Reversal of elastase-induced pulmonary emphysema and promotion of alveolar epithelial cell proliferation by simvastatin in mice

Abstract

Besides lowering cholesterol, statins exert multiple effects, such as anti-inflammatory activity and improvement of endothelial cell function. We examined whether simvastatin (SS) protects against the development of elastase-induced pulmonary emphysema in mice by using mean linear intercepts of alveoli (Lm) as a morphometric parameter of emphysema. After injection of intratracheal elastase on day 0, C57BL/6 mice were treated daily with SS (SS+ group) or PBS (SS− group) for 2 wk. A 21% decrease in Lm on day 7 was observed in the SS+ group vs. the SS− group. Anti-inflammatory effects of SS were observed as a decrease in percentage of neutrophils up to day 3, and in hydroxyproline concentration on day 3, in bronchoalveolar lavage fluid (BALF). SS also increased the number of proliferating cell nuclear antigen (PCNA)-positive alveolar epithelial cells between days 3 and 14. To confirm the role of statins in promoting proliferation of alveolar cells, mice were treated with SS (SS+) vs. PBS (SS−) for 12 days, starting 3 wk after elastase administration. After SS treatment, Lm decreased by 52% and PCNA-positive alveolar epithelial cells increased compared with the SS− group. Concentrations of vascular endothelial growth factor in BALF and endothelial nitric oxide synthase protein expression in pulmonary vessels tended to be higher in the SS+ group vs. the SS− group in this protocol. In conclusion, SS inhibited the development of elastase-induced pulmonary emphysema in mice. This therapeutic effect was due not only to anti-inflammation but also to the promotion of alveolar epithelial cell regeneration, partly mediated by restoring endothelial cell functions.

Systemic manifestations and comorbidities of COPD

“…Statins prevent the development of emphysema in mice exposed to cigarette smoke and this is associated with a reduction in the expression of TNF-a, IFN-c and MMP-2, -9 and -12 and a reduction in neutrophils in bronchoalveolar lavage fluid [183]. Statins also prevent elastase-mediated emphysema in mice and are associated with evidence for proliferation and regeneration of alveolar epithelial cells [184]. At a cellular level, statins inhibit the effects of IL-17 and TGF-b in stimulating mediator release from primary airway epithelial cells, indicating their potential to modulate the inflammatory response and small airway fibrosis in COPD [185].…”

Pulmonary Epithelial Neuropilin-1 Deletion Enhances Development of Cigarette Smoke–induced Emphysema

“…Augmented apoptosis (39,44,46) and attenuated proliferation (56,57) of alveolar cells were shown to be critical for the maintenance of normal alveolar structure in other animal models of emphysema. Evidence suggests that high levels of Nrp1 may attenuate apoptosis (58).…”

Bronchopulmonary dysplasia and emphysema: in search of common therapeutic targets

“…Curcumin [66], statins [67,68] and adenovirusmediated expression of HO-1 [69] have been successfully used to restore HO-1 levels and attenuate emphysema in mice.…”

“…antichemokine or receptor blockade in hyperoxia-exposed rats [17,65] pentoxyfilline in VLBW infants [64] No adverse effects observed inhibitory peptide in mouse model [43] curcumin [66], simvastatin [67], lovastatin [68], or HO-1 [69] Retinoids RA in hyperoxic model in rats [82] RA in angiogenic inhibition in mice [83] vitamin A in premature baboons [86] RA in rats and mice with or without inhibited alveolar septation [77,81] RA in mouse models [85] Growth factor supplementation VEGF [54] or FGF7 [98] in hyperoxia-exposed rats HGF [99] or EPO [83] in mouse models VEGF injurious in mouse prenatal lung [51] FGF7 in mouse model, preventive [101] HGF in rats [100] FGF7 in mouse model, curative [101] …”