Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263.
Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY 14263.
J Immunol. 2021 Mar 15;206(6):1348-1360. doi: 10.4049/jimmunol.2001228. Epub 2021 Feb 8.
Cigarette smoke is a potent proinflammatory trigger contributing to acute lung injury and the development of chronic lung diseases via mechanisms that include the impairment of inflammation resolution. We have previously demonstrated that secondhand smoke (SHS) exposure exacerbates bacterial infection-induced pulmonary inflammation and suppresses immune responses. It is now recognized that resolution of inflammation is a bioactive process mediated by lipid-derived specialized proresolving mediators that counterregulate proinflammatory signaling and promote resolution pathways. We therefore hypothesized that proresolving mediators could reduce the burden of inflammation due to chronic lung infection following SHS exposure and restore normal immune responses to respiratory pathogens. To address this question, we exposed mice to SHS followed by chronic infection with nontypeable (NTHI). Some groups of mice were treated with aspirin-triggered resolvin D1 (AT-RvD1) during the latter half of the smoke exposure period or during a period of smoking cessation and before infection. Treatment with AT-RvD1 markedly reduced the recruitment of neutrophils, macrophages, and T cells in lung tissue and bronchoalveolar lavage and levels of proinflammatory cytokines in the bronchoalveolar lavage. Additionally, treatment with AT-RvD1 improved Ab titers against the NTHI outer membrane lipoprotein Ag P6 following infection. Furthermore, treatment with AT-RvD1 prior to classically adjuvanted immunization with P6 increased Ag-specific Ab titers, resulting in rapid clearance of NTHI from the lungs after acute challenge. Collectively, we have demonstrated that AT-RvD1 potently reverses the detrimental effects of SHS on pulmonary inflammation and immunity and thus could be beneficial in reducing lung injury associated with smoke exposure and infection.
香烟烟雾是一种强烈的促炎触发物，通过包括损害炎症解决在内的机制导致急性肺损伤和慢性肺部疾病的发展。我们之前已经证明，二手烟（SHS）暴露会加剧细菌感染引起的肺部炎症，并抑制免疫反应。现在人们认识到，炎症的解决是一个由脂质衍生的专门的促解决介质介导的生物活性过程，这些介质可以抵消促炎信号并促进解决途径。因此，我们假设促解决介质可以减少 SHS 暴露后慢性肺部感染引起的炎症负担，并恢复对呼吸道病原体的正常免疫反应。为了解决这个问题，我们让小鼠暴露于 SHS 后，用非典型性（NTHI）进行慢性感染。一些小鼠组在烟雾暴露期的后半段或在吸烟停止和感染前用阿司匹林触发的分辨率 D1（AT-RvD1）治疗。AT-RvD1 的治疗显著减少了肺部组织和支气管肺泡灌洗液中中性粒细胞、巨噬细胞和 T 细胞的募集，以及支气管肺泡灌洗液中促炎细胞因子的水平。此外，AT-RvD1 的治疗改善了感染后针对 NTHI 外膜脂蛋白 Ag P6 的 Ab 滴度。此外，在 P6 进行经典佐剂免疫接种之前用 AT-RvD1 治疗，增加了 Ag 特异性 Ab 滴度，导致急性挑战后 NTHI 从肺部迅速清除。总的来说，我们已经证明，AT-RvD1 可以有效地逆转 SHS 对肺部炎症和免疫的有害影响，因此可能有助于减少与吸烟暴露和感染相关的肺部损伤。
