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

被引:62
作者
Pritchard, KA
Ou, JS
Ou, ZJ
Shi, Y
Franciosi, JP
Signorino, P
Kaul, S
Ackland-Berglund, C
Witte, K
Holzhauer, S
Mohandas, N
Guice, KS
Oldham, KT
Hillery, CA
机构
[1] Med Coll Wisconsin, Childrens Hosp Wisconsin, Blood Ctr SE Wisconsin,Div Pediat Surg, Dept Surg,Cardiovasc Ctr M4060, Milwaukee, WI 53226 USA
[2] Med Coll Wisconsin, Childrens Hosp Wisconsin, Blood Ctr SE Wisconsin, Dept Pharmacol & Toxicol, Milwaukee, WI 53226 USA
[3] Med Coll Wisconsin, Childrens Hosp Wisconsin, Blood Ctr SE Wisconsin, Ctr Cardiovasc, Milwaukee, WI 53226 USA
[4] Med Coll Wisconsin, Childrens Hosp Wisconsin, Blood Ctr SE Wisconsin, Free Rad Res Ctr, Milwaukee, WI 53226 USA
[5] Med Coll Wisconsin, Childrens Hosp Wisconsin, Blood Ctr SE Wisconsin, Dept Pediat,Div Hematol Oncol, Milwaukee, WI 53226 USA
[6] New York Blood Ctr, New York, NY 10021 USA
关键词
vaso-occlusion; heat shock protein 90; nitric oxide; sickle hemoglobin; xanthine oxidase; pulmonary microvascular endothelial cell;
D O I
10.1152/ajplung.00288.2002
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
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 (halphabeta(S)) transgene (SCD mice) or are heterozygous for the normal murine beta-globin gene and express the halphabeta(S) 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.
引用
收藏
页码:L705 / L714
页数:10
相关论文
共 59 条
[21]   Reconstitution of an endothelial nitric-oxide synthase (eNOS), hsp90, and caveolin-1 complex in vitro -: Evidence that hsp90 facilitates calmodulin stimulated displacement of eNOS from caveolin-1 [J].
Gratton, JP ;
Fontana, J ;
O'Connor, DS ;
García-Cardeña, G ;
McCabe, TJ ;
Sessa, WC .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (29) :22268-22272
[22]   What nitrates tyrosine? Is nitrotyrosine specific as a biomarker of peroxynitrite formation in vivo? [J].
Halliwell, B .
FEBS LETTERS, 1997, 411 (2-3) :157-160
[23]   Endothelial cell nitric oxide production in acute chest syndrome [J].
Hammerman, SI ;
Klings, ES ;
Hendra, KP ;
Upchurch, GR ;
Rishikof, DC ;
Loscalzo, J ;
Farber, HW .
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 1999, 277 (04) :H1579-H1592
[24]   Low concentrations of nitric oxide increase oxygen affinity of sickle erythrocytes in vitro and in vivo [J].
Head, CA ;
Brugnara, C ;
MartinezRuiz, R ;
Kacmarek, RM ;
Bridges, KR ;
Kuter, D ;
Bloch, KD ;
Zapol, WM .
JOURNAL OF CLINICAL INVESTIGATION, 1997, 100 (05) :1193-1198
[25]   SPONTANEOUS OXYGEN RADICAL GENERATION BY SICKLE ERYTHROCYTES [J].
HEBBEL, RP ;
EATON, JW ;
BALASINGAM, M ;
STEINBERG, MH .
JOURNAL OF CLINICAL INVESTIGATION, 1982, 70 (06) :1253-1259
[26]   CA2+/CALMODULIN-DEPENDENT FORMATION OF HYDROGEN-PEROXIDE BY BRAIN NITRIC-OXIDE SYNTHASE [J].
HEINZEL, B ;
JOHN, M ;
KLATT, P ;
BOHME, E ;
MAYER, B .
BIOCHEMICAL JOURNAL, 1992, 281 :627-630
[27]  
Hillery C A, 1998, Curr Opin Hematol, V5, P151
[28]   PEROXYNITRITE-MEDIATED TYROSINE NITRATION CATALYZED BY SUPEROXIDE-DISMUTASE [J].
ISCHIROPOULOS, H ;
ZHU, L ;
CHEN, J ;
TSAI, M ;
MARTIN, JC ;
SMITH, CD ;
BECKMAN, JS .
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 1992, 298 (02) :431-437
[29]   Hypoxia/reoxygenation causes inflammatory response in transgenic sickle mice but not in normal mice [J].
Kaul, DK ;
Hebbel, RP .
JOURNAL OF CLINICAL INVESTIGATION, 2000, 106 (03) :411-420
[30]   In vivo demonstration of red cell-endothelial interaction, sickling and altered microvascular response to oxygen in the sickle transgenic mouse [J].
Kaul, DK ;
Fabry, ME ;
Costantini, F ;
Rubin, EM ;
Nagel, RL .
JOURNAL OF CLINICAL INVESTIGATION, 1995, 96 (06) :2845-2853