Corbel M, Caulet-Maugendre S, Germain N, Molet S, Lagente V, Boichot E
INSERM U 456, Laboratoire de Pharmacodynamie et de Pharmacologie Moléculaire, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes 1, Avenue du Prof. Léon Bernard, 35043 Rennes Cedex, France.
J Pathol. 2001 Apr;193(4):538-45. doi: 10.1002/path.826.
Bleomycin-induced pulmonary fibrosis is known to be associated with the increased activity of two gelatinases, matrix metalloproteinase (MMP)-2 and MMP-9, in bronchoalveolar lavage (BAL). This study has investigated the effect of a synthetic inhibitor of MMP, batimastat, on the development of pulmonary fibrosis induced by bleomycin administration in mice. Animals were intranasally instilled with saline or bleomycin (0.5 mg in 100 microl per mouse). Batimastat (30 mg/kg) or vehicle alone was administered by intraperitoneal injection 24 h and 1 h before saline or bleomycin instillation, and then daily at the same dosage until the end of the study. Fifteen days after bleomycin administration, BAL was performed and the lung was removed. Treatment of mice with batimastat significantly reduced bleomycin-induced lung fibrosis, as shown in the lung by histopathological examination and by a decrease in hydroxyproline levels. Batimastat also prevented the increase in BAL macrophage and lymphocyte numbers, whereas it did not show any effect on the increased expression of active transforming growth factor-beta (TGF-beta) in BAL. Batimastat treatment was effective in reducing MMP-2 and MMP-9 activity as well as the tissue inhibitor of metalloproteinase-1 (TIMP-1) level in BAL. These results suggest that administration of the MMP inhibitor batimastat is useful in preventing experimental pulmonary fibrosis induced by bleomycin and raises the possibility of a therapeutic approach to human pulmonary fibrotic disease.
已知博来霉素诱导的肺纤维化与支气管肺泡灌洗（BAL）中两种明胶酶即基质金属蛋白酶（MMP）-2和MMP-9活性增加有关。本研究调查了MMP的合成抑制剂batimastat对博来霉素诱导的小鼠肺纤维化发展的影响。给动物经鼻内滴注生理盐水或博来霉素（每只小鼠100微升中含0.5毫克）。在滴注生理盐水或博来霉素前24小时和1小时，通过腹腔注射给予batimastat（30毫克/千克）或单独的赋形剂，然后每天以相同剂量给药直至研究结束。博来霉素给药15天后，进行BAL并取出肺脏。如组织病理学检查及羟脯氨酸水平降低所示，用batimastat治疗小鼠可显著减轻博来霉素诱导的肺纤维化。batimastat还可防止BAL中巨噬细胞和淋巴细胞数量增加，而对BAL中活性转化生长因子-β（TGF-β）表达增加未显示任何作用。batimastat治疗可有效降低BAL中MMP-2和MMP-9活性以及金属蛋白酶组织抑制剂-1（TIMP-1）水平。这些结果表明，给予MMP抑制剂batimastat有助于预防博来霉素诱导的实验性肺纤维化，并增加了对人类肺纤维化疾病进行治疗的可能性。
