Restoration of alveolar type II cell function contributes to simvastatin-induced attenuation of lung ischemia-reperfusion injury

Wu,Yaqin; Lv,Junjie; Feng,Dongjie; Jiang,Feng; Fan,Xiaohu; Zhang,Zhi; Yin,Rong; Xu,Lin

doi:10.3892/ijmm.2012.1161

Restoration of alveolar type II cell function contributes to simvastatin-induced attenuation of lung ischemia-reperfusion injury

Authors:
- Yaqin Wu
- Junjie Lv
- Dongjie Feng
- Feng Jiang
- Xiaohu Fan
- Zhi Zhang
- Rong Yin
- Lin Xu
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Affiliations: Department of Thoracic Surgery, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing 210009, P.R. China, Department of Thoracic Surgery, Huai'an First People's Hospital, Nanjing Medical University, Huai'an 223300, P.R. China, Department of Pediatrics, University of Alberta, Edmonton, Alberta T6E2E1, Canada
Published online on: October 16, 2012 https://doi.org/10.3892/ijmm.2012.1161
Pages: 1294-1306

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Abstract

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.

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