title: Potentiation of endogenous fibrinolysis and rescue from lung ischemia/reperfusion injury in interleukin (IL)-10-reconstituted IL-10 null mice.
abstract: Little is known about interactions between endogenous anti-inflammatory paradigms and microvascular thrombosis in lung ischemia/reperfusion (I/R) injury. Interleukin (IL)-10 suppresses macrophage activation and down-regulates proinflammatory cytokine production, but there are no available data to suggest a link between IL-10, thrombosis, and fibrinolysis in the setting of I/R. We hypothesized that hypoxia/ischemia triggers IL-10 production, to dampen proinflammatory cytokine and adhesion receptor cascades and to restore vascular patency by fibrinolytic potentiation. Studies were performed in a mouse lung I/R model. IL-10 mRNA levels in lung were increased 43-fold over base line by 1 h of ischemia/2 h of reperfusion, with a corresponding increase in plasma IL-10. Expression was prominently localized in bronchial epithelial cells and mononuclear phagocytes. To study the link between IL-10 and fibrinolysis in vivo, the induction of plasminogen activator inhibitor-1 (PAI-1) was evaluated. Northern analysis demonstrated exaggerated pulmonary PAI-1 expression in IL-10 (-/-) mice after I/R, with a corresponding increase in plasma PAI/tissue-type plasminogen activator activity. In vivo, IL-10 (-/-) mice showed poor postischemic lung function and survival after I/R compared with IL-10 (+/+) mice. Despite a decrease in infiltration of mononuclear phagocytes in I/R lungs of IL-10 (-/-) mice, an increased intravascular pulmonary fibrin deposition was observed by immunohistochemistry and Western blotting, along with increased IL-1 expression. Recombinant IL-10 given to IL-10 (-/-) mice normalized the PAI/tissue-type plasminogen activator ratio, reduced pulmonary vascular fibrin deposition, and rescued mice from lung injury. Since recombinant hirudin (direct thrombin inhibitor) also sufficed to rescue IL-10 (-/-) mice, these data suggest a preeminent role for microvascular thrombosis in I/R lung injury. Ischemia-driven IL-10 expression confers postischemic pulmonary protection by augmenting endogenous fibrinolytic mechanisms.
authors.affiliation: Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA.
authors.forename: K
authors.initials: K
authors.lastname: Okada
authors.forename: T
authors.initials: T
authors.lastname: Fujita
authors.forename: K
authors.initials: K
authors.lastname: Minamoto
authors.forename: H
authors.initials: H
authors.lastname: Liao
authors.forename: Y
authors.initials: Y
authors.lastname: Naka
authors.forename: D J
authors.initials: DJ
authors.lastname: Pinsky
mesh_terms: D000818:Animals; D005337:Fibrin / Q000378:metabolism; D005342:Fibrinolysis / Q000187:drug effects / Q000276:immunology*; D007249:Inflammation; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D007375:Interleukin-1 / Q000097:blood / Q000235:genetics; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology*; D007511:Ischemia / Q000097:blood / Q000276:immunology*; D008168:Lung / Q000098:blood supply* / Q000276:immunology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D015427:Reperfusion Injury / Q000097:blood / Q000188:drug therapy / Q000276:immunology*; D010959:Tissue Plasminogen Activator / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D007375:Interleukin-1; D017395:Plasminogen Activator Inhibitor 1; D018799:Intercellular Adhesion Molecule-1; D016753:Interleukin-10; D005337:Fibrin; D010959:Tissue Plasminogen Activator