Restoration of alveolar type II cell function contributes to simvastatin-induced             attenuation of lung ischemia-reperfusion injury.
Alveolar type (AT) II cells transdifferentiate into ATI cells and as such represent a promising source for regenerating lung epithelium following lung injury. ATII cells are characterized by the presence of lamellar bodies (LBs), which store and secrete the surfactant protein-C (SP-C). Lung ischemia-reperfusion injury (LIRI) causes a distinct impairment of the ATII cell function, subsequently hindering lung repair by loss of ATI transdifferentiation. In this study, we provide new evidence that the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor simvastatin may restore the function of impaired ATII cells in vitro and in vivo. ATII cell lines, A549 (human) and MLE-12 (mouse), were subjected to hypoxia-reoxygenation (H/R) injury. Simvastatin pretreatment at low (5-20 µM), but not high (50-100 µM) doses markedly reduced apoptosis and increased proliferation and SP-C expression. In a rat lung ischemia-reperfusion (I/R) model, simvastatin treatment also increased ATII cell proliferation in vivo, as demonstrated by proliferating cell nuclear antigen/SP-C double staining. Transmission electron microscopy revealed that the number and volume density of LBs were significantly increased in the simvastatin-treated rat lungs. The protective effects of simvastatin were reversed in vitro by PI3-kinase (PI3K) inhibitors wortmannin and L-mevalonate, indicating that the PI3K/Akt and mevalonate pathways may be involved in simvastatin-induced ATII cell function restoration. These data demonstrate that an appropriate dose of simvastatin has a protective effect on LIRI in vitro and in vivo, due at least partially to restored ATII cell function via the HMG-CoA reductase pathway-dependent activation of PI3K/Akt signaling in a mevalonate pathway-dependent manner.
Department of Thoracic Surgery, Nanjing Medical University Affiliated                     Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing 210009,                     P.R. China.
Yaqin
Y
Wu
Junjie
J
Lv
Dongjie
D
Feng
Feng
F
Jiang
Xiaohu
X
Fan
Zhi
Z
Zhang
Rong
R
Yin
Lin
L
Xu
D056809:Alveolar Epithelial Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D054338:Cell Transdifferentiation; D004353:Drug Evaluation, Preclinical; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D008168:Lung / Q000098:blood supply* / Q000473:pathology; D008297:Male; D008798:Mevalonic Acid / Q000378:metabolism; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D037721:Pulmonary Surfactant-Associated Protein C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D022142:Secretory Vesicles / Q000378:metabolism; D015398:Signal Transduction; D019821:Simvastatin / Q000494:pharmacology* / Q000627:therapeutic use; D000077191:Wortmannin
D000730:Androstadienes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008798:Mevalonic Acid; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D018809:Proliferating Cell Nuclear Antigen; D051057:Proto-Oncogene Proteins c-akt; D037721:Pulmonary Surfactant-Associated Protein C; D019821:Simvastatin; D000077191:Wortmannin