Yoo Young Jo, Jeon Seulgi, Jin Hee, Won Hee Yeon, Jeong Mi Gyeong, Cho Yeseul, Hwang Eun Sook, Na Younghwa, Cho Jaeho, Lee Yun-Sil
Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of Korea.
College of Pharmacy, CHA University, Pocheon-si, Gyeonggi-do, Republic of Korea.
Front Pharmacol. 2023 Jul 4;14:1203033. doi: 10.3389/fphar.2023.1203033. eCollection 2023.
Pulmonary fibrosis (PF) is a progressive lung disease characterized by fibroblast accumulation and collagen deposition, resulting in lung scarring and impaired gas exchange. Current treatments for idiopathic pulmonary fibrosis (IPF) have limited efficacy and significant side effects. Heat shock protein 27 (HSP27) has emerged as a potential therapeutic target for PF due to its involvement in fibrotic processes. However, effective HSP27 inhibitors for PF treatment are still lacking. To assess the anti-fibrotic effects of NA49, we utilized murine PF models induced by radiation (IR) or bleomycin (BLM). We administered NA49 to the PF mice and evaluated its impact on lung fibrosis progression. We also investigated the molecular mechanisms underlying NA49's effects, focusing on its inhibition of EMT-related signaling pathways. In our study, we evaluated the potential of a novel HSP27 inhibitor, NA49, in preclinical models of PF. NA49 effectively suppressed PF development in radiation and bleomycin-induced PF models. It reduced fibrosis, inhibited NFkB signaling, and downregulated EMT-related molecules. Importantly, we evaluated the safety profile of NA49 by assessing its impact on DNA strand breakage. Compared to previous HSP27 inhibitors, NA49 showed lower levels of DNA damage in human lung epithelial cells, and suggests that NA49 may have reduced toxicity compared to other HSP27 inhibitors. Overall, our results demonstrate that NA49 effectively inhibits PF development in preclinical models. It reduces lung fibrosis, inhibits EMT-related signaling pathways, and exhibits improved safety profiles. These findings highlight the potential of NA49 as a promising candidate for the treatment of PF. NA49 exhibited significant anti-fibrotic effects, inhibiting fibrosis development and EMT-related signaling pathways. Moreover, NA49 showed improved safety profiles compared to previous HSP27 inhibitors.
肺纤维化（PF）是一种进行性肺部疾病，其特征是成纤维细胞积聚和胶原蛋白沉积，导致肺瘢痕形成和气体交换受损。目前针对特发性肺纤维化（IPF）的治疗效果有限且副作用显著。热休克蛋白27（HSP27）因其参与纤维化过程而成为PF的潜在治疗靶点。然而，仍缺乏有效的用于PF治疗的HSP27抑制剂。为了评估NA49的抗纤维化作用，我们使用了辐射（IR）或博来霉素（BLM）诱导的小鼠PF模型。我们给PF小鼠施用NA49，并评估其对肺纤维化进展的影响。我们还研究了NA49作用的分子机制，重点是其对上皮-间质转化（EMT）相关信号通路的抑制作用。在我们的研究中，我们评估了一种新型HSP27抑制剂NA49在PF临床前模型中的潜力。NA49在辐射和博来霉素诱导的PF模型中有效抑制了PF的发展。它减少了纤维化，抑制了核因子κB（NFκB）信号传导，并下调了EMT相关分子。重要的是，我们通过评估其对DNA链断裂的影响来评估NA49的安全性。与先前的HSP27抑制剂相比，NA49在人肺上皮细胞中显示出较低水平的DNA损伤，这表明与其他HSP27抑制剂相比，NA49可能具有更低的毒性。总体而言，我们的结果表明，NA49在临床前模型中有效抑制PF的发展。它减少了肺纤维化，抑制了EMT相关信号通路，并表现出更好的安全性。这些发现突出了NA49作为PF治疗有前景候选药物的潜力。NA49表现出显著的抗纤维化作用，抑制纤维化发展和EMT相关信号通路。此外，与先前的HSP27抑制剂相比，NA49显示出更好的安全性。
