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EDITORIAL FOCUS

Hypoxia-induced acute lung injury in murine models of sickle cell disease

¹Department of Surgery, Division of Pediatric Surgery, ²Department of Pharmacology and Toxicology, ³Cardiovascular Center, ⁴Free Radical Research Center, and ⁵Department of Pediatrics, Division of Hematology-Oncology, Medical College of Wisconsin, Children's Hospital of Wisconsin, The Blood Center of Southeastern Wisconsin, Milwaukee, Wisconsin 53226; and ⁶New York Blood Center, New York, New York 10021

Submitted 21 August 2002 ; accepted in final form 11 September 2003

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 /sickle -globin (h^S) transgene (SCD mice) or are heterozygous for the normal murine -globin gene and express the h^S transgene (m^+/-, h^S+/-; 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.

vaso-occlusion; heat shock protein 90; nitric oxide; sickle hemoglobin; xanthine oxidase; pulmonary microvascular endothelial cell

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