Bexarotene ameliorated the pulmonary inflammation and M1 polarization of alveolar macrophages induced by cigarette smoke via PPARγ/HO-1.

Background: Alveolar macrophages (AMs) modulate pulmonary inflammation in chronic obstructive pulmonary disease (COPD), contributing to its progression. The PPARγ/RXRα heterodimer influences AM polarization induced by cigarette smoke (CS). Although PPARγ agonists suppress CS-induced M1 macrophage polarization, the impact of RXRα agonists on this process has not been determined. This study explored the effects and mechanisms of the RXRα agonist bexarotene on macrophage polarization in a COPD mouse model.

Methods: C57BL/6 mice were assigned to the control, model, bexarotene, or model + bexarotene group. The COPD model was induced by CS exposure and intraperitoneal injection of cigarette smoke extract (CSE), followed by intraperitoneal administration of bexarotene. Additionally, MH-S cells were exposed to CSE and bexarotene. Lung tissues were subjected to hematoxylin-eosin staining, and emphysema and inflammatory scores were assessed. Cytokine levels and cell differentials in bronchoalveolar lavage fluid were measured, and macrophage polarization was evaluated using immunohistochemistry, flow cytometry, and qPCR.

Results: Bexarotene effectively reduced inflammatory scores, cytokine levels, and neutrophil counts and ameliorated emphysema and M1 polarization of AMs in COPD model mice. Furthermore, while CSE exposure reduced PPARγ expression and the transcriptional activity of AMs, bexarotene enhanced the transcriptional response of PPARγ to CSE. HO-1 was identified as a potential target of PPARγ; its levels were assessed in AMs, revealing that bexarotene mitigated the CSE-induced reduction in HO-1. Notably, the effect of bexarotene was partially inhibited by the PPARγ inhibitor.

Conclusions: Our results indicated that bexarotene may curb inflammation and M1 polarization in COPD through activation of the PPARγ/HO-1 pathway.