Mechanotransduction of stretch-induced prostanoid release by fetal lung epithelial cells
Mechanotransduction of stretch-induced prostanoid release by fetal lung epithelial cells
复制标题
DOI：
10.1152/ajplung.00510.2005
复制
发表时间：
2006-09-01
影响因子：
4.9
通讯作者：
Post, Martin
中科院分区：
文献类型：
--
作者：
Copland, Ian B.;Reynaud, Denis;Post, Martin
机械通气是婴幼儿和成人严重呼吸衰竭的主要支持治疗方法。不利的机械通气(肺过度扩张)会引发促炎反应。除了细胞因子，生物活性脂类等炎症介质也参与了炎症反应的调节。花生四烯酸途径是生物活性脂质介质的关键来源，包括前列腺素类化合物。虽然已有研究表明，机械通气会影响肺内前列腺素的产生，但其机制-转导途径尚不清楚。在此，我们建立了循环拉伸胎儿肺上皮细胞，而不是成纤维细胞，可以通过环氧合酶(COX)-2依赖的机制在二十烷类代谢中引起极其敏感、快速的改变。周期性牵张可显著增加上皮细胞培养液中PGI(2)、PGF(2α)、PGD(2)、PGE(2)和血栓素B-2的水平，但不改变白三烯B-4或12-羟基二十碳四烯酸的水平。抑制COX-2，而不是COX-1，可减弱周期性拉伸引起的PG增加，表明周期性拉伸主要影响PG的合成。底物(游离花生四烯酸)可用于PG的生成，这是因为周期性拉伸通过细胞外钙内流和丝裂原激活的蛋白激酶p44/42MAPK激活胞浆磷脂酶A(2)(CPLA(2))而提高了PG生成的有效性。这些数据与CPLA(2)和COX-2密切参与调节不良机械通气的损伤反应是一致的。
Mechanical ventilation is the primary supportive treatment for infants and adults suffering from severe respiratory failure. Adverse mechanical ventilation (over-distension of the lung) triggers a proinflammatory response. Along with cytokines, inflammatory mediators such as bioactive lipids are involved in the regulation of the inflammatory response. The arachidonic acid pathway is a key source of bioactive lipid mediators, including prostanoids. Although ventilation has been shown to influence the production of prostanoids in the lung, the mech-anotransduction pathways are unknown. Herein, we established that cyclic stretch of fetal lung epithelial cells, but not fibroblasts, can evoke an extremely sensitive, rapid alteration in eicosanoid metabolism through a cyclooxygenase (COX)-2 dependent mechanism. Cyclic stretch significantly increased PGI(2), PGF(2 alpha), PGD(2), PGE(2), and thromboxane B-2 levels in the media of epithelial cells, but did not alter leukotriene B-4 or 12-hydroxyeicosatetraenoic acid levels. Inhibition of COX-2, but not COX-1, attenuated the cyclic stretch-induced PG increase in the media, suggesting that cyclic stretch primarily affected PG synthesis. Substrate (free arachidonic acid) availability for PG generation was increased because of a cyclic stretch-induced activation of cytosolic phospholipase A(2) (cPLA(2)) via an influx of extracellular calcium and phosphorylation by mitogen-activated protein kinase, p44/42MAPK. The data are compatible with cPLA(2) and COX-2 being intimately involved in regulating the injury response to adverse mechanical ventilation.