Alloimmune lung injury induced by local innate immune activation through inhaled lipopolysaccharide
Alloimmune lung injury induced by local innate immune activation through inhaled lipopolysaccharide
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DOI：
10.1097/01.tp.0000286040.85007.89
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发表时间：
2007-10-27
期刊：
影响因子：
6.2
通讯作者：
Schwartz, David A.
中科院分区：
文献类型：
--
作者：
Garantziotis, Stavros;Palmer, Scott M.;Schwartz, David A.
背景资料。同种异体免疫性肺损伤以血管周围淋巴细胞性炎症、淋巴细胞性毛细支气管炎和闭塞性毛细支气管炎为特征，可导致肺移植和骨髓移植后的大量并发症和死亡率，但其发病机制尚不清楚。我们提出并推行了一种假说，即通过Toll样受体(TLR)-4局部激活肺天然免疫在移植后同种异体免疫性肺损伤的发生发展中起关键作用。我们建立了一种完全主要组织相容性复合体不匹配的小鼠骨髓移植模型，没有系统性移植物抗宿主病，并用典型的TLR4激动剂雾化脂多糖(LPS)攻击小鼠，以确定其对肺同种异体免疫性肺损伤的影响。内毒素暴露的同种异基因骨髓移植小鼠出现了Lb和013的组织学和生物学特征，这在非内毒素暴露的同种异基因对照或同基因内毒素暴露的小鼠中没有观察到。LPS诱导的淋巴细胞性肺部炎症依赖于供体来源的造血细胞中完整的TLR4信号，而不依赖于受体结构的肺细胞，表明TLR4在介导同种异体免疫中具有明显的作用。我们证明了局部的、环境诱导的先天免疫激活在促进同种异体免疫性肺损伤中的关键作用。肺居民TLR4信号的局部抑制
Background. Alloimmune lung injury, characterized by perivascular lymphocytic inflammation, lymphocytic bronchiolitis (LB), and obliterative bronchiolitis (OB), causes substantial morbidity and mortality after lung transplantation and bone marrow transplantation (BMT), but little is known regarding its pathogenesis. We have developed and pursued the hypothesis that local activation of pulmonary innate immunity through toll-like receptor (TLR)-4 is critical to the development of posttransplant alloimmune lung injury.Methods. We developed a fully major histocompatibility complex-mismatched murine BMT model without systemic graft-versus-host disease, and challenged mice with aerosolized lipopolysaccharide (LPS), a prototypic TLR4 agonist, to determine the effect upon pulmonary alloimmune lung injury.Results. LPS-exposed allogeneic BMT recipient mice developed histological and biological features of LB and 013, which were not observed in non-LPS-exposed allogeneic controls or syngeneic LPS-exposed mice. LPS-induced lymphocytic lung inflammation was dependent upon intact TLR4 signaling in donor-derived hematopoietic cells but not recipient structural lung cells, demonstrating a distinct function for TLR4 on hematopoietic cells in mediating alloimmunity.Conclusions. We demonstrate a critical role for localized, environmentally induced innate immune activation in promoting alloimmune lung injury. Local inhibition of TLR4 signaling in pulmonary resident