Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory lung disease with high morbidity and mortality. The IL-36 family are proinflammatory cytokines that are known to shape innate immune responses, including those critical to bacterial pneumonia. The objective of this study was to determine whether IL-36 cytokines promote a proinflammatory milieu in the lungs of long-term smokers with and without COPD. Concentrations of IL-36 cytokines were measured in plasma and BAL fluid from subjects in a pilot study (n = 23) of long-term smokers with and without COPD in vivo and from a variety of lung cells (from 3–5 donors) stimulated with bacteria or cigarette smoke components in vitro. Pulmonary macrophages were stimulated with IL-36 cytokines in vitro, and chemokine and cytokine production was assessed. IL-36α and IL-36γ are produced to varying degrees in murine and human lung cells in response to bacterial stimuli and cigarette smoke components in vitro. Moreover, whereas IL-36γ production is upregulated early after cigarette smoke stimulation and wanes over time, IL-36α production requires a longer duration of exposure. IL-36α and IL-36γ are enhanced systemically and locally in long-term smokers with and without COPD, and local IL-36α concentrations display a positive correlation with declining ventilatory lung function and increasing proinflammatory cytokine concentrations. In vitro, IL-36α and IL-36γ induce proinflammatory chemokines and cytokines in a concentration-dependent fashion that requires IL-36R and MyD88. IL-36 cytokine production is altered in long-term smokers with and without COPD and contributes to shaping a proinflammatory milieu in the lungs.

慢性阻塞性肺病（COPD）是一种进行性炎症性肺病，发病率和死亡率都很高。IL-36 家族是已知可塑造先天免疫反应的促炎细胞因子，包括那些对细菌性肺炎至关重要的细胞因子。本研究的目的是确定 IL-36 细胞因子是否会促进患有和未患有 COPD 的长期吸烟者肺部的促炎环境。 对患有和未患有 COPD 的长期吸烟者在体内以及来自各种肺细胞（来自 3-5 个供体）进行刺激的初步研究 ( n = 23) 中的受试者血浆和 BAL 液中测量了 IL-36 细胞因子的浓度带有细菌或香烟烟雾成分的体外。用 IL-36 细胞因子刺激肺巨噬细胞在体外，评估了趋化因子和细胞因子的产生。IL-36α 和 IL-36γ在体外对细菌刺激和香烟烟雾成分的反应在鼠和人肺细胞中不同程度地产生。此外，虽然 IL-36γ 的产生在香烟烟雾刺激后早期上调并随着时间的推移而减弱，但 IL-36α 的产生需要更长的暴露时间。IL-36α 和 IL-36γ 在患有和未患有 COPD 的长期吸烟者中全身和局部增强，并且局部 IL-36α 浓度与肺通气功能下降和促炎细胞因子浓度增加呈正相关。体外，IL-36α 和 IL-36γ 以浓度依赖性方式诱导促炎趋化因子和细胞因子，需要 IL-36R 和 MyD88。IL-36 细胞因子的产生在患有和不患有 COPD 的长期吸烟者中发生了改变，并有助于在肺部形成促炎环境。