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Cytosolic phospholipase A₂ and arachidonic acid metabolites modulate ventilator-induced permeability increases in isolated mouse lungs

Departments of ¹Physiology and ²Pathology and ³Center for Lung Biology, University of South Alabama, Mobile, Alabama

Submitted 30 August 2006 ; accepted in final form 9 November 2007

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 (K_fc) after 30 min of ventilation with 9, 25, and 35 cmH₂O PIP. In high-PIP-ventilated lungs, K_fc 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 cPLA₂ 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 µM ibuprofen [a cyclooxygenase (COX) inhibitor], 100 µM nordihydroguaiaretic acid [a lipoxygenase (LOX) inhibitor], and 10 µM 17-octadecynoic acid (a cytochrome P-450 epoxygenase inhibitor) prevented the high-PIP-induced increase in K_fc. Combinations of the inhibitors of COX, LOX, or cytochrome P-450 epoxygenase did not prevent significant increases in K_fc, 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.

capillary permeability; ventilator-induced lung injury; cyclooxygenase; lipoxygenase; leukotrienes; cytochrome P-450