司格列他扎通过抑制NF-κB激活和减轻巨噬细胞M1极化改善小鼠肺纤维化进展。

Saroglitazar Ameliorates Pulmonary Fibrosis Progression in Mice by Suppressing NF-κB Activation and Attenuating Macrophage M1 Polarization.

作者信息

Zhang Yawen, Lin Jiaquan, Han Xiaodong, Chen Xiang

机构信息

State Key Laboratory of Analytical Chemistry for Life Science, Division of Anatomy and Histo-Embryology, Medical School, Nanjing University, Nanjing 210093, China.

Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing 210093, China.

出版信息

Medicina (Kaunas). 2025 Jun 26;61(7):1157. doi: 10.3390/medicina61071157.

DOI:10.3390/medicina61071157

PMID:40731787

Abstract

: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease with limited therapeutic options. Current therapies (pirfenidone, nintedanib) exhibit modest efficacy and significant side effects, underscoring the need for novel strategies targeting early pathogenic drivers. Saroglitazar (SGZ), a dual PPARα/γ agonist with anti-inflammatory properties approved for diabetic dyslipidemia, has not been explored for IPF. We aimed to investigate SGZ's therapeutic potential in pulmonary fibrosis and elucidate its mechanisms of action. : Using a bleomycin (BLM)-induced murine pulmonary fibrosis model, we administered SGZ therapeutically. A histopathological assessment (H&E, Masson's trichrome, collagen I immunofluorescence), Western blotting, and qRT-PCR analyzed the fibrosis progression and inflammatory markers. Flow cytometry evaluated the macrophage polarization. In vitro studies used RAW264.7 macrophages stimulated with BLM/LPS and MRC-5 fibroblast co-cultures. The NF-κB/NLRP3 pathway activation was assessed through protein and gene expression. : SGZ significantly attenuated BLM-induced histopathological hallmarks, including alveolar wall thickening, collagen deposition, and inflammatory infiltration. Fibrotic markers (OPN, α-SMA) and pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) were downregulated in the SGZ-treated mice. Mechanistically, SGZ suppressed the M1 macrophage polarization (reduced CD86 populations) and inhibited the NF-κB/NLRP3 pathway activation in the alveolar macrophages. In the RAW264.7 cells, SGZ decreased the NLRP3 inflammasome components (ASC, cleaved IL-1β) and cytokine secretion. Co-cultures demonstrated that the SGZ-treated macrophage supernatants suppressed the fibroblast activation (α-SMA, collagen I) in MRC-5 cells. : SGZ attenuates pulmonary fibrosis by suppressing macrophage-driven inflammation via NF-κB/NLRP3 inhibition and disrupting the macrophage-fibroblast crosstalk. These findings nominate SGZ as a promising candidate for preclinical optimization and future clinical evaluation in IPF.

摘要

特发性肺纤维化（IPF）是一种进行性且致命的间质性肺病，治疗选择有限。目前的治疗方法（吡非尼酮、尼达尼布）疗效一般且有显著副作用，这突出表明需要针对早期致病驱动因素的新策略。Saroglitazar（SGZ）是一种具有抗炎特性的双重PPARα/γ激动剂，已被批准用于治疗糖尿病血脂异常，但尚未针对IPF进行研究。我们旨在研究SGZ在肺纤维化中的治疗潜力并阐明其作用机制。

我们使用博来霉素（BLM）诱导的小鼠肺纤维化模型进行治疗性给予SGZ。通过组织病理学评估（苏木精-伊红染色、Masson三色染色、I型胶原蛋白免疫荧光）、蛋白质印迹法和定量逆转录-聚合酶链反应分析纤维化进展和炎症标志物。流式细胞术评估巨噬细胞极化。体外研究使用经BLM/LPS刺激的RAW264.7巨噬细胞和MRC-5成纤维细胞共培养。通过蛋白质和基因表达评估NF-κB/NLRP3途径的激活。

SGZ显著减轻了BLM诱导的组织病理学特征，包括肺泡壁增厚、胶原蛋白沉积和炎症浸润。在接受SGZ治疗的小鼠中，纤维化标志物（骨桥蛋白、α-平滑肌肌动蛋白）和促炎细胞因子（白细胞介素-1β、肿瘤坏死因子-α、白细胞介素-6）下调。从机制上讲，SGZ抑制M1巨噬细胞极化（减少CD86群体）并抑制肺泡巨噬细胞中NF-κB/NLRP3途径的激活。在RAW264.7细胞中，SGZ减少了NLRP3炎性小体成分（凋亡相关斑点样蛋白、裂解的白细胞介素-1β）和细胞因子分泌。共培养表明，经SGZ处理的巨噬细胞上清液抑制了MRC-5细胞中的成纤维细胞激活（α-平滑肌肌动蛋白、I型胶原蛋白）。

SGZ通过抑制NF-κB/NLRP3介导的巨噬细胞驱动的炎症并破坏巨噬细胞-成纤维细胞相互作用来减轻肺纤维化。这些发现表明SGZ是IPF临床前优化和未来临床评估的有希望的候选药物。