Adrenomedullin regenerates alveoli and vasculature in elastase-induced pulmonary emphysema in mice.
BACKGROUND
Adrenomedullin, a potent vasodilator peptide, regulates cell growth and survival. However, whether adrenomedullin contributes to lung regeneration remains unknown.


OBJECTIVE
To investigate whether adrenomedullin influences the kinetics of bone marrow cells, and whether adrenomedullin promotes regeneration of alveoli and vasculature and thereby improves lung structure and function in elastase-induced emphysema in mice.


METHODS
Adrenomedullin or vehicle was randomly administered to C57BL/6 mice for 5 days. We counted the numbers of mononuclear cells and stem cell antigen-1-positive cells in circulating blood. After intratracheal injection of elastase or saline, mice were randomized to receive continuous infusion of adrenomedullin or vehicle for 14 days. Functional and histologic analyses were performed 28 days after treatment.


RESULTS
Twenty-eight days after elastase injection, destruction of the alveolar walls was observed. However, adrenomedullin infusion significantly inhibited the increase in lung volume, static lung compliance, and mean linear intercept in mice given elastase. Adrenomedullin increased the numbers of mononuclear cells and stem cell antigen-1-positive cells in circulating blood. Adrenomedullin significantly increased the number of bone marrow-derived cells incorporated into the elastase-treated lung. Some of these cells were positive for cytokeratin or von Willebrand factor. Infusion of adrenomedullin after the establishment of emphysema also had beneficial effects on lung structure and function. In vitro, addition of adrenomedullin attenuates elastase-induced cell death in alveolar epithelial cells and endothelial cells.


CONCLUSIONS
Adrenomedullin improved elastase-induced emphysema at least in part through mobilization of bone marrow cells and the direct protective effects on alveolar epithelial cells and endothelial cells.
Murakami
Shinsuke
S
Department of Regenerative Medicine and Tissue Engineering, National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan.
Nagaya
Noritoshi
N
Itoh
Takefumi
T
Iwase
Takashi
T
Fujisato
Toshiya
T
Nishioka
Keisuke
K
Hamada
Kaoru
K
Kangawa
Kenji
K
Kimura
Hiroshi
H
D053607:Adrenomedullin; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects*; D004847:Epithelial Cells / Q000187:drug effects; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D010196:Pancreatic Elastase / Q000009:adverse effects; D010455:Peptides / Q000494:pharmacology* / Q000627:therapeutic use; D011650:Pulmonary Alveoli / Q000187:drug effects*; D011656:Pulmonary Emphysema / Q000139:chemically induced / Q000188:drug therapy*; D012038:Regeneration / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
D010455:Peptides; D014665:Vasodilator Agents; D053607:Adrenomedullin; D010196:Pancreatic Elastase