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Prepublished online as a Blood First Edition Paper on July 25, 2002; DOI 10.1182/blood-2002-04-1270.
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Blood, 1 December 2002, Vol. 100, No. 12, pp. 4201-4208
RED CELLS
Enhanced splenomegaly and severe liver inflammation in
haptoglobin/hemopexin double-null mice after acute hemolysis
Emanuela Tolosano,
Sharmila Fagoonee,
Emilio Hirsch,
Franklin G. Berger,
Heinz Baumann,
Lorenzo Silengo, and
Fiorella Altruda
From the Department of Genetics, Biology and
Biochemistry, University of Turin and the San Giovanni Battista
Hospital, Experimental Medicine Research Center, Turin,
Italy; the Department of Biological Sciences, University
of South Carolina, Columbia; and the Department of Molecular and
Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY.
Intravascular hemolysis is associated with several pathologic
conditions that include hemoglobinopathies, trauma, malaria, and
bacterial infections. Among plasma-protective proteins against oxidative damage caused by red blood cell rupture, haptoglobin and
hemopexin are thought to play a crucial role. Haptoglobin and
hemopexin, by binding with high-affinity hemoglobin and heme, respectively, exert an antioxidant action by preventing heme-catalyzed free radical production. Moreover, these proteins prevent iron loss by
inhibiting glomerular filtration of hemoglobin and heme diffusion
through plasma membranes. Analysis of single-null mice demonstrated the
antioxidant action of haptoglobin and hemopexin in vivo and suggests
that the 2 proteins cooperate in the resolution of hemolytic stress. To
evaluate the physiological relevance of the haptoglobin-hemopexin
system and the principal targets of its action, we generated
haptoglobin-hemopexin double-knockout mice and analyzed them under
basal conditions and after acute hemolysis. Whereas
haptoglobin-hemopexin double-null mice displayed no obvious alteration
in phenotype under basal conditions, nonlethal hemolytic stress in
these animals led to pronounced splenomegaly as well as liver
inflammation and fibrosis. These data demonstrate that haptoglobin and
hemopexin together are essential for protection from splenomegaly and
liver fibrosis resulting from intravascular hemolysis.
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