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Clara cell secretory protein and phospholipase A₂ activity modulate acute ventilator-induced lung injury in mice

¹Physiology and ²Pediatrics, ³Center for Lung Biology, University of South Alabama, Mobile, Alabama; and ⁴Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania

Submitted 12 October 2004 ; accepted in final form 19 November 2004

Lung vascular permeability is acutely increased by high-pressure and high-volume ventilation. To determine the roles of mechanically activated cytosolic PLA₂ (cPLA₂) and Clara cell secretory protein (CCSP), a modulator of cPLA₂ activity, we compared lung injury with and without a PLA₂ inhibitor in wild-type mice and CCSP-null mice (CCSP^–/–) ventilated with high and low peak inflation pressures (PIP) for 2- or 4-h periods. After ventilation with high PIP, we observed significant increases in the bronchoalveolar lavage albumin concentrations, lung wet-to-dry weight ratios, and lung myeloperoxidase in both genotypes compared with unventilated controls and low-PIP ventilated mice. All injury variables except myeloperoxidase were significantly greater in the CCSP^–/– mice relative to wild-type mice. Inhibition of cPLA₂ in wild-type and CCSP^–/– mice ventilated at high PIP for 4 h significantly reduced bronchoalveolar lavage albumin and total protein and lung wet-to-dry weight ratios compared with vehicle-treated mice of the same genotype. Membrane phospho-cPLA₂ and cPLA₂ activities were significantly elevated in lung homogenates of high-PIP ventilated mice of both genotypes but were significantly higher in the CCSP^–/– mice relative to the wild-type mice. Inhibition of cPLA₂ significantly attenuated both the phospho-cPLA₂ increase and increased cPLA₂ activity due to high-PIP ventilation. We propose that mechanical activation of the cPLA₂ pathway contributes to acute high PIP-induced lung injury and that CCSP may reduce this injury through inhibition of the cPLA₂ pathway and reduction of proinflammatory products produced by this pathway.

capillary permeability; arachidonyl trifluoromethyl ketone; mechanical stress; knockout mice

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