Manoury Boris, Nénan Soizig, Guénon Isabelle, Lagente Vincent, Boichot Elisabeth
INSERM U620, IFR140, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes 1, Rennes, 35043, France.
Int Immunopharmacol. 2007 Jul;7(7):900-11. doi: 10.1016/j.intimp.2007.02.009. Epub 2007 Mar 15.
Pulmonary fibrosis is characterized by excessive deposition of extracellular matrix in interstitium resulting in respiratory failure associated with inflammation showing mainly neutrophil (PMN) recruitment. The turn over of extracellular matrix is partially regulated by proteases such as metalloproteinases (MMPs) and their inhibitors (TIMPs). We investigated the impact of PMN depletion on the MMP/TIMP-1 imbalance and the development of fibrosis in mice induced by bleomycin (0.3 mg/mouse). Administration of 200 microL of rabbit anti-mouse PMN antibody i.p. blunted the neutrophil influx detected in BAL and in whole blood one day after bleomycin administration. At day(14), hydroxyproline content was increased both in anti-PMN treated and control mice, without any difference between groups. At day one, bleomycin elicited a raise in pro-MMP-9 level in BAL that was significantly attenuated in anti-PMN depleted mice, whereas TIMP-1 and MMP-2 release were similar in both groups at day(1) and day(14). Higher RNA levels were observed in PMN-treated mice at day(1) for MMP-9 and MMP-2 and at day(14) for MMP-2 only. At day(14), bleomycin elicited a raise of TIMP-1 protein and RNA levels regardless of anti-PMN treatment, whereas MMP-9 returned to basal level. Bleomycin enhanced MMP-8 level in BAL at day(14) only for the control group. The amount of MMP-8 was more important in BAL from anti-PMN treated mice than in control mice at day(1) and day(14). PMN-depletion and the associated modifications in pro-MMP-9/TIMP-1 imbalance in lung during the early inflammatory phase do not alter susceptibility to bleomycin-induced pulmonary fibrosis.
肺纤维化的特征是细胞外基质在间质中过度沉积，导致与炎症相关的呼吸衰竭，炎症主要表现为中性粒细胞（PMN）募集。细胞外基质的周转部分受蛋白酶如金属蛋白酶（MMPs）及其抑制剂（TIMPs）的调节。我们研究了中性粒细胞耗竭对博来霉素（0.3mg/只小鼠）诱导的小鼠MMP/TIMP-1失衡及纤维化发展的影响。腹腔注射200μL兔抗小鼠PMN抗体可抑制博来霉素给药后一天在支气管肺泡灌洗（BAL）液和全血中检测到的中性粒细胞流入。在第14天，抗PMN治疗组和对照组小鼠的羟脯氨酸含量均增加，两组之间无差异。在第1天，博来霉素使BAL液中前MMP-9水平升高，在抗PMN耗竭的小鼠中显著减弱，而在第1天和第14天，两组中TIMP-1和MMP-2的释放相似。在第1天，PMN治疗组小鼠中MMP-9和MMP-2的RNA水平较高，仅在第14天MMP-2的RNA水平较高。在第14天，无论是否进行抗PMN治疗，博来霉素均可使TIMP-1蛋白和RNA水平升高，而MMP-9恢复到基础水平。仅在第14天，博来霉素使对照组BAL液中MMP-8水平升高。在第1天和第14天，抗PMN治疗组小鼠BAL液中的MMP-8量比对照组小鼠中的更重要。在早期炎症阶段，中性粒细胞耗竭及肺中前MMP-9/TIMP-1失衡的相关改变不会改变对博来霉素诱导的肺纤维化的易感性。
