Division of Allergy-Immunology, Department of Medicine, Northwestern Feinberg School of Medicine, 676 North St. Clair Street, Chicago, IL 60611, USA.
Am J Respir Cell Mol Biol. 2012 Jun;46(6):842-6. doi: 10.1165/rcmb.2011-0369OC. Epub 2012 Feb 9.
We previously reported that plasminogen activator inhibitor (PAI)-1 deficiency prevents collagen deposition in the airways of ovalbumin (OVA)-challenged mice. In this study, we explored the therapeutic utility of blocking PAI-1 in preventing airway remodeling, using a specific PAI-1 inhibitor, tiplaxtinin. C57BL/6J mice were immunized with intraperitoneal injections of OVA on Days 0, 3, and 6. Starting on Day 11, mice were challenged with phosphate-buffered saline or OVA by nebulization three times per week for 4 weeks. Tiplaxtinin was mixed with chow and administered orally from 1 day before the phosphate-buffered saline or OVA challenge. Lung tissues were harvested after challenge and characterized histologically for infiltrating inflammatory cells, mucus-secreting goblet cells, and collagen deposition. Airway hyperresponsiveness was measured using whole-body plethysmography. Tiplaxtinin treatment significantly decreased levels of PAI-1 activity in bronchoalveolar lavage fluids, which indicates successful blockage of PAI-1 activity in the airways. The number of infiltrated inflammatory cells was reduced by tiplaxtinin treatment in the lungs of the OVA-challenged mice. Furthermore, oral administration of tiplaxtinin significantly attenuated the degree of goblet cell hyperplasia and collagen deposition in the airways of the OVA-challenged mice, and methacholine-induced airway hyperresponsiveness was effectively reduced by tiplaxtinin in these animals. This study supports our previous findings that PAI-1 promotes airway remodeling in a murine model of chronic asthma, and suggests that PAI-1 may be a novel target of treatment of airway remodeling in asthma.
我们之前曾报道过，纤溶酶原激活物抑制剂（PAI-1）缺乏可防止卵清蛋白（OVA）激发的小鼠气道中胶原沉积。在这项研究中，我们使用特异性 PAI-1 抑制剂替拉扎特宁（tiplaxtinin），探讨了阻断 PAI-1 预防气道重塑的治疗作用。C57BL/6J 小鼠于第 0、3 和 6 天经腹腔注射 OVA 进行免疫。从第 11 天开始，通过雾化将磷酸盐缓冲盐水或 OVA 每周三次激发小鼠，共 4 周。tiplaxtinin 与饲料混合，在磷酸盐缓冲盐水或 OVA 激发前 1 天开始经口给药。激发后收获肺组织，进行组织学特征分析以评估浸润性炎症细胞、分泌黏液的杯状细胞和胶原沉积。使用全身 plethysmography 测量气道高反应性。tiplaxtinin 治疗显著降低了支气管肺泡灌洗液中 PAI-1 活性的水平，表明成功阻断了气道中的 PAI-1 活性。tiplaxtinin 治疗减少了 OVA 激发小鼠肺部浸润性炎症细胞的数量。此外，口服 tiplaxtinin 显著减轻了 OVA 激发小鼠气道中杯状细胞增生和胶原沉积的程度，并有效降低了这些动物的乙酰甲胆碱诱导的气道高反应性。这项研究支持我们之前的发现，即 PAI-1 促进了慢性哮喘小鼠模型中的气道重塑，并提示 PAI-1 可能成为哮喘气道重塑治疗的一个新靶点。
