Lucattelli Monica, Bartalesi Barbara, Cavarra Eleonora, Fineschi Silvia, Lunghi Benedetta, Martorana Piero A, Lungarella Giuseppe
Department of Physiopathology and Experimental Medicine, University of Siena, 53100 Siena, Italy.
Respir Res. 2005 Jul 26;6(1):83. doi: 10.1186/1465-9921-6-83.
The separation of emphysema from fibrosis is not as clear-cut as it was thought in early studies. These two pathologies may be present at the same time in human lungs and in mice either instilled with elastolytic enzymes or bleomycin or exposed to cigarette-smoke. According to a current view, emphysema originates from a protease/antiprotease imbalance, and a role for antiproteases has also been suggested in the modulation of the fibrotic process. In this study we investigate in experimental animal models of emphysema and fibrosis whether neutrophil elastase may constitute a pathogenic link between these two pathologies.
This study was done in two animal models in which emphysema and fibrosis were induced either by bleomycin (BLM) or by chronic exposure to cigarette-smoke. In order to assess the protease-dependence of the BLM-induced lesion, a group mice was treated with 4-(2-aminoethyl)-benzenesulfonyl fluoride hydrochloride, a serine proteinase inhibitor active toward neutrophil elastase. Lungs from each experimental group were used for the immunohistochemical assessment of transforming growth factor-beta (TGF-beta) and transforming growth factor-alpha (TGF-alpha) and for determination of the mean linear intercept as well as the percent volume densities of fibrosis and of emphysematous changes. Additionally, the lungs were also assessed for desmosine content and for the determination of elastase levels in the pulmonary interstitium by means of immunoelectron microscopy.
We demonstrate that in BLM-treated mice (i) the development of elastolytic emphysema precedes that of fibrosis; (ii) significant amount of elastase in alveolar interstitium is associated with an increased expression of TGF-beta and TGF-alpha; and finally, (iii) emphysematous and fibrotic lesions can be significantly attenuated by using a protease inhibitor active against neutrophil elastase. Also, in a strain of mice that develop both emphysema and fibrosis after chronic cigarette-smoke exposure, the presence of elastase in alveolar structures is associated with a positive immunohistochemical reaction for reaction for both TGF-beta and TGF-alpha.
The results of the present study strongly suggest that neutrophil elastase may represent a common pathogenic link between emphysema and fibrosis. Proteases and in particular neutrophil elastase could act as regulatory factors in the generation of soluble cytokines with mitogenic activity for mesenchymal cells resulting either in emphysema or in fibrosis or both.
肺气肿与纤维化的区分并不像早期研究所认为的那样清晰。在人类肺部以及用弹性蛋白酶或博来霉素处理过的或暴露于香烟烟雾中的小鼠肺部，这两种病理状况可能同时存在。根据目前的观点，肺气肿源于蛋白酶/抗蛋白酶失衡，并且抗蛋白酶在纤维化过程的调节中也被认为发挥了作用。在本研究中，我们在肺气肿和纤维化的实验动物模型中探究中性粒细胞弹性蛋白酶是否可能构成这两种病理状况之间的致病联系。
本研究在两种动物模型中进行，其中肺气肿和纤维化分别通过博来霉素（BLM）或长期暴露于香烟烟雾诱导。为了评估BLM诱导损伤对蛋白酶的依赖性，一组小鼠用4-（2-氨基乙基）-苯磺酰氟盐酸盐处理，这是一种对中性粒细胞弹性蛋白酶有活性的丝氨酸蛋白酶抑制剂。每个实验组的肺用于转化生长因子-β（TGF-β）和转化生长因子-α（TGF-α）的免疫组织化学评估，以及测定平均线性截距以及纤维化和肺气肿性改变的体积密度百分比。此外，还通过免疫电子显微镜评估肺中的锁链素含量并测定肺间质中的弹性蛋白酶水平。
我们证明，在BLM处理的小鼠中，（i）弹性蛋白酶性肺气肿的发展先于纤维化；（ii）肺泡间质中大量的弹性蛋白酶与TGF-β和TGF-α表达增加相关；最后，（iii）使用对中性粒细胞弹性蛋白酶有活性的蛋白酶抑制剂可显著减轻肺气肿和纤维化病变。同样，在一组长期暴露于香烟烟雾后同时发生肺气肿和纤维化的小鼠中，肺泡结构中弹性蛋白酶的存在与TGF-β和TGF-α的阳性免疫组织化学反应相关。
本研究结果强烈表明，中性粒细胞弹性蛋白酶可能代表肺气肿和纤维化之间的共同致病联系。蛋白酶，尤其是中性粒细胞弹性蛋白酶，可能作为可溶性细胞因子生成的调节因子，这些细胞因子对间充质细胞具有促有丝分裂活性，从而导致肺气肿或纤维化或两者皆有。
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