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1 Department of Surgery, Division of Pediatric Surgery, Medical College of Wisconsin, Milwaukee, WI, USA; Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA; Free Radical Research Center, Medical College of Wisconsin, Milwaukee, WI, USA
2 Department of Surgery, Division of Pediatric Surgery, Medical College of Wisconsin, Milwaukee, WI, USA; Cardiovascular Center, The Blood Center of Southeastern Wisconsin, Milwaukee, WI, USA
3 Department of Surgery, Division of Pediatric Surgery, Medical College of Wisconsin, Milwaukee, WI, USA
4 Department of Pediatrics, Division of Hematology-Oncology, Children's Hospital of Wisconsin, Milwaukee, WI, USA
5 Department of Hematology, New York Blood Center, NY, NY, USA
* To whom correspondence should be addressed. E-mail: kpritch{at}mcw.edu.
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 (hS) transgene ("SCD mice") or are heterozygous for the normal murine -globin gene and express the hS transgene (m+/-, hS+/-, "heterozygote SCD mice"). Under normoxic conditions, lungs from the SCD mice contained higher levels of xanthine oxidase (XO), nitrotyrosine and cGMP than controls (C57BL6 mice). Hypoxia increased XO and nitrotyrosine and decreased cGMP content in the lungs of all mice. After hypoxia, vascular congestion was increased in the lungs with higher XO and nitrotyrosine. Under normoxic conditions, the association of heat shock protein 90 (hsp90) with eNOS in lungs of SCD and heterozygote SCD mice was decreased compared to the levels of association in lungs of controls. Hypoxia further decreased the association of hsp90 with eNOS in lungs of SCD and heterozygote SCD mice, but not in the lungs of control mice. Pretreatment of rat pulmonary microvascular endothelial cells (PMVEC) in vitro with xanthine/XO decreased A23187-stimulated nitrite + nitrate production and hsp90 interactions with eNOS. Collectively, these data support the hypothesis that hypoxia increases XO release from ischemic tissues and that the local increase in oxidative stress induced by XO can in turn, inhibit hsp90 interactions with eNOS, thus decreasing .NO generation and predisposing the lung to vaso-occlusion.
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