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.

慢性阻塞性肺疾病（COPD）是一种进行性炎症性肺部疾病，具有高发病率和死亡率。 IL-36 家族是促炎细胞因子，已知可塑造先天免疫反应，包括对细菌性肺炎至关重要的反应。本研究的目的是确定 IL-36 细胞因子是否会促进患有或不患有 COPD 的长期吸烟者肺部促炎环境。在一项试点研究（ n = 23）中，对体内患有和不患有 COPD 的长期吸烟者以及来自刺激的各种肺细胞（来自 3-5 个供体）的受试者的血浆和 BAL 液中的 IL-36 细胞因子浓度进行了测量带有细菌或香烟烟雾成分的体外。在体外用 IL-36 细胞因子刺激肺巨噬细胞，并评估趋化因子和细胞因子的产生。小鼠和人类肺细胞在体外对细菌刺激和香烟烟雾成分作出反应时不同程度地产生 IL-36α 和 IL-36γ。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在患有或不患有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。在体外，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，这需要IL-36R和MyD88。无论患有或不患有慢性阻塞性肺病，长期吸烟者的 IL-36 细胞因子产生都会发生改变，并有助于在肺部形成促炎环境。