Pingyuan Laboratory, State Key Laboratory of Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Organ Fibrosis, College of Life Science, Henan Normal University, Xinxiang, 453007, P. R. China.
College of Chemical and Pharmaceutical Engineering, Huanghuai University, Zhumadian, 463000, P. R. China.
Adv Sci (Weinh). 2024 Nov;11(44):e2401931. doi: 10.1002/advs.202401931. Epub 2024 Oct 7.
Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a life-threatening condition with a high mortality rate of ≈40%. Thyroid hormones (THs) play crucial roles in maintaining homeostasis of the cellular microenvironment under stress. The previous studies confirmed that the clinical-stage TH analog GC-1 significantly alleviates pulmonary fibrosis by improving the function of mitochondria in epithelial cells. However, the effects of GC-1 on macrophages in lung injury and the related mechanisms remain unclear. This study evaluated the therapeutic effects of GC-1 in two murine models of lipopolysaccharide (LPS)- or hydrochloric acid (HCl)-induced ALI. Additionally, mouse alveolar macrophages (AMs) and human THP-1-derived macrophages are utilized to investigate the impact of GC-1 on macrophage polarization. GC-1 effectively reduces the inflammatory response and lung injury in ALI mice, as evidenced by neutrophil infiltration, cytokine levels, alveolar fluid clearance, and pulmonary pathology. Notably, GC-1 selectively inhibits M1 macrophage polarization, which may be achieved by impeding NF-κB signaling activation through the DNMT3b-PPARγ-NF-κB pathway in a TH receptor β1 (TRβ1)-dependent manner, consequently suppressing the polarization of macrophages toward the M1 phenotype and overproduction of inflammatory cytokines. Overall, these findings highlight the immunomodulatory property of GC-1 as an anti-inflammatory strategy for ALI/ARDS and inflammation-related diseases.
急性肺损伤（ALI）/急性呼吸窘迫综合征（ARDS）是一种危及生命的疾病，死亡率约为 40%。甲状腺激素（THs）在维持应激状态下细胞微环境的内稳态方面发挥着至关重要的作用。先前的研究证实，临床阶段的 TH 类似物 GC-1 通过改善上皮细胞中线粒体的功能显著缓解肺纤维化。然而，GC-1 对肺损伤中巨噬细胞的影响及其相关机制尚不清楚。本研究评估了 GC-1 在脂多糖（LPS）或盐酸（HCl）诱导的 ALI 两种小鼠模型中的治疗效果。此外，还利用小鼠肺泡巨噬细胞（AMs）和人 THP-1 衍生的巨噬细胞来研究 GC-1 对巨噬细胞极化的影响。GC-1 可有效减轻 ALI 小鼠的炎症反应和肺损伤，表现为中性粒细胞浸润、细胞因子水平、肺泡液清除和肺病理学改变。值得注意的是，GC-1 选择性抑制 M1 巨噬细胞极化，这可能是通过 DNMT3b-PPARγ-NF-κB 途径抑制 NF-κB 信号激活，从而依赖于 TH 受体 β1（TRβ1）抑制巨噬细胞向 M1 表型极化和炎症细胞因子的过度产生来实现的。总之，这些发现强调了 GC-1 的免疫调节特性，可作为 ALI/ARDS 和炎症相关疾病的抗炎策略。
