Lourenço Juliana D, Ito Juliana T, Cervilha Daniela A B, Sales Davi S, Riani Alyne, Suehiro Camila L, Genaro Isabella S, Duran Adriana, Puzer Luciano, Martins Milton A, Sasaki Sérgio D, Lopes Fernanda D T Q S
Department of Medicine, University of Sao Paulo, Sao Paulo, Brazil.
Department of Pathology, University of Sao Paulo, Sao Paulo, Brazil.
Histol Histopathol. 2018 Mar;33(3):289-298. doi: 10.14670/HH-11-927. Epub 2017 Sep 4.
Smoking is the main risk factor for chronic obstructive pulmonary disease development and cigarette smoke (CS) exposure is considered an important approach to reproduce in rodents this human disease. We have previously shown that in an elastase-induced model of emphysema, the administration of a protease inhibitor (rBmTI-A) prevented and attenuated tissue destruction in mice. Thus, in this study we aimed to verify the effects of rBmTI-A administration on the physiopathological mechanisms of CS-induced emphysema.
Mice (C57BL/6) were exposed to CS or room air for 12 weeks. In this period, 3 nasal instillations of rBmTI-A inhibitor or its vehicle were performed. After euthanasia, respiratory mechanics were evaluated and lungs removed for analysis of mean linear intercept, volume proportion of collagen and elastic fibers, density of polymorphonuclear cells, macrophages, and density of positive cells for MMP-12, MMP-9, TIMP-1 and gp91phox.
The rBmTI-A administration improved tissue elastance, decreased alveolar enlargement and collagen fibers accumulation to control levels and attenuated elastic fibers accumulation in animals exposed to CS. There was an increase of MMP-12, MMP-9 and macrophages in CS groups and the rBmTIA only decreased the number of MMP-12 positive cells. Also, we demonstrated an increase in gp91phox in CS treated group and in TIMP-1 levels in both rBmTI-A treated groups.
In summary, the rBmTI-A administration attenuated emphysema development by an increase of gp91phox and TIMP-1, accompanied by a decrease in MMP-12 levels.
吸烟是慢性阻塞性肺疾病发生的主要危险因素，香烟烟雾（CS）暴露被认为是在啮齿动物中重现这种人类疾病的重要方法。我们之前已经表明，在弹性蛋白酶诱导的肺气肿模型中，给予蛋白酶抑制剂（rBmTI-A）可预防和减轻小鼠的组织破坏。因此，在本研究中，我们旨在验证给予rBmTI-A对CS诱导的肺气肿的生理病理机制的影响。
将小鼠（C57BL/6）暴露于CS或室内空气中12周。在此期间，进行3次鼻腔滴注rBmTI-A抑制剂或其赋形剂。安乐死后，评估呼吸力学，并取出肺脏以分析平均线性截距、胶原蛋白和弹性纤维的体积比例、多形核细胞、巨噬细胞的密度以及MMP-12、MMP-9、TIMP-1和gp91phox阳性细胞的密度。
给予rBmTI-A可改善组织弹性，将肺泡扩大和胶原纤维积累减少至对照水平，并减轻暴露于CS的动物的弹性纤维积累。CS组中MMP-12、MMP-9和巨噬细胞增加，而rBmTI-A仅减少MMP-阳性细胞的数量。此外，我们证明CS处理组中gp91phox增加，而两个rBmTI-A处理组中TIMP-1水平增加。
总之，给予rBmTI-A通过增加gp91phox和TIMP-1，同时降低MMP-12水平，减轻了肺气肿的发展。
