title: Platelets induce endothelial tissue factor expression in a mouse model of acid-induced lung injury.
abstract: Although the lung expresses procoagulant proteins under inflammatory conditions, underlying mechanisms remain unclear. Here, we addressed lung endothelial expression of tissue factor (TF), which initiates the coagulation cascade and expression of which signifies development of a procoagulant phenotype in the vasculature. To establish the model of acid-induced acute lung injury (ALI), we intranasally instilled anesthetized mice with saline or acid. Then 2 h later, we isolated pulmonary vascular cells for flow cytometry and confocal microscopy to detect the leukocyte antigen, CD45 and the endothelial markers VE-cadherin and von Willebrand factor (vWf). Acid increased both the number of vWf-expressing cells as well as TF and P-selectin expressions on these cells. All of these effects were markedly inhibited by treating mice with antiplatelet serum, suggesting the involvement of platelets. The increased expressions of TF, vWf, and P-selectin in response to acid also occurred in platelets. Moreover, the effects were replicated in endothelial cells derived from isolated, blood-perfused lungs. However, the effect was inhibited completely in lungs perfused with platelet-depleted and, to a lesser extent, with leukocyte-depleted blood. Acid injury increased endothelial expressions of the platelet proteins, CD41 and CD42b, providing evidence that platelet proteins were transferred to the vascular surface. Reactive oxygen species (ROS) were implicated in these responses, in that the endothelial and platelet protein expressions were inhibited. We conclude that acid-induced ALI causes NOX2-mediated ROS generation that activates platelets, which then generate a procoagulant endothelial surface.
authors.affiliation: Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
authors.forename: Memet T
authors.initials: MT
authors.lastname: Emin
authors.forename: Li
authors.initials: L
authors.lastname: Sun
authors.forename: Alice
authors.initials: A
authors.lastname: Huertas
authors.forename: Shonit
authors.initials: S
authors.lastname: Das
authors.forename: Jahar
authors.initials: J
authors.lastname: Bhattacharya
authors.forename: Sunita
authors.initials: S
authors.lastname: Bhattacharya
mesh_terms: D055371:Acute Lung Injury / Q000097:blood* / Q000139:chemically induced*; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D001777:Blood Coagulation; D001792:Blood Platelets / Q000276:immunology / Q000378:metabolism*; D015820:Cadherins / Q000096:biosynthesis; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism*; D006851:Hydrochloric Acid / Q000009:adverse effects / Q000633:toxicity; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D008168:Lung / Q000276:immunology / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D019007:P-Selectin / Q000096:biosynthesis / Q000378:metabolism; D015539:Platelet Activation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000276:immunology; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000096:biosynthesis; D040201:Platelet Membrane Glycoprotein IIb / Q000096:biosynthesis; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013925:Thromboplastin / Q000096:biosynthesis* / Q000378:metabolism; D014841:von Willebrand Factor / Q000096:biosynthesis / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D006851:Hydrochloric Acid; D017493:Leukocyte Common Antigens; D008562:Membrane Glycoproteins; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D019007:P-Selectin; D010975:Platelet Aggregation Inhibitors; D019038:Platelet Glycoprotein GPIb-IX Complex; D040201:Platelet Membrane Glycoprotein IIb; D017382:Reactive Oxygen Species; D013925:Thromboplastin; D014841:von Willebrand Factor; D000099152:Cadherin 5; C488842:Cybb protein, mouse