Clara cell secretory protein and phospholipase A2 activity modulate acute ventilator-induced lung injury in mice.
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.
Yoshikawa
Sawako
S
Dept. of Physiology, MSB 3074, Univ. of South Alabama, Mobile, AL 36688, USA.
Miyahara
Takashige
T
Reynolds
Susan D
SD
Stripp
Barry R
BR
Anghelescu
Mircea
M
Eyal
Fabien G
FG
Parker
James C
JC
D000222:Adaptation, Physiological; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D008168:Lung / Q000503:physiopathology*; D055370:Lung Injury; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054467:Phospholipases A2; D012123:Pulmonary Ventilation; D012121:Respiration, Artificial / Q000009:adverse effects*; D014598:Uteroglobin / Q000172:deficiency / Q000378:metabolism*; D012122:Ventilators, Mechanical / Q000009:adverse effects*
D001095:Arachidonic Acids; C556390:Scgb1a1 protein, mouse; C081565:arachidonyltrifluoromethane; D014598:Uteroglobin; D010741:Phospholipases A; D054467:Phospholipases A2