Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States.
Alcohol. 2019 Nov;80:119-130. doi: 10.1016/j.alcohol.2018.08.016. Epub 2018 Sep 5.
Community-acquired pneumonia due to Streptococcus pneumoniae occurs commonly in alcohol use disorders (AUDs). Pneumonia in the AUD patient is associated with poorer outcomes, and specific therapies to mitigate disease severity in these patients do not exist. Numerous investigations have attributed increased severity of pneumonia in AUDs to aberrant function of the alveolar macrophage (AM), a lung immune cell critical in host defense initiation. No studies have examined the response of human AMs to S. pneumoniae in AUDs. We hypothesized that the inflammatory mediators released by AMs after S. pneumoniae stimulation would differ quantitatively in individuals with AUDs compared to non-AUD participants. We further postulated that AM inflammatory mediators would be diminished after exposure to the antioxidant, N-acetylcysteine (NAC). For comparison, responses of peripheral blood mononuclear cells (PBMCs) to pneumococcal protein were also examined. Otherwise healthy participants with AUDs and smoking-matched controls underwent bronchoalveolar lavage and peripheral blood sampling to obtain AMs and PBMCs, respectively. Freshly collected cells were cultured with increasing doses of heat-killed S. pneumoniae protein, with and without exposure to N-acetylcysteine. Cell culture supernatants were collected, and inflammatory mediators were measured, including interferon (IFN)-γ, interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α. IFN-γ and IL-6 were significantly higher in unstimulated AM cell culture supernatants from subjects with AUDs. After stimulation with pneumococcal protein, a dose-response and time-dependent increase in pro-inflammatory cytokine production by both AMs and PBMCs was also observed; differences were not observed between AUD and non-AUD subjects. Addition of NAC to pneumococcal-stimulated AMs and PBMCs was generally associated with diminished cytokine production, with the exception of IL-1β that was elevated in AM culture supernatants from subjects with AUDs. Our observations suggest that AUDs contribute to basal alterations in AM pro-inflammatory cytokine elaboration, but did not support consistent differences in pneumococcal-stimulated AM or PBMC inflammatory mediator secretion that were referable to AUDs.
社区获得性肺炎由肺炎链球菌引起，常发生于酒精使用障碍（AUD）患者中。AUD 患者的肺炎与较差的预后相关，并且针对这些患者减轻疾病严重程度的特定疗法尚不存在。许多研究将 AUD 中肺炎的严重程度增加归因于肺泡巨噬细胞（AM）的功能异常，肺泡巨噬细胞是宿主防御起始中至关重要的肺部免疫细胞。目前尚无研究检测 AUD 患者中 AM 对肺炎链球菌的反应。我们假设，与非 AUD 参与者相比，肺炎链球菌刺激后 AM 释放的炎症介质在 AUD 个体中的数量会有所不同。我们进一步假设，AM 炎症介质在暴露于抗氧化剂 N-乙酰半胱氨酸（NAC）后会减少。为了进行比较，还检测了外周血单核细胞（PBMC）对肺炎球菌蛋白的反应。健康的 AUD 患者和吸烟匹配的对照者进行了支气管肺泡灌洗和外周血采样，以分别获得 AM 和 PBMC。新鲜采集的细胞在不同剂量的热灭活肺炎链球菌蛋白存在和不存在 N-乙酰半胱氨酸的情况下进行培养。收集细胞培养上清液，并测量炎症介质，包括干扰素（IFN）-γ、白细胞介素（IL）-1β、IL-6 和肿瘤坏死因子（TNF）-α。与非 AUD 患者相比，AUD 患者 AM 细胞培养上清液中的 IFN-γ 和 IL-6 明显更高。在用肺炎球菌蛋白刺激后，还观察到 AM 和 PBMC 产生促炎细胞因子的剂量反应和时间依赖性增加；在 AUD 和非 AUD 受试者之间未观察到差异。向肺炎球菌刺激的 AM 和 PBMC 添加 NAC 通常与细胞因子产生减少相关，除了 AUD 患者 AM 培养上清液中升高的 IL-1β 之外。我们的观察结果表明，AUD 导致 AM 促炎细胞因子表达的基础改变，但并未支持 AUD 与肺炎球菌刺激的 AM 或 PBMC 炎症介质分泌的一致性差异有关。
