Martí-Lliteras Pau, Regueiro Verónica, Morey Pau, Hood Derek W, Saus Carles, Sauleda Jaume, Agustí Alvar G N, Bengoechea José Antonio, Garmendia Junkal
Programa de Infección e Inmunidad, Fundación Caubet-CIMERA, recinto Hospital Joan March, Bunyola, Spain.
Infect Immun. 2009 Oct;77(10):4232-42. doi: 10.1128/IAI.00305-09. Epub 2009 Jul 20.
Nontypeable Haemophilus influenzae (NTHI) is an opportunistic gram-negative pathogen that causes respiratory infections and is associated with progression of respiratory diseases. Cigarette smoke is a main risk factor for development of respiratory infections and chronic respiratory diseases. Glucocorticoids, which are anti-inflammatory drugs, are still the most common therapy for these diseases. Alveolar macrophages are professional phagocytes that reside in the lung and are responsible for clearing infections by the action of their phagolysosomal machinery and promotion of local inflammation. In this study, we dissected the interaction between NTHI and alveolar macrophages and the effect of cigarette smoke on this interaction. We showed that alveolar macrophages clear NTHI infections by adhesion, phagocytosis, and phagolysosomal processing of the pathogen. Bacterial uptake requires host actin polymerization, the integrity of plasma membrane lipid rafts, and activation of the phosphatidylinositol 3-kinase (PI3K) signaling cascade. Parallel to bacterial clearance, macrophages secrete tumor necrosis factor alpha (TNF-alpha) upon NTHI infection. In contrast, exposure to cigarette smoke extract (CSE) impaired alveolar macrophage phagocytosis, although NTHI-induced TNF-alpha secretion was not abrogated. Mechanistically, our data showed that CSE reduced PI3K signaling activation triggered by NTHI. Treatment of CSE-exposed cells with the glucocorticoid dexamethasone reduced the amount of TNF-alpha secreted upon NTHI infection but did not compensate for CSE-dependent phagocytic impairment. The deleterious effect of cigarette smoke was observed in macrophage cell lines and in human alveolar macrophages obtained from smokers and from patients with chronic obstructive pulmonary disease.
非典型流感嗜血杆菌（NTHI）是一种机会性革兰氏阴性病原体，可引起呼吸道感染，并与呼吸道疾病的进展相关。香烟烟雾是呼吸道感染和慢性呼吸道疾病发生的主要危险因素。糖皮质激素作为抗炎药物，仍是这些疾病最常用的治疗方法。肺泡巨噬细胞是驻留在肺部的专职吞噬细胞，负责通过其吞噬溶酶体机制清除感染并促进局部炎症。在本研究中，我们剖析了NTHI与肺泡巨噬细胞之间的相互作用以及香烟烟雾对这种相互作用的影响。我们发现肺泡巨噬细胞通过对病原体的黏附、吞噬和吞噬溶酶体处理来清除NTHI感染。细菌摄取需要宿主肌动蛋白聚合、质膜脂筏的完整性以及磷脂酰肌醇3激酶（PI3K）信号级联的激活。与细菌清除同时发生的是，巨噬细胞在感染NTHI后会分泌肿瘤坏死因子α（TNF-α）。相比之下，暴露于香烟烟雾提取物（CSE）会损害肺泡巨噬细胞的吞噬作用，尽管NTHI诱导的TNF-α分泌并未被消除。从机制上讲，我们的数据表明CSE降低了NTHI触发的PI3K信号激活。用糖皮质激素地塞米松处理暴露于CSE的细胞可减少NTHI感染后分泌的TNF-α量，但不能弥补CSE依赖性吞噬功能障碍。在巨噬细胞系以及从吸烟者和慢性阻塞性肺疾病患者获得的人肺泡巨噬细胞中均观察到了香烟烟雾的有害作用。
