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
09/16/2003Pubmed ID
12972407DOI
10.1152/ajplung.00288.2002Scopus ID
2-s2.0-12144291636 (requires institutional sign-in at Scopus site) 68 CitationsAbstract
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 CAAuthor
Kirkwood A. Pritchard PhD Professor in the Surgery department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Acute DiseaseAnemia, 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