Kathera Chandra Sekhar, Yadavalli Chandra Sekhar, Mishra Anil
John W. Deming Department of Medicine, Tulane Eosinophilic Disorders Center (TEDC), Section of Pulmonary Diseases, Tulane University School of Medicine, New Orleans, LA 70112, USA.
Cells. 2025 Aug 23;14(17):1307. doi: 10.3390/cells14171307.
Matrix metalloproteinases (MMPs) are a major group of proteases known to regulate the turnover of the extracellular matrix (ECM). We observed that induced MMP-12 promotes eosinophilic inflammation-related epithelial cell mesenchymal transition (EMT), bronchial fibrosis, and airway obstruction in an allergen-exposed mouse model of chronic airway diseases in allergen-exposed mice and in airway-specific CC10-IL-13-overexpressed mice. Our histological analysis showed that the parabronchial and perivascular accumulation of eosinophils, fibroblasts, and collagen is significantly decreased in MMP-12 allergen-exposed mice and airway-specific rtTA-MMP-12CC-10-IL-13-overexpressed mice compared to allergen-exposed wild-type mice and rtTA-CC10-IL-13-overexpressed mice. ELISA and Western blot analyses validated these histological findings, demonstrating that EMT and profibrotic protein levels were significantly decreased in allergen-challenged MMP-12 mice and rtTA-MMP-12CC10-IL-13-overexpressed mice in comparison to the allergen-exposed wild-type mice and rtTA-CC10-IL-13-overexpressed mice. In addition, we also observed that allergen-challenged MMP-12 mice have improved resistance and compliance compared to allergen-challenged wild-type mice. Most importantly, we show that treatment with MMP-12 inhibitors (PF-00356231 and MMP408) restricts the induction and progression of bronchial fibrosis and airway restrictions in allergen-exposed mice and airway-specific rtTA-CC10-IL-13 mice compared to the respective control mice. Taken together, the novelty of these findings lie in the fact that induced MMP-12 regulates eosinophilic inflammation-induced bronchial fibrosis and associated airway restriction, which may be reduced by treatment with MMP-12 inhibitors.
基质金属蛋白酶（MMPs）是一类主要的蛋白酶，已知其可调节细胞外基质（ECM）的更新。我们观察到，在变应原暴露的慢性气道疾病小鼠模型以及气道特异性CC10-IL-13过表达小鼠中，诱导型MMP-12会促进嗜酸性粒细胞炎症相关的上皮细胞间充质转化（EMT）、支气管纤维化和气道阻塞。我们的组织学分析表明，与变应原暴露的野生型小鼠和rtTA-CC10-IL-13过表达小鼠相比，在MMP-12变应原暴露小鼠和气道特异性rtTA-MMP-12CC-10-IL-13过表达小鼠中，支气管旁和血管周围嗜酸性粒细胞、成纤维细胞和胶原蛋白的积聚显著减少。酶联免疫吸附测定（ELISA）和蛋白质印迹分析证实了这些组织学结果，表明与变应原暴露的野生型小鼠和rtTA-CC10-IL-13过表达小鼠相比，变应原激发的MMP-12小鼠和rtTA-MMP-12CC10-IL-13过表达小鼠中的EMT和促纤维化蛋白水平显著降低。此外，我们还观察到，与变应原激发的野生型小鼠相比，变应原激发的MMP-12小鼠的抵抗力和顺应性有所改善。最重要的是，我们发现，与各自的对照小鼠相比，用MMP-12抑制剂（PF-00356231和MMP408）治疗可限制变应原暴露小鼠和气道特异性rtTA-CC10-IL-13小鼠中支气管纤维化的诱导和进展以及气道狭窄。综上所述，这些发现的新颖之处在于，诱导型MMP-12可调节嗜酸性粒细胞炎症诱导的支气管纤维化及相关气道狭窄，而用MMP-12抑制剂治疗可能会减轻这种情况。
