Pathogenesis of Diffuse Alveolar Hemorrhage in Murine Lupus.
Pathogenesis of Diffuse Alveolar Hemorrhage in Murine Lupus.
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DOI：
10.1002/art.40077
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发表时间：
2017-06
期刊：
影响因子：
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通讯作者：
Reeves WH
中科院分区：
文献类型：
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作者：
Zhuang H;Han S;Lee PY;Khaybullin R;Shumyak S;Lu L;Chatha A;Afaneh A;Zhang Y;Xie C;Nacionales D;Moldawer L;Qi X;Yang LJ;Reeves WH
狼疮患者弥漫性肺泡出血(DAH)致死率为50%。原因尚不清楚。本文研究了人狼疮相关性DAH模型C57BL/6狼疮小鼠DAH的发病机制。比较原发性狼疮和人类DAH的临床、病理和免疫学表现。用质谱联用法考察其在组织中的分布。通过使用氯膦酸盐脂质体(CloLip)和抗中性粒细胞单抗(GR1)体内耗竭来确定导致疾病的细胞类型。观察眼镜蛇毒因子(CVF)对补体耗竭的影响。在IP之后。注射后，Pristane迁移到肺部，导致细胞死亡、小血管炎症和肺泡出血，类似于人类DAH。B细胞缺陷小鼠对DAH的诱导具有抵抗力，但通过注射IgM可恢复敏感性。C3缺陷小鼠和CD18缺陷小鼠也是耐药的，野生型小鼠的DAH可以被CVF预防。DAH的诱导与TLRs、炎性小体和诱导型一氧化氮(INOS)无关。IL-10缺陷小鼠的死亡率增加，Pristane治疗降低了单核细胞中IL-10受体的表达和肺巨噬细胞中STAT3的磷酸化。在体内，中性粒细胞的耗尽没有保护作用，而使用CloLip治疗可以预防DAH，这表明巨噬细胞的激活是DAH发病的中心。DAH的发病机制涉及天然IgM和补体对死亡细胞的调理作用，继而是补体受体介导的肺炎症。这种疾病依赖巨噬细胞，而IL-10具有保护性作用。补体抑制和/或巨噬细胞靶向治疗可降低狼疮相关性DAH的死亡率。
Diffuse alveolar hemorrhage (DAH) in lupus patients is >50% fatal. The cause is unknown. The pathogenesis of DAH in C57BL/6 mice with pristane-induced lupus, a model of human lupus-associated DAH, was examined. Clinical/pathological and immunological manifestations DAH in pristane-lupus were compared with human DAH. Tissue distribution of pristane was examined by mass spectrometry. Cell types responsible for disease were determined by in vivo depletion using clodronate liposomes (CloLip) and anti-neutrophil monoclonal antibodies (GR1). The effect of complement depletion with cobra venom factor (CVF) was examined. After i.p. injection, pristane migrated to the lung, causing cell death, small vessel vasculitis, and alveolar hemorrhage similar to human DAH. B-cell-deficient mice were resistant to induction of DAH, but susceptibility was restored by infusing IgM. C3-deficient and CD18-deficient mice also were resistant and DAH was prevented in wild-type mice by CVF. Induction of DAH was independent of TLRs, inflammasomes, and inducible nitric oxide (iNOS). Mortality was increased in IL-10-deficient mice and pristane treatment decreased IL-10 receptor expression in monocytes and Stat3 phosphorylation in lung macrophages. In vivo neutrophil depletion was not protective, whereas treatment with CloLip prevented DAH, suggesting 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.