Acute lung injury by sepsis and acid aspiration: a key role for cytosolic phospholipase A2.
Adult respiratory distress syndrome (ARDS) is characterized by acute lung injury with a high mortality rate and yet its mechanism is poorly understood. Sepsis syndrome and acid aspiration are the most frequent causes of ARDS, leading to increased lung permeability, enhanced polymorphonuclear neutrophil (PMN) sequestration and respiratory failure. Using a murine model of acute lung injury induced by septic syndrome or acid aspiration, we investigated the role of cytosolic phospholipase A2 (cPLA2) in ARDS. We found that disruption of the gene encoding cPLA2 significantly reduced pulmonary edema, PMN sequestration and deterioration of gas exchange caused by lipopolysaccharide and zymosan administration. Acute lung injury induced by acid aspiration was similarly reduced in mice with a disrupted cpla2 gene. Our observations suggest that cPLA2 is a mediator of acute lung injury induced by sepsis syndrome or acid aspiration. Thus, the inhibition of cPLA2-initiated pathways may provide a therapeutic approach to acute lung injury, for which no pharmaceutical agents are currently effective.
Nagase
T
T
Department of Geriatric Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113, Japan.
Uozumi
N
N
Ishii
S
S
Kume
K
K
Izumi
T
T
Ouchi
Y
Y
Shimizu
T
T
D000818:Animals; D004791:Enzyme Inhibitors / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D054467:Phospholipases A2; D011015:Pneumonia, Aspiration / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D012128:Respiratory Distress Syndrome / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D018746:Systemic Inflammatory Response Syndrome / Q000201:enzymology* / Q000235:genetics / Q000276:immunology
D004791:Enzyme Inhibitors; D010741:Phospholipases A; D054467:Phospholipases A2