Zeng Huaxiu, Singh Pooja, Sinha Rajesh, Stephens Crystal T, Ahmad Aftab, Athar Mohammad, Antony Veena B
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States.
Superfund Research Center, University of Alabama at Birmingham, Birmingham, AL, United States.
Front Mol Biosci. 2025 Jul 30;12:1644792. doi: 10.3389/fmolb.2025.1644792. eCollection 2025.
Arsenicals like lewisite are highly toxic vesicant chemical warfare agents that cause severe skin damage and systemic inflammation. Exposure activates cytokine release, leading to pulmonary injury, including edema, hemorrhage, and in severe cases, Bronchiolitis Obliterans Syndrome (BOS), marked by airway fibrosis and narrowing. The only approved treatment, British anti-lewisite (BAL), has limitations due to toxicity and field administration challenges. BRD4, a BET family protein, regulates inflammatory gene expression, and its inhibition has shown therapeutic potential. CPI-0610 (Pelabresib), a selective BRD4 inhibitor, is currently being explored for its anti-fibrotic and anti-inflammatory effects.
In a murine model, we evaluated the therapeutic potential of CPI-0610 in mitigating lewisite-induced pulmonary damage. Mice were exposed to a single cutaneous dose of lewisite to induce systemic lung injury. Following exposure, one group of mice received CPI-0610 treatment, while a control group remained untreated. Lung tissues were harvested for molecular and histological analysis. The expression of inflammatory and fibrotic markers, including interleukin-6 (IL-6) and alpha-smooth muscle actin (α-SMA), was quantified via RT-PCR and immunohistochemistry.
Treatment with CPI-0610 significantly reduced the expression of IL-6 and α-SMA in lung tissues of lewisite-exposed mice compared to untreated controls. Histological analysis revealed reduced signs of inflammation, extracellular matrix deposition, and fibrotic remodeling in the CPI-0610 group. These findings indicate a protective effect of BRD4 inhibition on arsenical-induced lung injury.
Our study provides the first experimental evidence that BRD4 inhibition via CPI-0610 attenuates the development of pulmonary fibrosis following cutaneous lewisite exposure in mice. These results suggest that targeting BRD4 signaling can effectively reduce inflammation and fibrotic progression in the lungs. Given CPI-0610's favorable clinical safety profile, it holds promise as a novel therapeutic strategy for treating arsenical-induced pulmonary complications, potentially improving outcomes where current countermeasures like BAL fall short. Further studies are warranted to explore its mechanism of action and therapeutic efficacy in broader exposure models.
路易氏剂等砷化合物是剧毒的糜烂性化学战剂，可导致严重的皮肤损伤和全身炎症。暴露会激活细胞因子释放，导致肺部损伤，包括水肿、出血，严重时会引发闭塞性细支气管炎综合征（BOS），其特征为气道纤维化和狭窄。唯一获批的治疗药物英国抗路易氏剂（BAL），由于毒性和现场给药挑战存在局限性。BRD4是一种BET家族蛋白，可调节炎症基因表达，对其抑制已显示出治疗潜力。CPI-0610（派拉布瑞西）是一种选择性BRD4抑制剂，目前正在探索其抗纤维化和抗炎作用。
在小鼠模型中，我们评估了CPI-0610减轻路易氏剂诱导的肺部损伤的治疗潜力。给小鼠单次皮肤涂抹路易氏剂以诱导全身性肺损伤。暴露后，一组小鼠接受CPI-0610治疗，而对照组不进行治疗。采集肺组织进行分子和组织学分析。通过逆转录聚合酶链反应（RT-PCR）和免疫组织化学对炎症和纤维化标志物（包括白细胞介素-6（IL-6）和α-平滑肌肌动蛋白（α-SMA））的表达进行定量。
与未治疗的对照组相比，用CPI-0610治疗可显著降低路易氏剂暴露小鼠肺组织中IL-6和α-SMA的表达。组织学分析显示，CPI-0610组的炎症、细胞外基质沉积和纤维化重塑迹象减少。这些发现表明抑制BRD4对砷化合物诱导的肺损伤具有保护作用。
我们的研究提供了首个实验证据，即通过CPI-0610抑制BRD4可减轻小鼠皮肤暴露于路易氏剂后肺纤维化的发展。这些结果表明，靶向BRD4信号传导可有效减轻肺部炎症和纤维化进展。鉴于CPI-0610良好的临床安全性，它有望成为治疗砷化合物诱导的肺部并发症的一种新治疗策略，可能改善当前像BAL等对策效果不佳的情况。有必要进一步研究以探索其在更广泛暴露模型中的作用机制和治疗效果。
