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1 Department of Biomedical Sciences,, Colorado State University, Fort Collins, CO, USA
2 Department of Anesthesiology, Univesity of Colorado Health Science Center, Denver, CO, USA
* To whom correspondence should be addressed. E-mail: Davidcirwin{at}earthlink.net.
Atrial natriuretic peptide (ANP) has been shown to reduce hypoxia-induced pulmonary vascular leak in vivo, but no explanation of a mechanism as been offered other than its
vasodiltory and natriuretic actions. Recently, data has shown that ANP can protect endothelial barrier functions in TNF-
-stimulated human umbilical vein endothelial cells (HUVEC). Therefore, we hypothesized that ANP actions would inhibit pulmonary vascular leak by inhibition of TNF- secretion and F-actin formation. Bovine pulmonary microvascular (MVEC) and macrovascular (LEC) endothelial cell monolayers were
stimulated with hypoxia, TNF- or bacterial endotoxin (LPS) in the presence or absence of ANP, and albumin flux, NF-B activation, TNF- secretion, p38 mitogen activated protein kinase (MAPK) and F-actin (stress fiber) formation were assessed. In transwell cultures ANP reduced hypoxia-induced permeability in MVEC, and TNF--induced
permeability in MVEC and LEC. ANP inhibited hypoxia and LPS increased NF-
B activation and TNF- synthesis in MVEC and LEC. Hypoxia decreased activation of
p38 MAPK in MVEC, but increased activation of p38 MAPK and stress fiber formation in LEC. TNF- had the opposite effect. ANP inhibited an activation of p38 MAPK in
MVEC or LEC. These data indicate that in endothelial cell monolayers, hypoxia activates a signal cascade analogous to that initiated by inflammatory agents, and ANP has a direct cytoprotective affect on the pulmonary endothelium other then its vasodilatory and natriuretic properties. Furthermore, our data shows that MVEC and LEC respond
differently to hypoxia, TNF--stimulation and ANP treatment.
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