BP，Pirzai W，Mumy KL，Gronert K，McCormick BA.铜绿假单胞菌感染的上皮细胞胞质磷脂酶A（2）选择性产生类花生酸的能力。美国生理学杂志肺细胞分子生理学300：L286-L294，2011年。首次发表于2010年11月19日; doi：10.1152/ajplung.00147.2010.-气道中性粒细胞浸润是在包括肺炎和囊性纤维化在内的多种肺部疾病中观察到的病理标志。细菌病原体如铜绿假单胞菌促使中性粒细胞募集到空气空间。中性粒细胞在肺中的过度积聚通常会导致组织破坏。先前的研究已经揭示了肝氧素A（3）是驱动中性粒细胞穿过上皮屏障的关键分子信号。类花生酸肝氧素A（3）是一种有效的中性粒细胞化学引诱物，由上皮细胞响应铜绿假单胞菌感染产生。磷脂酶A（2）从膜磷脂中释放花生四烯酸，这是所有类花生酸合成的限速步骤，包括肝氧素A（3）。一旦产生，花生四烯酸被多种环加氧酶和脂氧合酶作用，产生一系列功能多样的类花生酸。虽然有许多磷脂酶A（2）亚型能够产生花生四烯酸，但最常与类花生酸产生相关的亚型是胞质磷脂酶A（2）α。在目前的研究中，我们观察到胞质磷脂酶A（2）α亚型是介导铜绿假单胞菌诱导的某些类花生酸如前列腺素E-2产生所必需的。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胞质磷脂酶A（2）α。此外，尽管胞质磷脂酶A（2）α受到抑制，但铜绿假单胞菌诱导的肝氧素A（3）的产生仍然存在，并且在这种情况下，12-脂氧合酶代谢物12-HETE的产生实际上得到了增强。这些结果表明，替代磷脂酶A（2）异构体被用来合成12-脂氧合酶代谢产物。当考虑基于靶向类花生酸合成途径的抗炎疗法时，这些发现的治疗意义是显著的。
Hurley BP, Pirzai W, Mumy KL, Gronert K, McCormick BA. Selective eicosanoid-generating capacity of cytoplasmic phospholipase A(2) in Pseudomonas aeruginosa-infected epithelial cells. Am J Physiol Lung Cell Mol Physiol 300: L286-L294, 2011. First published November 19, 2010; doi:10.1152/ajplung.00147.2010.-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)alpha. In the current study, we observed that the cytoplasmic phospholipase A(2)alpha 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)alpha. Furthermore, P. aeruginosa-induced hepoxilin A(3) production persists despite cytoplasmic phospholipase A(2)alpha 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.