Corbel M, Caulet-Maugendre S, Germain N, Lagente V, Boichot E
INSERM U 456, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes 1 and Anatomie Pathologie B, CHR Pontchaillou, Rennes, France.
Clin Exp Allergy. 2003 May;33(5):696-704. doi: 10.1046/j.1365-2222.2003.01581.x.
Chronic asthma is characterized by inflammatory cell infiltration and tissue remodelling leading to subepithelial fibrosis. Metalloproteinases (MMPs) are involved in degradation of extracellular matrix in most chronic inflammatory diseases.
The aim of this study was to investigate the expression of MMPs in the development of inflammatory processes associated or not with the concomitant development of subepithelial fibrosis in an experimental model of asthma.
Sensitized BP2 mice were challenged with ovalbumin (OA) every 2 weeks during 8 months. Several mice were removed once a month and bronchoalveolar lavages (BAL) or lung biopsies were performed.
Lung sections stained with picrosirius and hydroxyproline measurements showed a significant collagen deposition after 16 weeks of OA challenge, demonstrating the development of subepithelial fibrosis. Pulmonary inflammation was present from the first OA challenge and was consistent throughout the 8 months of the study. Moreover, an up-regulation and activation of MMP-9 and, to a less extent, MMP-2 were observed in BAL fluid from challenged mice. The level of tissue inhibitor of metalloproteinases (TIMP)-1 increased after 12 weeks of OA challenge vs. control mice.
This study reveals that a decrease in the activation of the MMP-9 due to the increase in TIMP-1, could contribute to excessive collagen deposition following repeated antigen challenge in sensitized mice.
慢性哮喘的特征为炎症细胞浸润和组织重塑，进而导致上皮下纤维化。金属蛋白酶（MMPs）参与大多数慢性炎症性疾病的细胞外基质降解。
本研究旨在探讨在哮喘实验模型中，与上皮下纤维化伴随或不伴随发生的炎症过程发展中MMPs的表达情况。
致敏的BP2小鼠在8个月内每2周用卵清蛋白（OA）激发一次。每月处死几只小鼠并进行支气管肺泡灌洗（BAL）或肺活检。
用天狼星红染色的肺切片和羟脯氨酸测量结果显示，OA激发16周后有明显的胶原沉积，表明上皮下纤维化的发展。从首次OA激发开始即存在肺部炎症，且在整个8个月的研究过程中持续存在。此外，在激发小鼠的BAL液中观察到MMP-9上调并激活，MMP-2的激活程度较小。与对照小鼠相比，OA激发12周后金属蛋白酶组织抑制剂（TIMP）-1水平升高。
本研究表明，由于TIMP-1增加导致MMP-9激活减少，可能导致致敏小鼠反复抗原激发后胶原过度沉积。
