Diffuse alveolar
hemorrhage is an uncommon, yet often fatal, complication of
systemic lupus erythematosus (SLE). Advances in the treatment of alveolar
hemorrhage have been hampered because of the heterogeneity of clinical findings and the lack of suitable animal models. A single
intraperitoneal injection of
pristane induces a lupus-like syndrome characterized by lupus-related
autoantibodies and
glomerulonephritis in non-autoimmune-prone strains of mice. In addition, C57BL/6 (B6) mice frequently develop alveolar
hemorrhage within a few weeks of
pristane injection. Immunopathogenesis of
pristane-induced alveolar
hemorrhage was investigated in the present study. Early (2-4 weeks after injection) mortality due to
hemorrhage was unique to C57BL/6 and C57BL/10 strains of mice. Recruitment of the macrophages and neutrophils preceded the
hemorrhage by several days, and
hemorrhage started 3-7 days after
pristane injection in some mice, peaked at 2 weeks (84% in B6) and then resolved by 4 weeks in a majority of mice. Alveolar
hemorrhage was independent of MyD88 (
myeloid differentiation factor 88), or TLR7 pathways, in contrast to
autoantibody production and
glomerulonephritis, and was also independent of FcγR or Fas. Rag1(-/-) mice had a reduced prevalence of alveolar
hemorrhage compared with B6 (P=0.01) congenics. However,
T-cell receptor-deficient mice developed alveolar
hemorrhage at a rate comparable to wild-type controls, whereas B6 Igμ(-/-) mice surprisingly had a strikingly reduced prevalence (7% vs 84% in B6, P<0.0001). Reconstitution of B6 Igμ(-/-) mice with wild-type B cells increased the prevalence to 50% (P=0.028).
Pristane-induced alveolar
hemorrhage is a useful model to study the pathogenesis and develop new
therapy for this underappreciated and often life-threatening complication of SLE.