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: K Okada, T Fujita, K Minamoto, H Liao, Y Naka, D J Pinsky
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 275 Issue 28 Pg. 21468-76 (Jul 14 2000) ISSN: 0021-9258 [Print] United States
• PMID: 10806208 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Interleukin-1
• Plasminogen Activator Inhibitor 1
• Intercellular Adhesion Molecule-1
• Interleukin-10
• Fibrin
• Tissue Plasminogen Activator

Topics

• Animals
• Fibrin (metabolism)
• Fibrinolysis (drug effects, immunology)
• Inflammation
• Intercellular Adhesion Molecule-1 (blood)
• Interleukin-1 (blood, genetics)
• Interleukin-10 (deficiency, genetics, pharmacology, physiology)
• Ischemia (blood, immunology)
• Lung (blood supply, immunology, physiopathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Plasminogen Activator Inhibitor 1 (genetics)
• Reperfusion Injury (blood, drug therapy, immunology)
• Tissue Plasminogen Activator (genetics)
• Transcription, Genetic