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J. Biol. Chem., Vol. 275, Issue 28, 21468-21476, July 14, 2000
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From the Columbia University, College of Physicians and Surgeons,
New York, New York 10032
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 (
Potentiation of Endogenous Fibrinolysis and Rescue from Lung
Ischemia/Reperfusion Injury in Interleukin (IL)-10-reconstituted
IL-10 Null Mice*
/) 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.
*
This work was supported in part by the U. S. Public Health
Service, National Institutes of Health, Grants R01 HL55397, R01 HL59488, and R01 60900.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
An Established Investigator of the American Heart Association. To
whom correspondence should be addressed: Columbia University, College
of Physicians and Surgeons, PH 10 Stem, 630 West, 168th St., New York,
NY 10032. Tel.: 212-305-6071; Fax: 212-305-7638; E-mail
djp5@columbia.edu.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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