title: Pathogenesis of Diffuse Alveolar Hemorrhage in Murine Lupus.
abstract: Diffuse alveolar hemorrhage (DAH) in lupus patients confers >50% mortality, and the cause is unknown. We undertook this study to examine the pathogenesis of DAH in C57BL/6 mice with pristane-induced lupus, a model of human lupus-associated DAH.
  
  
  
  Clinical/pathologic and immunologic manifestations of DAH in pristane-induced lupus were compared with those of DAH in humans. Tissue distribution of pristane was examined by mass spectrometry. Cell types responsible for disease were determined by in vivo depletion using clodronate liposomes and antineutrophil monoclonal antibodies (anti-Ly-6G). The effect of complement depletion with cobra venom factor (CVF) was examined.
  
  
  
  After intraperitoneal injection, pristane migrated to the lung, causing cell death, small vessel vasculitis, and alveolar hemorrhage similar to that seen in DAH in humans. B cell-deficient mice were resistant to induction of DAH, but susceptibility was restored by infusing IgM. C3-/-and CD18-/-mice were also resistant, and DAH was prevented in wild-type mice by CVF. Induction of DAH was independent of Toll-like receptors, inflammasomes, and inducible nitric oxide. Mortality was increased in interleukin-10 (IL-10)-deficient mice, and pristane treatment decreased IL-10 receptor expression in monocytes and STAT-3 phosphorylation in lung macrophages. In vivo neutrophil depletion was not protective, while treatment with clodronate liposomes prevented DAH, which suggests that macrophage activation is central to DAH pathogenesis.
  
  
  
  The pathogenesis of DAH involves opsonization of dead cells by natural IgM and complement followed by complement receptor-mediated lung inflammation. The disease is macrophage dependent, and IL-10 is protective. Complement inhibition and/or macrophage-targeted therapies may reduce mortality in lupus-associated DAH.
authors.affiliation: University of Florida, Gainesville.
authors.forename: Haoyang
authors.initials: H
authors.lastname: Zhuang
authors.affiliation: University of Florida, Gainesville.
authors.forename: Shuhong
authors.initials: S
authors.lastname: Han
authors.affiliation: Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Pui Y
authors.initials: PY
authors.lastname: Lee
authors.affiliation: University of Florida, Gainesville.
authors.forename: Ravil
authors.initials: R
authors.lastname: Khaybullin
authors.affiliation: University of Florida, Gainesville.
authors.forename: Stepan
authors.initials: S
authors.lastname: Shumyak
authors.affiliation: University of Florida, Gainesville.
authors.forename: Li
authors.initials: L
authors.lastname: Lu
authors.affiliation: University of Florida, Gainesville.
authors.forename: Amina
authors.initials: A
authors.lastname: Chatha
authors.affiliation: University of Florida, Gainesville.
authors.forename: Anan
authors.initials: A
authors.lastname: Afaneh
authors.affiliation: University of Florida, Gainesville.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: University of Florida, Gainesville.
authors.forename: Chao
authors.initials: C
authors.lastname: Xie
authors.affiliation: University of Florida, Gainesville.
authors.forename: Dina
authors.initials: D
authors.lastname: Nacionales
authors.affiliation: University of Florida, Gainesville.
authors.forename: Lyle
authors.initials: L
authors.lastname: Moldawer
authors.affiliation: University of Florida, Gainesville.
authors.forename: Xin
authors.initials: X
authors.lastname: Qi
authors.affiliation: University of Florida, Gainesville.
authors.forename: Li-Jun
authors.initials: LJ
authors.lastname: Yang
authors.affiliation: University of Florida, Gainesville.
authors.forename: Westley H
authors.initials: WH
authors.lastname: Reeves
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006470:Hemorrhage / Q000209:etiology* / Q000473:pathology; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D008168:Lung / Q000473:pathology; D008171:Lung Diseases / Q000209:etiology* / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000139:chemically induced / Q000150:complications* / Q000473:pathology; D008262:Macrophage Activation / Q000502:physiology; D008264:Macrophages / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D011650:Pulmonary Alveoli / Q000473:pathology; D013729:Terpenes
chemical_list: D013729:Terpenes; D016753:Interleukin-10; C009042:pristane