title: Thromboxane A2 exacerbates acute lung injury via promoting edema formation.
abstract: Thromboxane A2 (TXA2) is produced in the lungs of patients suffering from acute lung injury (ALI). We assessed its contribution in disease progression using three different ALI mouse models. The administration of hydrochloric acid (HCl) or oleic acid (OA)+ lipopolysaccharide (LPS) caused tissue edema and neutrophil infiltration with TXA2 production in the lungs of the experimental mice. The administration of LPS induced only neutrophil accumulation without TXA2 production. Pretreatment with T prostanoid receptor (TP) antagonist attenuated the tissue edema but not neutrophil infiltration in these models. Intravital imaging and immunostaining demonstrated that administration of TP agonist caused vascular hyper-permeability by disrupting the endothelial barrier formation in the mouse ear. In vitro experiments showed that TP-stimulation disrupted the endothelial adherens junction, and it was inhibited by Ca(2+) channel blockade or Rho kinase inhibition. Thus endogenous TXA2 exacerbates ALI, and its blockade attenuates it by modulating the extent of lung edema. This can be explained by the endothelial hyper-permeability caused by the activation of TXA2-TP axis, via Ca(2+)- and Rho kinase-dependent signaling.
authors: Department of Animal Radiology, Graduate school of Agriculture and Life Sciences, The University of Tokyo, Japan.
authors: Koji
authors: K
authors: Kobayashi
authors: Department of Animal Radiology, Graduate school of Agriculture and Life Sciences, The University of Tokyo, Japan.
authors: Daiki
authors: D
authors: Horikami
authors: Department of Animal Radiology, Graduate school of Agriculture and Life Sciences, The University of Tokyo, Japan.
authors: Keisuke
authors: K
authors: Omori
authors: Department of Animal Radiology, Graduate school of Agriculture and Life Sciences, The University of Tokyo, Japan.
authors: Tatsuro
authors: T
authors: Nakamura
authors: Department of Animal Radiology, Graduate school of Agriculture and Life Sciences, The University of Tokyo, Japan.
authors: Arisa
authors: A
authors: Yamazaki
authors: Department of Animal Radiology, Graduate school of Agriculture and Life Sciences, The University of Tokyo, Japan.
authors: Shingo
authors: S
authors: Maeda
authors: Department of Animal Radiology, Graduate school of Agriculture and Life Sciences, The University of Tokyo, Japan.
authors: Takahisa
authors: T
authors: Murata
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D006851:Hydrochloric Acid / Q000633:toxicity; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D019301:Oleic Acid / Q000633:toxicity; D011654:Pulmonary Edema / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D013928:Thromboxane A2 / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D019301:Oleic Acid; D013928:Thromboxane A2; D006851:Hydrochloric Acid