Berenson Charles S, Kruzel Ragina L, Sethi Sanjay
a Divisions of Infectious Diseases and Pulmonary, Critical Care, Sleep, Department of Veterans Affairs , Western New York Healthcare System, State University of New York at Buffalo School of Medicine , Buffalo , NY , USA.
Immunol Invest. 2016;45(2):130-47. doi: 10.3109/08820139.2015.1113427. Epub 2016 Feb 6.
Alveolar macrophages in chronic obstructive pulmonary disease (COPD) have fundamentally impaired innate immune responses to toll-like receptor (TLR) ligands of nontypeable Haemophilus influenzae (NTHI). However, whether dysfunctional inflammatory responses in COPD extend to macrophage interactions with intact respiratory pathogens beyond NTHI has not been explored. Furthermore, the influences of exogenous factors, including active smoking and medications, on pathogen-induced innate immune responses have only begun to be investigated. We hypothesized that distinct alveolar macrophage impairments in COPD are not limited to NTHI TLR ligands and that active smoking and select COPD medications modulate innate responses. Alveolar macrophages, obtained from COPD ex-smokers (n = 32) and active smokers (n = 64) by bronchoalveolar lavage (BAL), were incubated with NTHI, Moraxella catarrhalis, and Streptococcus pneumoniae, and with TLR2 and TLR4 ligands. Elicited IL-8 and TNF-α were measured by multianalyte microsphere flow cytometry to determine proinflammatory responsiveness. Induced IL-8, but not TNF-α, was greater from alveolar macrophages of active smokers compared with ex-smokers, in response to NTHI (p = 0.04), M. catarrhalis (p = 0.003), and S. pneumoniae (p = 0.03). Both IL-8 and TNF-α induction by TLR2 and TLR4 ligands were greater in active smokers. While intergroup NTHI- and M. catarrhalis-induced TNF-α levels were no different, they were notably lower among ex-smokers taking anticholinergic medications (p < 0.04 for each), but not with any other bronchoactive medications. Our results support a paradigm of distinct immunologic responses of COPD alveolar macrophages of ex- and active smokers to diverse respiratory pathogens and highlight a subset of ex-smokers whose diminished alveolar macrophage responsiveness may be associated with anticholinergic agents.
慢性阻塞性肺疾病（COPD）中的肺泡巨噬细胞对不可分型流感嗜血杆菌（NTHI）的Toll样受体（TLR）配体的固有免疫反应存在根本性损害。然而，COPD中功能失调的炎症反应是否扩展到巨噬细胞与除NTHI之外的完整呼吸道病原体的相互作用尚未得到研究。此外，包括主动吸烟和药物在内的外源性因素对病原体诱导的固有免疫反应的影响才刚刚开始被研究。我们假设，COPD中不同的肺泡巨噬细胞损伤不仅限于NTHI TLR配体，并且主动吸烟和某些COPD药物会调节固有反应。通过支气管肺泡灌洗（BAL）从COPD戒烟者（n = 32）和主动吸烟者（n = 64）中获取肺泡巨噬细胞，将其与NTHI、卡他莫拉菌和肺炎链球菌以及TLR2和TLR4配体一起孵育。通过多分析物微球流式细胞术测量诱导产生的白细胞介素-8（IL-8）和肿瘤坏死因子-α（TNF-α），以确定促炎反应性。与戒烟者相比，主动吸烟者的肺泡巨噬细胞对NTHI（p = 0.04）、卡他莫拉菌（p = 0.003）和肺炎链球菌（p = 0.03）的反应中，诱导产生的IL-8增加，但TNF-α未增加。TLR2和TLR4配体诱导的IL-8和TNF-α在主动吸烟者中均更高。虽然组间NTHI和卡他莫拉菌诱导的TNF-α水平没有差异，但在服用抗胆碱能药物的戒烟者中显著较低（每种情况p < 0.04），但与任何其他支气管活性药物无关。我们的结果支持一种模式，即COPD肺泡巨噬细胞对不同呼吸道病原体的免疫反应不同，并且突出了一部分戒烟者，其肺泡巨噬细胞反应性降低可能与抗胆碱能药物有关。
