Pharmacological actions of statins: potential utility in COPD

R. P. Young; R. Hopkins; T. E. Eaton

doi:10.1183/09059180.00005309

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FIGURE 1.
Proposed pathogenesis of chronic obstructive pulmonary disease. ROS: reactive oxygen species; LPS: lipopolysaccharide; PAH: polyaromatic hydrocarbons; BEC: bronchial epithelial cell; IL: interleukin; TNF: tumour necrosis factor; GM-CSF: granulocyte-monocyte colony-stimulating factor; TGF: transforming growth factor; PMN: polymorphic neutrophil; MPO: myeloperoxidase; MØ: macrophage; MMP: matrix metalloproteinase; NE: neutrophil elastatse; TIMP: tissue inhibitors of metalloproteinase; αAT: α₁-antitrypsin; VEGF: vascular endothelial growth factor; END: endothelial cell; CRP: C-reactive protein. ^#: denotes the site of action of statins.
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FIGURE 2.
Proposed pathogenesis of lung cancer. ECM: extracellular matrix; ROS: reactive oxygen species; LPS: lipopolysaccharide; PAH: polyaromatic hydrocarbons; HMG CoA: 3-hydroxy-3-methylglutaryl coenzyme A; GTPase; guanosine triphosphatase; SHH: sonic hedgehog homologue; NADPH: reduced nicotinamide adenine dinucleotide phosphate; EGFR: epidermal growth factor receptor; TGF: transforming growth factor; NF-κB: nuclear factor-κB; AP-1: activator protein-1; MMP: matrix metalloproteinase; MPO: myeloperoxidase; PMN: polymorphic neutrophil; FGF: fibroblast growth factor. ^#: denotes the site of action of statins.
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FIGURE 3.
Morbidity and mortality benefits with statin use in observational studies on a logarithmic scale. CVS: cardiovascular; COPD: chronic obstructive pulmonary disease. Data are presented as odds ratio (95% confidence interval), except hospital cohort which is presented as relative risk (95% confidence interval) and following COPD exacerbation which is presented as hazard ratio (95% confidence interval).

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Table. 1—

Summary of statin mediated pharmacological effects on pulmonary inflammation and remodeling

COPD pathway	Study type	Statin effect on pathogenic pathways	[Ref.]
Cytokine production	MM, HM in vitro (liver cell line), HM in vivo (mononuclear cells)	Reduce IL-6 induced CRP production by hepatocytes	[52, 67, 68]
	HM in vitro (VSM cells and PBE cells)	Reduce IL-8 production by VSM cells	[69, 70]
	MM	Inhibition of neutrophil accumulation and IL-8 and TNF-α concentration in BALF in rats	[71]
	HM in vivo (serum), MM	Reduce production of IL-β1 and TNF-α	[52, 72]
	MM	Reduced expression of IFN-γ TNF-α and MMP12 in whole lung	[73]
Matrix remodelling	MM	Reduced lung parenchymal destruction and MMP 9 activity in smoke exposed rat lung	[74, 75]
	HM ex vivo (bronchial epithelial cells)	Reduce release of MMP2 and MMP9 from bronchial epithelial cells from lung transplant patients	[70]
Neutrophil/macrophage influx	HM ex vivo (bronchial epithelial cells), HM in vivo (PMN)	Reduce neutrophil influx in lung transplant recipients by inhibiting release of IL-8 and GM-CSF from bronchial epithelial cells	[70, 76, 77]
	HM in vitro (PMN), HM in vivo (serum)	Reduce neutrophil endothelial adhesion and transendothelial migration	[76, 78–80]
	MM	Reduce neutrophil influx and inhibit the development of elastase induced pulmonary emphysema in mice	[74, 75]
	MM, HM ex vivo (human monocytes)	Reduce CRP-induced monocyte migration by inhibition of ICAM-1 in human monocytes	[81]
	MM, HM in vitro (endothelial cells), HM in vivo (BALF)	Reduced concentration of neutrophils and lymphocytes in BALF	[74, 75]
	MM, HM in vitro	Reduce chemokine and adhesion molecule expression to reduce migration of inflammatory cells into the airways	[74, 81, 82]
Epithelial/endothelial integrity	MM	Promotes alveolar cell regeneration and restores endothelial cell function	[75]
	MM	Reduce LPS-induced IL-6 gene expression leading to reduced lung vascular leak and pulmonary inflammation in mice lung	[83]
	HM in vitro (endothelial and smooth muscle cells)	Inhibition of VEGF in smooth muscle cells and endothelial cells	[84]
Apoptosis	HM in vitro (macrophages and PMN)	Enhances clearance of apoptotic cells in alveolar macrophages from patients with COPD	[85]
	HM in vitro (endothelial cells), HM in vitro (endothelial and smooth muscle cells)	Increase apoptosis in human vascular endothelial cells	[84, 86]
Oxidant response	HM in vivo (PMN)	Reduce IL-8 release from neutrophils and neutrophil derived reactive oxidant species	[77]
	HM in vivo (serum), MM	Strong anti-oxidant properties	[87, 88]
Mucus production	MM	Reduced LPS-induced goblet cell hyperplasia in bronchial epithelium and Muc5A induced mucus hypersecretion	[71]
CRP level	HM in vitro (liver cell)	Reduce CRP levels at the transcriptional level thorough Rac-1 mediated inhibition of STAT3 phosphorylation	[67]

COPD: chronic obstructive pulmonary disease; CRP: C-reactive protein; MM: murine model; HM: human model; VSM: vascular smooth muscle; PBE: primary bronchial epithelial; PMN: polymorphic neutrophil; BALF: bronchoalveolar lavage fluid; IL: interleukin; TNF: tumour necrosis factor; IFN: interferon; MMP: matrix metalloproteinase; GM-CSF: granulocyte-monocyte colony-stimulating factor; ICAM: intracellular adhesion molecule; LPS: lipopolysaccharide; VEGF: vascular endothelial growth factor.

Table. 2—

Mortality benefit of statin use in the general population diagnosed with community acquired pneumonia

Cohort	Subject n		Risk reduction	[Ref.]
Retrospective cohort study in teaching hospital	787	0.36 (0.14–0.92)	64% reduction in 30-day mortality	[102]
Population based prospective cohort study	3415	0.78 (0.57–1.07)	22% reduction in mortality or admission to an ICU	[103]
Population based retrospective nested case–control	6089	0.47 (0.25–0.88)	53% reduction in fatal pneumonia	[104]
Prospective hospital based observational study	1007	0.46 (0.25–0.85)	54% reduction in 30-day mortality	[105]
Population based cohort study	29900	0.69 (0.58–0.82)	31% reduction in 30-day mortality	[106]
		0.75 (0.65–0.86)	25% reduction in 90-day mortality
Retrospective national cohort study	8652	0.54 (0.42–0.70)	46% reduction in 30-day mortality	[107]
Population based case–control study	2235	0.81 (0.46–1.42)	19% reduction in risk of pneumonia (after excluding those with CAD)	[108]
Population based cohort study	3681	0.33 (0.19–0.58)	67% reduction in 30-day mortality	[109]
		0.45 (0.32–0.62)	55% reduction in long-term mortality

Data are presented as odds ratio (95% confidence interval). Data for population based case–control study and cohort study are presented as hazard ration (95% confidence interval). ICU: intensive care unit; CAD: coronary artery disease.