Department of Thoracic Medicine, Royal Adelaide Hospital, Lung Research Laboratory, Hanson Institute, South Australia, Australia.
Am J Respir Cell Mol Biol. 2011 May;44(5):673-81. doi: 10.1165/rcmb.2009-0459OC. Epub 2010 Jul 1.
Defective efferocytosis may perpetuate inflammation in smokers with or without chronic obstructive pulmonary disease (COPD). Macrophages may phenotypically polarize to classically activated M1 (proinflammatory; regulation of antigen presentation) or alternatively activated M2 (poor antigen presentation; improved efferocytosis) markers. In bronchoalveolar lavage (BAL)-derived macrophages from control subjects and smoker/ex-smoker COPD subjects, we investigated M1 markers (antigen-presenting major histocompatibility complex [MHC] Classes I and II), complement receptors (CRs), the high-affinity Fc receptor involved with immunoglobulin binding for phagocytosis (Fc-gamma receptor, FcγR1), M2 markers (dendritic cell-specific intercellular adhesion molecule-grabbing nonintegrin [DC-SIGN] and arginase), and macrophage function (efferocytosis and proinflammatory cytokine production in response to LPS). The availability of glutathione (GSH) in BAL was assessed, because GSH is essential for both M1 function and efferocytosis. We used a murine model to investigate macrophage phenotype/function further in response to cigarette smoke. In lung tissue (disaggregated) and BAL, we investigated CRs, the available GSH, arginase, and efferocytosis. We further investigated the therapeutic effects of an oral administration of a GSH precursor, cysteine l-2-oxothiazolidine-4-carboxylic acid (procysteine). Significantly decreased efferocytosis, available GSH, and M1 antigen-presenting molecules were evident in both COPD groups, with increased DC-SIGN and production of proinflammatory cytokines. Increased CR-3 was evident in the current-smoker COPD group. In smoke-exposed mice, we found decreased efferocytosis (BAL and tissue) and available GSH, and increased arginase, CR-3, and CR-4. Treatment with procysteine significantly increased GSH, efferocytosis (BAL: control group, 26.2%; smoke-exposed group, 17.66%; procysteine + smoke-exposed group, 27.8%; tissue: control group, 35.9%; smoke-exposed group, 21.6%; procysteine + smoke-exposed group, 34.5%), and decreased CR-4 in lung tissue. Macrophages in COPD are of a mixed phenotype and function. The increased efferocytosis and availability of GSH in response to procysteine indicates that this treatment may be useful as adjunct therapy for improving macrophage function in COPD and in susceptible smokers.
吞噬作用缺陷可能使无论是否患有慢性阻塞性肺疾病（COPD）的吸烟者的炎症持续存在。巨噬细胞可能表现出经典激活的 M1（促炎；抗原呈递）或替代激活的 M2（抗原呈递差；吞噬作用改善）表型标志物。在来自对照受试者和吸烟者/戒烟者 COPD 受试者的支气管肺泡灌洗液（BAL）衍生的巨噬细胞中，我们研究了 M1 标志物（抗原呈递主要组织相容性复合体 [MHC] 类 I 和 II）、补体受体（CR）、与免疫球蛋白结合用于吞噬作用的高亲和力 Fc 受体（Fc-γ 受体，FcγR1）、M2 标志物（树突状细胞特异性细胞间黏附分子抓取非整联蛋白 [DC-SIGN]和精氨酸酶）以及巨噬细胞功能（对 LPS 的吞噬作用和促炎细胞因子产生）。还评估了 BAL 中谷胱甘肽（GSH）的可用性，因为 GSH 对 M1 功能和吞噬作用都是必不可少的。我们使用一种小鼠模型进一步研究了对香烟烟雾的巨噬细胞表型/功能反应。在肺组织（离散）和 BAL 中，我们研究了 CR、可用 GSH、精氨酸酶和吞噬作用。我们进一步研究了口服 GSH 前体半胱氨酸 l-2-氧代噻唑烷-4-羧酸（L-半胱氨酸）的治疗效果。在两个 COPD 组中均明显存在吞噬作用、可用 GSH 和 M1 抗原呈递分子减少，DC-SIGN 和促炎细胞因子产生增加。当前吸烟者 COPD 组中 CR-3 增加。在暴露于烟雾的小鼠中，我们发现吞噬作用（BAL 和组织）和可用 GSH 减少，而精氨酸酶、CR-3 和 CR-4 增加。用 L-半胱氨酸治疗显著增加了 GSH、吞噬作用（BAL：对照组，26.2%；暴露于烟雾组，17.66%；L-半胱氨酸+暴露于烟雾组，27.8%；组织：对照组，35.9%；暴露于烟雾组，21.6%；L-半胱氨酸+暴露于烟雾组，34.5%）和肺组织中的 CR-4 减少。COPD 中的巨噬细胞具有混合表型和功能。对 L-半胱氨酸的吞噬作用和 GSH 可用性增加表明，这种治疗方法可能有助于改善 COPD 和易感吸烟者的巨噬细胞功能。
