Decrease in lung nitric oxide production after peritonitis in mice with sickle cell disease.
OBJECTIVE
Nitric oxide bioavailability may limit the occurrence or severity of acute vaso-occlusive episodes in patients with sickle cell disease. Because sepsis is frequently involved in the initiation of vaso-occlusive crisis and acute chest syndrome, we designed the present study in transgenic (SAD) sickle cell mice to investigate whether acute infectious peritonitis affects the enzymatic balance (nitric oxide synthases/arginases) that governs lung nitric oxide production.


METHODS
Controlled animal study.


METHODS
Research laboratory of an academic institution.


METHODS
Transgenic Hbbsingle/single SAD1 (SAD) mice and nontransgenic wild-type littermates (C57/Black mice, control group).


METHODS
Cecal ligation and puncture-induced peritonitis.


RESULTS
We found that 24 hrs after peritonitis, control littermate mice showed an increase in inducible and endothelial nitric oxide synthase messenger RNA and proteins, together with an increase in exhaled nitric oxide (shift of the balance toward nitric oxide synthesis). In contrast, SAD mice, which showed elevated inducible and endothelial nitric oxide synthase protein expression at baseline, showed a marked decrease in nitric oxide synthase proteins, lung nitric oxide end-products, and exhaled nitric oxide after peritonitis, reflecting a shift of the enzymatic balance toward inhibition of nitric oxide synthesis. Peritonitis increased messenger RNA levels of arginase I and arginase II in controls and SAD mice but with a greater increase in arginase I in SAD than in control mice. Peritonitis was associated with a higher mortality rate at 24 hrs in SAD mice. Inhalation of nitric oxide (40 ppm in air) abolished the mortality rate induced by acute peritonitis in SAD mice.


CONCLUSIONS
Acute peritonitis in SAD mice is associated with a defect in lung nitric oxide production and bioavailability that may participate in the acute systemic and lung vaso-occlusive complications of sickle cell disease.
Bartolucci
Pablo
P
Unité INSERM U492-Université Paris XII, Créteil, and Laboratoire de Thérapie Génique Hématopoïétique, Hôpital Saint Louis, Paris, France.
Ngo
Minh-Triet
MT
Beuzard
Yves
Y
Galactéros
Frédéric
F
Saber
Guitanouch
G
Rideau
Dominique
D
Eddahibi
Saadia
S
Maitre
Bernard
B
Adnot
Serge
S
Delclaux
Christophe
C
D000755:Anemia, Sickle Cell / Q000150:complications / Q000378:metabolism*; D000818:Animals; D008168:Lung / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000096:biosynthesis*; D010538:Peritonitis / Q000150:complications / Q000378:metabolism*
D009569:Nitric Oxide