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1 Lung Biology Program, Hospital for Sick Children, Toronto, Canada; Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
2 Integrative Biology Program, Hospital for Sick Children, Toronto, Canada
3 Integrative Biology Program, Hospital for Sick Children, Toronto, Canada; Pharmacology, University of Toronto, Toronto, Canada
4 Lung Biology Program, Hospital for Sick Children, Toronto, Canada; Pediatrics, University of Toronto, Toronto, Canada; Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
* To whom correspondence should be addressed. E-mail: martin.post{at}sickkids.ca.
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 TXB2 levels in the media of epithelial cells, but did not alter LTB4 or 12-HETE 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 prostaglandin generation was increased due to 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.
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