Peng Zhihong, Konai Mohini Mohan, Avila-Cobian Luis F, Wang Man, Mobashery Shahriar, Chang Mayland
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States.
ACS Pharmacol Transl Sci. 2022 Jul 18;5(8):548-554. doi: 10.1021/acsptsci.2c00050. eCollection 2022 Aug 12.
Idiopathic pulmonary fibrosis (IPF), a fatal disease characterized by excessive matrix degradation and fibrosis, destroys the lung architecture and results in the inability of the lungs to absorb oxygen. The cause(s) of IPF is unknown and current treatments are palliative. Matrix metalloproteinases (MMPs) and A Disintegrin And Metalloproteinases (ADAMs) likely play roles in IPF progression. However, specific MMPs and ADAMs in IPF have not been identified due to challenges in MMP/ADAM profiling. We employed a designer affinity resin that binds exclusively to the active forms of MMPs and ADAMs and found by mass spectrometry higher levels of active MMP-1, ADAM9, ADAM10, and ADAM17 in lung tissues of IPF patients. Inhibition of MMP-1 and ADAM10 with the small-molecule inhibitor GI254023X in an lung fibrosis assay decreased the profibrotic protein α-smooth muscle actin (α-SMA). Our results indicate that inhibition of MMP-1 and ADAM10 may hold promise in treatment of IPF.
特发性肺纤维化（IPF）是一种致命疾病，其特征为基质过度降解和纤维化，会破坏肺部结构，导致肺部无法吸收氧气。IPF的病因不明，目前的治疗方法只是姑息性的。基质金属蛋白酶（MMPs）和去整合素金属蛋白酶（ADAMs）可能在IPF进展中发挥作用。然而，由于MMP/ADAM分析存在挑战，IPF中具体的MMPs和ADAMs尚未确定。我们使用了一种专门与MMPs和ADAMs的活性形式结合的定制亲和树脂，并通过质谱法发现IPF患者肺组织中活性MMP-1、ADAM9、ADAM10和ADAM17的水平较高。在肺纤维化试验中，用小分子抑制剂GI254023X抑制MMP-1和ADAM10可降低促纤维化蛋白α-平滑肌肌动蛋白（α-SMA）。我们的结果表明，抑制MMP-1和ADAM10可能在IPF治疗中具有前景。
