Lovastatin Enhances Clearance of Apoptotic Cells (Efferocytosis) with Implications for Chronic Obstructive Pulmonary Disease

Abstract

Statins are potent, cholesterol-lowering agents with newly appreciated, broad anti-inflammatory properties, largely based upon their ability to block the prenylation of Rho GTPases, including RhoA. Because phagocytosis of apoptotic cells (efferocytosis) is a pivotal regulator of inflammation, which is inhibited by RhoA, we sought to determine whether statins enhanced efferocytosis. The effect of lovastatin on efferocytosis was investigated in primary human macrophages, in the murine lung, and in human alveolar macrophages taken from patients with chronic obstructive pulmonary disease. In this study, we show that lovastatin increased efferocytosis in vitro in an 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase-dependent manner. Lovastatin acted by inhibiting both geranylgeranylation and farnesylation, and not by altering expression of key uptake receptors or by increasing binding of apoptotic cells to phagocytes. Lovastatin appeared to exert its positive effect on efferocytosis by inhibiting RhoA, because it 1) decreased membrane localization of RhoA, to a greater extent than Rac-1, and 2) prevented impaired efferocytosis by lysophosphatidic acid, a potent inducer of RhoA. Finally, lovastatin increased efferocytosis in the naive murine lung and ex vivo in chronic obstructive pulmonary disease alveolar macrophages in an HMG-CoA reductase-dependent manner. These findings indicate that statins enhance efferocytosis in vitro and in vivo, and suggest that they may play an important therapeutic role in diseases where efferocytosis is impaired and inflammation is dysregulated.

Recovery from pneumonia requires efferocytosis which is impaired in smokers and those with low body mass index and enhanced by statins

“…8 These studies suggest smoking and statins have antagonistic effects on Rac1 and RhoA, and as a consequence opposite effects on efferocytosis, providing a possible mechanistic explanation for our finding of a negative association between efferocytosis and smoking, a positive association with statins and a statistical interaction between smoking and statin use.…”

Systemic manifestations and comorbidities of COPD

“…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]. Statins also stimulate the uptake of apoptotic neutrophils by alveolar macrophages (efferocytosis), an effect that is mediated via inhibition of the prenylation and activation of RhoA, which is involved in the phagocytosis of apoptotic cells [186]. Phagocytosis of apoptotic cells is impaired in COPD [187], which suggests that statins may accelerate the resolution of neutrophilic inflammation in COPD.…”

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] …”