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This Article Full Text Full Text (PDF) All Versions of this Article: 291/3/L487    most recent 00510.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Copland, I. B. Articles by Post, M. Search for Related Content PubMed PubMed Citation Articles by Copland, I. B. Articles by Post, M.

Mechanotransduction of stretch-induced prostanoid release by fetal lung epithelial cells

¹Lung and ³Integrative Biology Programs, The Hospital for Sick Children Research Institute and Departments of ²Pharmacology, ⁴Laboratory Medicine and Pathobiology, and ⁵Pediatrics, University of Toronto, Toronto, Ontario Canada

Submitted 5 December 2005 ; accepted in final form 6 April 2006

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 PGI₂, PGF₂, PGD₂, PGE₂, and thromboxane B₂ levels in the media of epithelial cells, but did not alter leukotriene B₄ 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 A₂ (cPLA₂) via an influx of extracellular calcium and phosphorylation by mitogen-activated protein kinase, p44/42MAPK. The data are compatible with cPLA₂ and COX-2 being intimately involved in regulating the injury response to adverse mechanical ventilation.

cyclooxygenase-2; phospholipase A₂; calcium; mechanical ventilation

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