title: HO-1 induction restores c-AMP-dependent lung epithelial fluid transport following severe hemorrhage in rats.
abstract: Inhibition of cAMP-dependent stimulation of the vectorial fluid transport across the lung epithelium following hemorrhagic shock is mediated by NO released within the airspaces of the lung. We tested here the hypothesis that prior induction of HO-1 would attenuate the release of NO in the airspaces, thus preventing the inhibition of the c-AMP stimulation of alveolar fluid clearance (ALC) in rats. Indeed, HO-1 induction restored the cAMP-mediated up-regulation of ALC after hemorrhage by decreasing NO released within the airspaces of the lung. In vitro studies demonstrated that HO-1 induction significantly reduced the iNOS-mediated release of NO by alveolar macrophages stimulated with endotoxin for 24 h. This effect is explained in part by a HO-1-dependent attenuation of the LPS-mediated nuclear translocation of NF-kappaB. In addition, HO-1 induction also significantly reduced the iNOS-mediated release of NO by MH-S cells that were stimulated with interferon-gamma by decreasing the phosphorylation of STAT 1, another transcription factor important for the activation of the iNOS promoter. In contrast, HO-1 induction did not affect the production of NO by rat alveolar epithelial type II cells that were stimulated with cytomix (a mixture of TNF-alpha, IL-1beta, and IFN-gamma) for 24 h. In summary, these results provide the first in vivo evidence that the induction of HO-1 in the lung restores a normal fluid transport capacity of the alveolar epithelium following hemorrhagic shock by inhibiting the iNOS-mediated release of NO by alveolar macrophages.
authors.affiliation: Laboratory of Surgical Research, Department of Anesthesia, Cardiovascular Research Institute, University of California, San Francisco, California, USA.
authors.forename: H
authors.initials: H
authors.lastname: Lee
authors.forename: M
authors.initials: M
authors.lastname: Pespeni
authors.forename: J
authors.initials: J
authors.lastname: Roux
authors.forename: P A
authors.initials: PA
authors.lastname: Dennery
authors.forename: M A
authors.initials: MA
authors.lastname: Matthay
authors.forename: J F
authors.initials: JF
authors.lastname: Pittet
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000502:physiology*; D001826:Body Fluids / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D004268:DNA-Binding Proteins; D004730:Endothelium, Vascular / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D004731:Endotoxins / Q000037:antagonists & inhibitors; D004789:Enzyme Activation / Q000502:physiology; D004790:Enzyme Induction / Q000502:physiology; D004847:Epithelial Cells / Q000201:enzymology / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism*; D018869:Heat-Shock Response / Q000502:physiology; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism* / Q000502:physiology; D051547:Heme Oxygenase-1; D006439:Hemodynamics / Q000502:physiology; D006470:Hemorrhage / Q000201:enzymology / Q000473:pathology*; D007371:Interferon-gamma / Q000378:metabolism; D053613:Janus Kinase 1; D008168:Lung / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology / Q000502:physiology; D016676:Macrophages, Alveolar / Q000201:enzymology / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology / Q000502:physiology; D011659:Pulmonary Gas Exchange / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D050794:STAT1 Transcription Factor; D012771:Shock, Hemorrhagic / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D015534:Trans-Activators
chemical_list: D004268:DNA-Binding Proteins; D004731:Endotoxins; D016328:NF-kappa B; D050794:STAT1 Transcription Factor; C494081:Stat1 protein, rat; D015534:Trans-Activators; D009569:Nitric Oxide; D007371:Interferon-gamma; D000242:Cyclic AMP; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D011505:Protein-Tyrosine Kinases; C507906:Jak1 protein, rat; D053613:Janus Kinase 1