Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
1] Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA [2] Tecnológico de Monterrey School of Medicine, Monterrey, Nuevo León, Mexico.
Mucosal Immunol. 2014 Jan;7(1):78-88. doi: 10.1038/mi.2013.26. Epub 2013 May 1.
Infectious pneumonias are the leading cause of death worldwide, particularly among immunocompromised patients. Therapeutic stimulation of the lungs' intrinsic defenses with a unique combination of inhaled Toll-like receptor (TLR) agonists broadly protects mice against otherwise lethal pneumonias. As the survival benefit persists despite cytotoxic chemotherapy-related neutropenia, the cells required for protection were investigated. The inducibility of resistance was tested in mice with deficiencies of leukocyte lineages due to genetic deletions and in wild-type mice with leukocyte populations significantly reduced by antibodies or toxins. Surprisingly, these serial reductions in leukocyte lineages did not appreciably impair inducible resistance, but targeted disruption of TLR signaling in the lung epithelium resulted in complete abrogation of the protective effect. Isolated lung epithelial cells were also induced to kill pathogens in the absence of leukocytes. Proteomic and gene expression analyses of isolated epithelial cells and whole lungs revealed highly congruent antimicrobial responses. Taken together, these data indicate that lung epithelial cells are necessary and sufficient effectors of inducible resistance. These findings challenge conventional paradigms about the role of epithelia in antimicrobial defense and offer a novel potential intervention to protect patients with impaired leukocyte-mediated immunity from fatal pneumonias.
感染性肺炎是全球范围内导致死亡的主要原因，尤其是在免疫功能低下的患者中。通过吸入 Toll 样受体 (TLR) 激动剂的独特组合来治疗性地刺激肺部固有防御机制，可以广泛保护小鼠免受致命性肺炎的侵害。由于细胞毒性化疗相关中性粒细胞减少症的存在，生存获益仍然存在，因此研究了保护所必需的细胞。通过基因缺失导致白细胞谱系缺陷的小鼠和通过抗体或毒素显著减少白细胞群体的野生型小鼠测试了抗性的诱导能力。令人惊讶的是，这些白细胞谱系的连续减少并没有明显损害可诱导的抗性，但靶向破坏肺上皮细胞中的 TLR 信号会导致保护作用完全丧失。还分离了肺上皮细胞，在没有白细胞的情况下杀死病原体。对分离的上皮细胞和整个肺进行蛋白质组学和基因表达分析揭示了高度一致的抗菌反应。综上所述，这些数据表明肺上皮细胞是诱导性抗性的必要和充分效应器。这些发现挑战了关于上皮细胞在抗菌防御中的作用的传统观念，并为保护白细胞介导免疫受损的患者免受致命性肺炎提供了一种新的潜在干预措施。
