Mechanotransduction of stretch-induced prostanoid release by fetal lung epithelial cells.
Mechanical ventilation is the primary supportive treatment for infants and adults suffering from severe respiratory failure. Adverse mechanical ventilation (overdistension 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 mechanotransduction 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(2alpha), 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.
Copland
Ian B
IB
Lung, The Hospital for Sick Children Research Institute, University of Toronto, Ontario Canada.
Reynaud
Denis
D
Pace-Asciak
Cecil
C
Post
Martin
M
D000818:Animals; D003470:Culture Media; D015777:Eicosanoids / Q000138:chemical synthesis*; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D008168:Lung / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D040542:Mechanotransduction, Cellular; D008954:Models, Biological; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012121:Respiration, Artificial; D013314:Stress, Mechanical
D003470:Culture Media; D015777:Eicosanoids; D011453:Prostaglandins; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A