Thompson R W, Holmes D R, Mertens R A, Liao S, Botney M D, Mecham R P, Welgus H G, Parks W C
Department of Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
J Clin Invest. 1995 Jul;96(1):318-26. doi: 10.1172/JCI118037.
Abdominal aortic aneurysms (AAA) are characterized by disruption and degradation of the elastic media, yet the elastolytic proteinases involved and their cellular sources are undefined. We examined if 92-kD gelatinase, an elastolytic matrix metalloproteinase, participates in the pathobiology of AAA. Gelatin zymography of conditioned medium from normal, atheroocclusive disease (AOD), or AAA tissues in organ culture showed that all tissues produced 72-kD gelatinase. AOD and AAA cultures also secreted 92-kD gelatinase, but significantly more enzyme was released from AAA tissues. ELISA confirmed that AAA tissues released approximately 2-fold more 92-kD gelatinase than AOD tissue and approximately 10-fold more than normal aorta. Phorbol ester induced a 5.3-fold increase in 92-kD gelatinase secretion by normal aorta and AOD and an 11.5-fold increase by AAA. By immunohistochemistry, 92-kD gelatinase was not detected in normal aorta and was only occasionally seen within the neointimal lesions of AOD tissue. In all AAA specimens, however, 92-kD gelatinase was readily localized to numerous macrophages in the media and at the adventitial-medial junction. The expression of 92-kD gelatinase mRNA by aneurysm-infiltrating macrophages was confirmed by in situ hybridization. These results demonstrate that diseased aortic tissues secrete greater amounts of gelatinolytic activity than normal aorta primarily due to increased production of 92-kD gelatinase. In addition, the localization of 92-kD gelatinase to macrophages in the damaged wall of aneurysmal aortas suggests that chronic release of this elastolytic metalloproteinase contributes to extracellular matrix degradation in AAA.
腹主动脉瘤（AAA）的特征是弹性中膜遭到破坏和降解，然而，参与其中的弹性蛋白酶及其细胞来源尚不清楚。我们研究了一种弹性溶解基质金属蛋白酶——92-kD明胶酶是否参与了腹主动脉瘤的病理生物学过程。对正常组织、动脉粥样硬化闭塞性疾病（AOD）组织或器官培养中的腹主动脉瘤组织的条件培养基进行明胶酶谱分析，结果显示所有组织均产生72-kD明胶酶。AOD组织和腹主动脉瘤组织培养物也分泌92-kD明胶酶，但腹主动脉瘤组织释放的酶明显更多。酶联免疫吸附测定（ELISA）证实，腹主动脉瘤组织释放的92-kD明胶酶比AOD组织多约2倍，比正常主动脉多约10倍。佛波酯可使正常主动脉和AOD组织中92-kD明胶酶的分泌增加5.3倍，使腹主动脉瘤组织中该酶的分泌增加11.5倍。通过免疫组织化学方法，在正常主动脉中未检测到92-kD明胶酶，在AOD组织的新内膜病变中也仅偶尔可见。然而，在所有腹主动脉瘤标本中，92-kD明胶酶很容易定位到中膜和外膜-中膜交界处的大量巨噬细胞中。原位杂交证实了动脉瘤浸润巨噬细胞表达92-kD明胶酶mRNA。这些结果表明，患病的主动脉组织比正常主动脉分泌更多的明胶溶解活性，这主要是由于92-kD明胶酶产生增加所致。此外，92-kD明胶酶在动脉瘤性主动脉受损壁中的巨噬细胞上定位，表明这种弹性溶解金属蛋白酶的持续释放有助于腹主动脉瘤中细胞外基质的降解。
