Serban Karina A, Petrusca Daniela N, Mikosz Andrew, Poirier Christophe, Lockett Angelia D, Saint Lauren, Justice Matthew J, Twigg Homer L, Campos Michael A, Petrache Irina
Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, National Jewish Health, Denver, Colorado, United States of America.
Pulmonary, Critical Care, Sleep and Occupational Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
PLoS One. 2017 Apr 27;12(4):e0176073. doi: 10.1371/journal.pone.0176073. eCollection 2017.
Cigarette smoking (CS), the main risk factor for COPD (chronic obstructive pulmonary disease) in developed countries, decreases alveolar macrophages (AM) clearance of both apoptotic cells and bacterial pathogens. This global deficit of AM engulfment may explain why active smokers have worse outcomes of COPD exacerbations, episodes characterized by airway infection and inflammation that carry high morbidity and healthcare cost. When administered as intravenous supplementation, the acute phase-reactant alpha-1 antitrypsin (A1AT) reduces the severity of COPD exacerbations in A1AT deficient (AATD) individuals and of bacterial pneumonia in murine models, but the effect of A1AT on AM scavenging functions has not been reported. Apoptotic cell clearance (efferocytosis) was measured in human AM isolated from patients with COPD, in primary rat AM or differentiated monocytes exposed to CS ex vivo, and in AM recovered from mice exposed to CS. A1AT (100 μg/mL, 16 h) significantly ameliorated efferocytosis (by ~50%) in AM of active smokers or AM exposed ex vivo to CS. A1AT significantly improved AM global engulfment, including phagocytosis, even when cells were simultaneously challenged with apoptotic and Fc-coated (bacteria-like) targets. The improved efferocytosis in A1AT-treated macrophages was associated with inhibition of tumor necrosis factor-α converting enzyme (TACE) activity, decreased mannose receptor shedding, and markedly increased abundance of efferocytosis receptors (mannose- and phosphatidyl serine receptors and the scavenger receptor B2) on AM plasma membrane. Directed airway A1AT treatment (via inhalation of a nebulized solution) restored in situ airway AM efferocytosis after CS exposure in mice. The amelioration of CS-exposed AM global engulfment may render A1AT as a potential therapy for COPD exacerbations.
吸烟（CS）是发达国家慢性阻塞性肺疾病（COPD）的主要危险因素，它会降低肺泡巨噬细胞（AM）对凋亡细胞和细菌病原体的清除能力。AM吞噬功能的这种整体缺陷可能解释了为什么吸烟者的COPD急性加重期预后更差，急性加重期的特征是气道感染和炎症，发病率和医疗成本都很高。当作为静脉补充剂给药时，急性期反应物α-1抗胰蛋白酶（A1AT）可降低A1AT缺乏症（AATD）个体的COPD急性加重期严重程度，并降低小鼠模型中细菌性肺炎的严重程度，但A1AT对AM清除功能的影响尚未见报道。我们在从COPD患者中分离出的人AM、体外暴露于CS的原代大鼠AM或分化单核细胞以及从暴露于CS的小鼠中回收的AM中测量了凋亡细胞清除（胞葬作用）。A1AT（100μg/mL，16小时）显著改善了主动吸烟者的AM或体外暴露于CS的AM中的胞葬作用（提高约50%）。即使细胞同时受到凋亡和Fc包被（类细菌）靶标的挑战，A1AT也显著改善了AM的整体吞噬能力，包括吞噬作用。A1AT处理的巨噬细胞中改善的胞葬作用与肿瘤坏死因子-α转换酶（TACE）活性的抑制、甘露糖受体脱落的减少以及AM质膜上胞葬作用受体（甘露糖和磷脂酰丝氨酸受体以及清道夫受体B2）丰度的显著增加有关。在小鼠中，定向气道A1AT治疗（通过雾化溶液吸入）在CS暴露后恢复了原位气道AM的胞葬作用。CS暴露后AM整体吞噬能力的改善可能使A1AT成为COPD急性加重期的一种潜在治疗方法。
