期刊
JOURNAL OF IMMUNOLOGY
卷 202, 期 9, 页码 2760-2771出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1900039
关键词
-
类别
资金
- U.S. Department of Veterans Affairs Merit Review [1I01BX001176]
- National Institutes of Health (NIH) [R01 HL119436]
- NIH [P30 ES013508, HL129150, 2T32 HL007586]
Patients with idiopathic pulmonary fibrosis (IPF) often experience precipitous deteriorations, termed acute exacerbations (AE), marked by diffuse alveolitis and altered gas exchange, resulting in a significant loss of lung function or mortality. The missense isoleucine to threonine substitution at position 73 (I73T) in the alveolar type 2 cell-restricted surfactant protein-C (SP-C) gene (SFTPC) has been linked to clinical IPF. To better understand the sequence of events that impact AE-IPF, we leveraged a murine model of inducible SP-C-I73T (SP-C-I73T(/)I73T Flp(+/-)) expression. Following administration of tamoxifen to 8-12-wk-old mice, an upregulation of Sftpc(I)(73T) initiated a diffuse lung injury marked by increases in bronchoalveolar lavage fluid (BALF) protein and histochemical evidence of CD45(+) and CD11b(+) cell infiltrates. Flow cytometry of collagenase-digested lung cells revealed a transient, early reduction in SiglecF(hi) CD11b(Iow)CD64(hi)CD11c(hi) macrophages, countered by the sequential accumulation of SiglecF(hi)CD11b(+)CD64(-)CD11c(-)CCR2(+)Ly6C(+) immature macrophages (3 d), Ly6G(+) neutrophils (7 d), and SiglecF(hi)CD11b(hi)CD11c(Io) eosinophils (2 wk). By mRNA analysis, BALF cells demonstrated a time-dependent phenotypic shift from a proinflammatory (3 d) to an anti-inflammatory/profibrotic activation state, along with serial elaboration of monocyte and eosinophil recruitment factors. The i.v. administration of clodronate effectively reduced total BALF cell numbers, CCR2(+) immature macrophages, and eosinophil influx while improving survival. In contrast, resident macrophage depletion from the intratracheal delivery of clodronate liposomes enhanced Sftpc(I)(73T)-induced mortality. These results using Sftpc(I)(73T) mice provide a detailed ontogeny for AE-IPF driven by alveolar epithelial dysfunction that induces a polycellular inflammation initiated by the early influx of proinflammatory CCR2(+) Ly6C(hi) immature macrophages.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据