Hegab Ahmed E, Kubo Hiroshi, Yamaya Mutsuo, Asada Masanori, He Mei, Fujino Naoya, Mizuno Shinya, Nakamura Toshikazu
Department of Geriatric and Respiratory Medicine, Tohoku University School of Medicine, Aobaku, Sendai, Japan.
Mol Ther. 2008 Aug;16(8):1417-26. doi: 10.1038/mt.2008.137. Epub 2008 Jun 17.
Hepatocyte growth factor (HGF) has multiple biological effects on stem cells, epithelial proliferation, and wound healing. In this study, we investigated a possible therapeutic benefit of intranasal HGF on elastase-induced emphysema, and assessed the role of stem/progenitor cells in this process. HGF was given twice a week for 1-4 weeks after the establishment of emphysema in mice. HGF inhalation significantly ameliorated the enlargement of airspaces and alveolar wall destruction. Also, elevated static lung compliance returned to control levels within 2 weeks of HGF treatment. The expressions of stem-cell markers, c-kit, stem-cell antigen 1 (Sca-1), and CD34 were also significantly influenced by HGF. Most of the c-kit(+) cells were bone marrow derived, while most Sca-1(+) were lung endogenous cells. CD34(+) cells were from both sources, and a portion of the endogenous CD34(+) cells was also Sca-1(+). Further, HGF increased the expression levels of proliferating cell nuclear antigen (PCNA) and cytokeratin-19. Also, their immunohistochemical staining patterns were colocalized, indicative of epithelial multiplication. The results of the study show that intranasal treatment with HGF reverses both the physiological and morphometric changes of lung emphysema, possibly through stem-cell mobilization and alveolar regeneration, providing a nonsurgical treatment and suggesting the possibility of achieving a similar effect in humans.
肝细胞生长因子（HGF）对干细胞、上皮细胞增殖及伤口愈合具有多种生物学效应。在本研究中，我们调查了经鼻给予HGF对弹性蛋白酶诱导的肺气肿可能的治疗益处，并评估了干/祖细胞在此过程中的作用。在小鼠肺气肿形成后，每周两次给予HGF，持续1 - 4周。吸入HGF显著改善了气腔扩大和肺泡壁破坏。此外，在HGF治疗2周内，升高的静态肺顺应性恢复到对照水平。HGF对干细胞标志物c-kit、干细胞抗原1（Sca-1）和CD34的表达也有显著影响。大多数c-kit(+)细胞来源于骨髓，而大多数Sca-1(+)细胞是肺内源性细胞。CD34(+)细胞来自这两种来源，并且一部分内源性CD34(+)细胞也是Sca-1(+)。此外，HGF增加了增殖细胞核抗原（PCNA）和细胞角蛋白-19的表达水平。而且，它们的免疫组化染色模式共定位，表明上皮细胞增殖。研究结果表明，经鼻给予HGF可逆转肺气肿的生理和形态学变化，可能是通过干细胞动员和肺泡再生实现的，这提供了一种非手术治疗方法，并提示在人类中可能取得类似效果。
