Department of Pulmonary and Critical Care Medicine, Shengjing Hospital of China Medical University, Shenyang, PR China.
Department of Pulmonary and Critical Care Medicine, Institute of Respiratory Diseases, the First Affiliated Hospital of China Medical University, Shenyang, PR China.
Int Immunopharmacol. 2021 Aug;97:107809. doi: 10.1016/j.intimp.2021.107809. Epub 2021 Jun 25.
Rosiglitazone, an exogenous ligand of PPARγ, plays an important anti-inflammatory role during the inflammation caused by cigarette smoke (CS). CS exposure induces pulmonary inflammation via activating macrophage polarization. However, the effects of rosiglitazone on macrophage polarization induced by CS are unclear.
36 male Wistar rats were randomly divided into 3 groups: control, CS and ROSI. In the CS group, rats were passively exposed to cigarette smoke for consecutive 3 months. In the ROSI group, rats were treated with rosiglitazone (3 mg/kg/day, ip) during CS exposure period. Alveolar macrophages of rats were isolated and cultured with CSE. The slices of lung tissues were stained with hematoxylin and eosin. The histomorphology was observed to evaluate emphysema and the pulmonary function was detected. Cells in bronchoalveolar lavage fluid (BALF) were examined and the expression of cytokines TNF-α and IL-1β was detected by ELISA and qPCR. The alveolar macrophage polarization was evaluated by immunohistochemistry and flow cytometry assay in vivo and by qPCR in vitro. The protein level of PPARγ and RXRα was measured by Western blot.
CS exposure induced significant emphysema, diminished FEV0.2/FVC, elevated PEF, and higher level of total cells, neutrophils and cytokines (TNF-α and IL-1β) in BALF compared with control group, whereas rosiglitazone partly ameliorated above disorders. CS exposure activated M1 and M2 macrophage polarization in vivo and in vitro, whereas rosiglitazone inhibited CS induced M1 macrophage polarization and decreased the ratio of M1/M2. The effects of rosiglitazone on macrophage polarization were partly blocked after AMs treated with the antagonists of PPARγ and RXRα, and were synergistically enhanced by the agonist of RXRα. CS exposure decreased the expression of PPARγ and RXRα in lung tissues and AMs, and rosiglitazone partly reversed CS-mediated suppression of PPARγ and RXRα.
Rosiglitazone ameliorated the emphysema and inflammation in lung tissues induced by CS exposure via inhibiting the M1 macrophage polarization through activating PPARγ and RXRα.
罗格列酮是过氧化物酶体增殖物激活受体 γ（PPARγ）的外源性配体，在香烟烟雾（CS）引起的炎症中发挥重要的抗炎作用。CS 暴露通过激活巨噬细胞极化诱导肺部炎症。然而，罗格列酮对 CS 诱导的巨噬细胞极化的影响尚不清楚。
36 只雄性 Wistar 大鼠随机分为 3 组：对照组、CS 组和 ROSI 组。CS 组大鼠连续 3 个月被动暴露于香烟烟雾中。ROSI 组大鼠在 CS 暴露期间给予罗格列酮（3mg/kg/天，腹腔注射）。分离大鼠肺泡巨噬细胞并用 CSE 培养。用苏木精和伊红染色肺组织切片。观察组织形态学以评估肺气肿，并检测肺功能。检测支气管肺泡灌洗液（BALF）中的细胞，并通过 ELISA 和 qPCR 检测细胞因子 TNF-α 和 IL-1β的表达。通过免疫组化和流式细胞术检测体内肺泡巨噬细胞极化，通过 qPCR 检测体外肺泡巨噬细胞极化。通过 Western blot 测定 PPARγ和 RXRα的蛋白水平。
CS 暴露引起明显的肺气肿，FEV0.2/FVC 降低，PEF 升高，BALF 中的总细胞、中性粒细胞和细胞因子（TNF-α和 IL-1β）水平升高，而罗格列酮部分改善了上述异常。CS 暴露在体内和体外激活了 M1 和 M2 巨噬细胞极化，而罗格列酮抑制了 CS 诱导的 M1 巨噬细胞极化并降低了 M1/M2 比值。用 PPARγ和 RXRα的拮抗剂处理 AMs 后，罗格列酮对巨噬细胞极化的作用部分阻断，而用 RXRα的激动剂协同增强。CS 暴露降低了肺组织和 AMs 中 PPARγ和 RXRα的表达，罗格列酮部分逆转了 CS 介导的对 PPARγ和 RXRα的抑制。
罗格列酮通过激活 PPARγ和 RXRα抑制 M1 巨噬细胞极化，改善 CS 暴露引起的肺气肿和肺组织炎症。
