Cytosolic phospholipase A2 and arachidonic acid metabolites modulate ventilator-induced permeability increases in isolated mouse lungs
We previously reported that the cytosolic phospholipase A2 (cPLA2) pathway is involved in ventilator-induced lung injury (VILI) produced by high peak inflation pressures (PIP) (J Appl Physiol 98: 1264-1271, 2005), but the relative contributions of the various downstream products of cPLA2 on the acute permeability response were not determined. Therefore, we investigated the role of cPLA2 and the downstream products of arachidonic acid metabolism in the high-PIP ventilation-induced increase in vascular permeability. We perfused isolated mouse lungs and measured the capillary filtration coefficient (Kfc) after 30 min of ventilation with 9, 25, and 35 cmH2O PIP. In high-PIP-ventilated lungs, Kfc increased significantly, 2.7-fold, after ventilation with 35 cmH2O PIP compared with paired baseline values and low-PIP-ventilated lungs. Also, increased phosphorylation of lung cPLA 2 suggested enzyme activation after high-PIP ventilation. However, treatment with 40 mg/kg arachidonyl trifluoromethyl ketone (an inhibitor of cPLA2) or a combination of 30 ÂµM ibuprofen [a cyclooxygenase (COX) inhibitor], 100 ÂµM nordihydroguaiaretic acid [a lipoxygenase (LOX) inhibitor], and 10 ÂµM 17-octadecynoic acid (a cytochrome P-450 epoxygenase inhibitor) prevented the high-PIP-induced increase in Kfc. Combinations of the inhibitors of COX, LOX, or cytochrome P-450 epoxygenase did not prevent significant increases in Kfc, even though bronchoalveolar lavage levels of the COX or LOX products were significantly reduced. These results suggest that multiple mediators from each pathway contribute to the acute ventilator-induced permeability increase in isolated mouse lungs by mutual potentiation. Copyright Â© 2008 the American Physiological Society.
Journal of applied physiology
Miyahara, T.; Hamanaka, K.; Weber, D. S.; Anghelescu, Mircea; Frost, J. R.; King, J. A.; and Parker, J. C., "Cytosolic phospholipase A2 and arachidonic acid metabolites modulate ventilator-induced permeability increases in isolated mouse lungs" (2008). PCOM Scholarly Papers. 1523.