Dhami R, Gilks B, Xie C, Zay K, Wright J L, Churg A
Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada.
Am J Respir Cell Mol Biol. 2000 Feb;22(2):244-52. doi: 10.1165/ajrcmb.22.2.3809.
Recent studies have suggested that macrophage-derived metalloproteases are the critical mediators of cigarette smoke-induced emphysema, in contrast to earlier hypotheses that this process was mediated by neutrophil elastase. To determine whether smoke can acutely induce connective tissue breakdown in the lung and to examine the mediators of this process, we exposed C57-BL/6 mice to whole cigarette smoke and used high-performance liquid chromatography to examine lavage fluid levels of desmosine (DES), a marker of elastin breakdown, and hydroxyproline (HP), a marker of collagen breakdown. Smoke produced a dose-response increase in lavage neutrophils, DES, and HP, but not lavage macrophages (MACs). This effect was evident by 6 h after exposure to two cigarettes. Pretreatment with an antibody against polymorphonuclear leukocytes (PMNs) reduced lavage PMNs to undetectable levels after smoke exposure, did not affect MAC numbers, and prevented increases in lavage DES and HP. Intraperitoneal injection of a commercial human alpha1-antitrypsin (alpha1AT) 24 h before smoke exposure increased serum alpha1AT levels approximately 3-fold and completely abolished smoke-induced connective tissue breakdown as well as the increase in lavage PMNs, again without affecting MAC numbers. We conclude that in this model cigarette smoke can acutely induce connective tissue breakdown and that this effect is mediated by neutrophil-derived serine proteases, most likely neutrophil elastase. Exogenous alpha1AT is protective and appears to inhibit both matrix degradation and PMN influx, suggesting that alpha1AT has anti-inflammatory as well as antiproteolytic effects in this system.
最近的研究表明，巨噬细胞衍生的金属蛋白酶是香烟烟雾诱导的肺气肿的关键介质，这与早期认为该过程由中性粒细胞弹性蛋白酶介导的假说相反。为了确定烟雾是否能急性诱导肺部结缔组织分解，并研究该过程的介质，我们将C57-BL/6小鼠暴露于全香烟烟雾中，并使用高效液相色谱法检测灌洗液中弹性蛋白分解标志物异锁链素（DES）和胶原蛋白分解标志物羟脯氨酸（HP）的水平。烟雾使灌洗中性粒细胞、DES和HP呈剂量反应性增加，但对灌洗巨噬细胞（MACs）无影响。暴露于两支香烟后6小时，这种效应就很明显。用抗多形核白细胞（PMN）抗体预处理可使烟雾暴露后灌洗PMN降至检测不到的水平，不影响MAC数量，并防止灌洗DES和HP增加。在烟雾暴露前24小时腹腔注射市售人α1抗胰蛋白酶（α1AT）可使血清α1AT水平增加约3倍，并完全消除烟雾诱导的结缔组织分解以及灌洗PMN的增加，同样不影响MAC数量。我们得出结论，在该模型中，香烟烟雾可急性诱导结缔组织分解，且这种效应由中性粒细胞衍生的丝氨酸蛋白酶介导，最有可能是中性粒细胞弹性蛋白酶。外源性α1AT具有保护作用，似乎能抑制基质降解和PMN流入，表明α1AT在该系统中具有抗炎和抗蛋白水解作用。
