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Am J Physiol Lung Cell Mol Physiol 287: L1215-L1219, 2004. First published August 20, 2004; doi:10.1152/ajplung.00179.2004
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Hypoxic pulmonary vasoconstriction and pulmonary artery tissue cytokine expression are mediated by protein kinase C

Ben M. Tsai,1 Meijing Wang,1,2 Jeffrey M. Pitcher,1 Kirstan K. Meldrum,3 and Daniel R. Meldrum1,2,4

Departments of 1Surgery, 4Cellular and Integrative Physiology, and 3Urology, Indiana University School of Medicine; and 2Indiana Center for Vascular Biology and Medicine, Indianapolis, Indiana 46202

Submitted 18 May 2004 ; accepted in final form 12 August 2004

Pulmonary arteries exhibit a marked vasoconstriction when exposed to hypoxic conditions. Although this may be an adaptive response to match lung ventilation with perfusion, the potential consequences of sustained pulmonary vasoconstriction include pulmonary hypertension and right heart failure. Concomitant production of proinflammatory mediators during hypoxia may exacerbate acute increases in pulmonary vascular resistance. We hypothesized that acute hypoxia causes pulmonary arterial contraction and increases the pulmonary artery tissue expression of proinflammatory cytokines via a protein kinase C (PKC)-mediated mechanism. To study this, isometric force displacement was measured in isolated rat pulmonary artery rings during hypoxia in the presence and absence of the PKC inhibitors calphostin C or chelerythrine. In separate experiments, pulmonary artery rings were treated with the PKC activator thymeleatoxin for 60 min. After hypoxia, with or without PKC inhibition, or PKC activation alone, pulmonary artery rings were subjected to mRNA analysis for TNF-{alpha} and IL-1{beta} via RT-PCR. Our results showed that, in isolated pulmonary arteries, hypoxia caused a biphasic contraction and increased expression of TNF-{alpha} and IL-1{beta} mRNA. Both effects were inhibited by PKC inhibition. PKC activation resulted in pulmonary artery contraction and increased the pulmonary artery expression of TNF-{alpha} and IL-1{beta} mRNA. These findings suggest that hypoxia induces the expression of inflammatory cytokines and causes vasoconstriction via a PKC-dependent mechanism. We conclude that PKC may have a central role in modulating hypoxic pulmonary vasoconstriction, and further elucidation of its involvement may lead to therapeutic application.

hypoxia; pulmonary hypertension; inflammation; tumor necrosis factor


Address for reprint requests and other correspondence: D. R. Meldrum, 545 Barnhill Dr., Emerson Hall 215, Indianapolis, IN 46202 (E-mail: dmeldrum{at}iupui.edu)




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