Intranasal HGF administration ameliorates the physiologic and morphologic changes in lung emphysema.
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.
Department of Geriatric and Respiratory Medicine, Tohoku University School of Medicine, Aobaku, Sendai, Japan.
Ahmed E
AE
Hegab
Hiroshi
H
Kubo
Mutsuo
M
Yamaya
Masanori
M
Asada
Mei
M
He
Naoya
N
Fujino
Shinya
S
Mizuno
Toshikazu
T
Nakamura
D000281:Administration, Intranasal; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D000950:Antigens, Ly / Q000378:metabolism; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000008:administration & dosage / Q000494:pharmacology*; D007150:Immunohistochemistry; D053539:Keratin-19 / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010196:Pancreatic Elastase; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011656:Pulmonary Emphysema / Q000139:chemically induced / Q000188:drug therapy*
D018952:Antigens, CD34; D000950:Antigens, Ly; D053539:Keratin-19; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D018809:Proliferating Cell Nuclear Antigen; D049452:Green Fluorescent Proteins; D017228:Hepatocyte Growth Factor; D019009:Proto-Oncogene Proteins c-kit; D010196:Pancreatic Elastase