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This Article Full Text Full Text (PDF) All Versions of this Article: 288/5/L849    most recent 00294.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (16) Citing Articles via Google Scholar Google Scholar Articles by Irwin, D. C. Articles by Bowen, R. Search for Related Content PubMed PubMed Citation Articles by Irwin, D. C. Articles by Bowen, R.

Direct ANP inhibition of hypoxia-induced inflammatory pathways in pulmonary microvascular and macrovascular endothelial monolayers

¹Department of Biomedical Sciences, College of Veterinary and Biomedical Sciences, Colorado State University, Fort Collins, and ²Department of Anesthesiology, University of Colorado Health Science Center, Denver, Colorado

Submitted 5 August 2004 ; accepted in final form 16 December 2004

Atrial natriuretic peptide (ANP) has been shown to reduce hypoxia-induced pulmonary vascular leak in vivo, but no explanation of a mechanism has been offered other than its vasodilatory and natriuretic actions. Recently, data have shown that ANP can protect endothelial barrier functions in TNF--stimulated human umbilical vein endothelial cells. 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 endothelial cell (LEC) 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 effect on the pulmonary endothelium other than its vasodilatory and natriuretic properties. Furthermore, our data show that MVEC and LEC respond differently to hypoxia, TNF--stimulation, and ANP treatment.

altitude; atrial natriuretic peptide; endothelial cell permeability; tumor necrosis factor-; lipopolysaccharide

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