Department of Pediatrics and the Wall Center for Pulmonary Vascular Disease, Stanford University School of Medicine, Stanford, California, USA.
Am J Pathol. 2011 Sep;179(3):1560-72. doi: 10.1016/j.ajpath.2011.05.051. Epub 2011 Jul 19.
Previously, we reported that murine gammaherpesvirus-68 (M1-MHV-68) induces pulmonary artery (PA) neointimal lesions in S100A4-overexpressing, but not in wild-type (C57), mice. Lesions were associated with heightened lung elastase activity and PA elastin degradation. We now investigate a direct relationship between elastase and PA neointimal lesions, the nature and source of the enzyme, and its presence in clinical disease. We found an association exists between the percentage of PAs with neointimal lesions and elastin fragmentation in S100A4 mice 6 months after viral infection. Confocal microscopy documented the heightened susceptibility of S100A4 versus C57 PA elastin to degradation by elastase. A transient increase in lung elastase activity occurs in S100A4 mice, 7 days after M1-MHV-68, unrelated to inflammation or viral load and before neointimal lesions. Administration of recombinant elafin, an elastase-specific inhibitor, ameliorates early increases in serine elastase and attenuates later development of neointimal lesions. Neutrophils are the source of elevated elastase (NE) in the S100A4 lung, and NE mRNA and protein levels are greater in PA smooth muscle cells (SMC) from S100A4 mice than from C57 mice. Furthermore, elevated NE is observed in cultured PA SMC from idiopathic PA hypertension versus that in control lungs and localizes to neointimal lesions. Thus, PA SMC produce NE, and heightened production and activity of NE is linked to experimental and clinical pulmonary vascular disease.
此前，我们曾报道过鼠γ疱疹病毒-68（M1-MHV-68）在 S100A4 过表达但不在野生型（C57）小鼠中诱导肺小动脉（PA）新生内膜病变。病变与肺弹性蛋白酶活性升高和 PA 弹性蛋白降解有关。我们现在研究弹性蛋白酶与 PA 新生内膜病变之间的直接关系、酶的性质和来源及其在临床疾病中的存在。我们发现，在病毒感染后 6 个月的 S100A4 小鼠中，PA 新生内膜病变的百分比与弹性蛋白片段化之间存在相关性。共聚焦显微镜记录到 S100A4 与 C57 PA 弹性蛋白相比，弹性蛋白酶降解的敏感性更高。在 M1-MHV-68 感染后 7 天，S100A4 小鼠的肺弹性蛋白酶活性短暂升高，与炎症或病毒载量无关，也早于新生内膜病变。给予重组 Elafin（一种弹性蛋白酶特异性抑制剂）可改善 S100A4 小鼠早期丝氨酸弹性酶的升高，并减轻后期新生内膜病变的发展。中性粒细胞是 S100A4 肺中升高的弹性蛋白酶（NE）的来源，来自 S100A4 小鼠的 PA 平滑肌细胞（SMC）中 NE mRNA 和蛋白水平高于 C57 小鼠。此外，在特发性 PA 高血压患者的培养 PA SMC 中观察到升高的 NE，而在对照肺中则未观察到，并且定位于新生内膜病变处。因此，PA SMC 产生 NE，NE 的高产生和活性与实验性和临床肺血管疾病有关。
