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Hypoxia-induced acute lung injury in murine models of sickle cell disease. Am J Physiol Lung Cell Mol Physiol 2004 Apr;286(4):L705-14

Date

09/16/2003

Pubmed ID

12972407

DOI

10.1152/ajplung.00288.2002

Scopus ID

2-s2.0-12144291636   57 Citations

Abstract

Vaso-occlusive events are the major source of morbidity and mortality in sickle cell disease (SCD); however, the pathogenic mechanisms driving these events remain unclear. Using hypoxia to induce pulmonary injury, we investigated mechanisms by which sickle hemoglobin increases susceptibility to lung injury in a murine model of SCD, where mice either exclusively express the human alpha/sickle beta-globin (halphabetaS) transgene (SCD mice) or are heterozygous for the normal murine beta-globin gene and express the halphabetaS transgene (mbeta+/-, halphabetaS+/-; heterozygote SCD mice). Under normoxia, lungs from the SCD mice contained higher levels of xanthine oxidase (XO), nitrotyrosine, and cGMP than controls (C57BL/6 mice). Hypoxia increased XO and nitrotyrosine and decreased cGMP content in the lungs of all mice. After hypoxia, vascular congestion was increased in lungs with a greater content of XO and nitrotyrosine. Under normoxia, the association of heat shock protein 90 (HSP90) with endothelial nitric oxide synthase (eNOS) in lungs of SCD and heterozygote SCD mice was decreased compared with the levels of association in lungs of controls. Hypoxia further decreased association of HSP90 with eNOS in lungs of SCD and heterozygote SCD mice, but not in the control lungs. Pretreatment of rat pulmonary microvascular endothelial cells in vitro with xanthine/XO decreased A-23187-stimulated nitrite + nitrate production and HSP90 interactions with eNOS. These data support the hypotheses that hypoxia increases XO release from ischemic tissues and that the local increase in XO-induced oxidative stress can then inhibit HSP90 interactions with eNOS, decreasing *NO generation and predisposing the lung to vaso-occlusion.

Author List

Pritchard KA Jr, Ou J, Ou Z, Shi Y, Franciosi JP, Signorino P, Kaul S, Ackland-Berglund C, Witte K, Holzhauer S, Mohandas N, Guice KS, Oldham KT, Hillery CA

Authors

Keith T. Oldham MD Professor in the Surgery department at Medical College of Wisconsin
Kirkwood A. Pritchard PhD Professor in the Surgery department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Acute Disease
Anemia, Sickle Cell
Animals
Disease Models, Animal
HSP90 Heat-Shock Proteins
Hemoglobin, Sickle
Humans
Hypoxia
Lung Diseases
Mice
Mice, Inbred C57BL
Mice, Transgenic
Nitric Oxide
Nitric Oxide Synthase
Nitric Oxide Synthase Type II
Nitric Oxide Synthase Type III
Tyrosine
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a