Blood 2002 Dec 1;100(12):4201-8
Enhanced splenomegaly and severe liver inflammation in
haptoglobin/hemopexin
double-null mice after
acute hemolysis.
Tolosano E, Fagoonee S, Hirsch E, Berger FG, Baumann H, Silengo L, Altruda F.
Department of Genetics, Biology and Biochemistry, University of
Turin
and the San Giovanni Battista Hospital, Turin, Italy.
emanuela.tolosano@unito.it
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.