Complete reversal of acid-induced acute lung injury by blocking of platelet-neutrophil aggregation.
Acute lung injury (ALI) causes high mortality, but its molecular mechanisms are poorly understood. Acid aspiration is a frequent cause of ALI, leading to neutrophil sequestration, increased permeability, and deterioration of gas exchange. We investigated the role of platelet-neutrophil interactions in a murine model of acid-induced ALI. Acid aspiration induced P-selectin-dependent platelet-neutrophil interactions in blood and in lung capillaries. Reducing circulating platelets or blocking P-selectin halted the development of ALI. Bone marrow chimeras showed that platelet, not endothelial, P-selectin was responsible for the injury. The interaction of platelets with neutrophils and endothelia was associated with TXA(2) formation, with detrimental effects on permeability and tissue function. Activated platelets induced endothelial expression of ICAM-1 and increased neutrophil adhesion. Inhibition of platelet-neutrophil aggregation improved gas exchange, reduced neutrophil recruitment and permeability, and prolonged survival. The key findings were confirmed in a sepsis-induced model of ALI. These findings may translate into improved clinical treatments for ALI.
Zarbock
Alexander
A
Robert M Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908-1394, USA.
Singbartl
Kai
K
Ley
Klaus
K
D000143:Acids / Q000633:toxicity*; D000818:Animals; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects; D002066:Busulfan / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D002450:Cell Communication / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D019007:P-Selectin / Q000378:metabolism / Q000502:physiology; D015539:Platelet Activation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors; D012128:Respiratory Distress Syndrome / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*
D000143:Acids; D019007:P-Selectin; D017482:Receptors, Thromboxane; D002066:Busulfan