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1 Department of Surgery and Celluar and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana, USA
* To whom correspondence should be addressed. E-mail: dmeldrum{at}iupui.edu.
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 inhibitor chelerythrine. In separate experiments, pulmonary artery rings were treated with the protein kinase C activator
thymeleatoxin for 60 minutes. Following hypoxia or PKC activation, pulmonary artery rings were subjected to mRNA analysis for TNF-
and IL-1
via RT-PCR. Our results demonstrate that, in isolated pulmonary artery, hypoxia causes a biphasic contraction and increases expression of TNF- and IL-1 mRNA. Both effects are inhibited by chelerythrine. Protein kinase C activation resulted in pulmonary artery contraction and increased the pulmonary artery expression of TNF-
and IL-1 mRNA. These findings suggest that hypoxia induces the expression of inflammatory cytokines while increasing 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.
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