Blockade of pentraxin 3/CD44 interaction on attenuation and reversal of lung injury-induced fibrosis. Blockade of pentraxin 3/CD44 interaction on attenuation and reversal of lung injury-induced fibrosis

Fibrosing interstitial lung disease (fILD) is a fatal fibrotic lung disease with limited therapeutic options and no effective therapeutic strategies to reverse pulmonary fibrosis. Here, we found that PTX3 is upregulated in the lungs of bleomycin-treated mice and fILD patients. Lung injury and fibrosis were significantly attenuated in inducible conditional Ptx3-deficient mice in response to bleomycin treatment. Moreover, we dissected mechanistic insights into PTX3/CD44-dependent fibrotic pathways and effectors in lung myofibroblast activation and collagen production. Importantly, αPTX3i disrupts the interaction of PTX3 and CD44 and effectively attenuated bleomycin-treated lung injury and fibrosis in vivo and myofibroblast activation in vitro. Our study provides new insight into the regulation of PTX3 in pulmonary fibrosis and a potential target for developing future novel therapy for fILDs. Overall design: C57BL/6 mice were exposed to either saline or bleomycin (2 mg/kg) via intratracheal instillation. Administration of αPTX3i (10 mg/kg) or IgG1κ (10 mg/kg) was performed on days 14 and 21 after bleomycin administration by intraperitoneal injection. At day 28, the lungs were harvested, total RNA was extracted and subjected to RNA-sequencing.

纤维化性间质性肺疾病（Fibrosing interstitial lung disease, fILD）是一类致死性纤维化肺部疾病，临床治疗选择有限，且暂无能够逆转肺纤维化的有效治疗策略。本研究发现，博莱霉素处理小鼠的肺组织及fILD患者肺部样本中，PTX3均呈高表达。在博莱霉素诱导造模后，诱导型条件性Ptx3敲除小鼠的肺损伤与纤维化程度显著减轻。此外，本研究阐明了PTX3/CD44依赖的纤维化通路及下游效应分子在肺肌成纤维细胞活化与胶原生成中的作用机制。值得注意的是，αPTX3i可阻断PTX3与CD44的相互作用，并在体内有效减轻博莱霉素诱导的肺损伤与纤维化，在体外可抑制肌成纤维细胞活化。本研究为肺纤维化中PTX3的调控机制提供了新视角，同时为未来开发fILD的新型治疗手段提供了潜在靶点。整体实验设计：将C57BL/6小鼠经气管内滴注给予生理盐水或博莱霉素（2 mg/kg）。于博莱霉素给药后的第14天和第21天，分别通过腹腔注射给予αPTX3i（10 mg/kg）或IgG1κ（10 mg/kg）。造模第28天时收取肺组织，提取总RNA并进行RNA测序（RNA-sequencing）。