Facultad de Ciencias, Universidad Nacional Autónoma de México, Mexico DF, Mexico.
Am J Respir Crit Care Med. 2012 Oct 15;186(8):752-62. doi: 10.1164/rccm.201202-0302OC. Epub 2012 Aug 2.
Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by epithelial phenotypic changes and fibroblast activation. Based on the temporal heterogeneity of IPF, we hypothesized that hyperplastic alveolar epithelial cells regulate the fibrotic response.
To identify novel mediators of fibrosis comparing the transcriptional signature of hyperplastic epithelial cells and conserved epithelial cells in the same lung.
Laser capture microscope and microarrays analysis were used to identify differentially expressed genes in IPF lungs. Bleomycin-induced lung fibrosis was evaluated in Mmp19-deficient and wild-type (WT) mice. The role of matrix metalloproteinase (MMP)-19 was additionally studied by transfecting the human MMP19 in alveolar epithelial cells.
Laser capture microscope followed by microarray analysis revealed a novel mediator, MMP-19, in hyperplastic epithelial cells adjacent to fibrotic regions. Mmp19(-/-) mice showed a significantly increased lung fibrotic response to bleomycin compared with WT mice. A549 epithelial cells transfected with human MMP19 stimulated wound healing and cell migration, whereas silencing MMP19 had the opposite effect. Gene expression microarray of transfected A549 cells showed that PTGS2 (prostaglandin-endoperoxide synthase 2) was one of the highly induced genes. PTGS2 was overexpressed in IPF lungs and colocalized with MMP-19 in hyperplastic epithelial cells. In WT mice, PTGS2 was significantly increased in bronchoalveolar lavage and lung tissues after bleomycin-induced fibrosis, but not in Mmp19(-/-) mice. Inhibition of Mmp-19 by siRNA resulted in inhibition of Ptgs2 at mRNA and protein levels.
Up-regulation of MMP19 induced by lung injury may play a protective role in the development of fibrosis through the induction of PTGS2.
特发性肺纤维化（IPF）是一种破坏性疾病，其特征为上皮表型改变和成纤维细胞激活。基于 IPF 的时间异质性，我们假设增生的肺泡上皮细胞调节纤维化反应。
通过比较同一肺中增生上皮细胞和保守上皮细胞的转录特征，鉴定纤维化的新介质。
使用激光捕获显微镜和微阵列分析来鉴定 IPF 肺中差异表达的基因。在 MMP19 缺陷型和野生型（WT）小鼠中评估博来霉素诱导的肺纤维化。通过转染肺泡上皮细胞中的人 MMP19，进一步研究基质金属蛋白酶（MMP）-19 的作用。
激光捕获显微镜后进行微阵列分析显示，在纤维化区域附近的增生上皮细胞中存在一种新型介质 MMP-19。与 WT 小鼠相比，Mmp19(-/-) 小鼠对博来霉素的肺纤维化反应明显增加。转染人 MMP19 的 A549 上皮细胞刺激伤口愈合和细胞迁移，而沉默 MMP19 则产生相反的效果。转染的 A549 细胞的基因表达微阵列显示，PTGS2（前列腺素内过氧化物合酶 2）是高度诱导的基因之一。PTGS2 在 IPF 肺中过度表达，并与增生上皮细胞中的 MMP-19 共定位。在 WT 小鼠中，博来霉素诱导纤维化后，PTGS2 在支气管肺泡灌洗液和肺组织中显著增加，但在 Mmp19(-/-) 小鼠中没有增加。用 siRNA 抑制 MMP-19 可导致 Ptgs2 在 mRNA 和蛋白水平的抑制。
肺损伤诱导的 MMP19 上调可能通过诱导 PTGS2 在纤维化的发展中发挥保护作用。
