Repurposing Treatments to Enhance Innate Immunity. Can Statins Improve Neutrophil Functions and Clinical Outcomes in COPD?

Abstract

Drug classes used in the treatment of Chronic Obstructive Pulmonary Disease (COPD) have not changed for many years, and none to date have shown disease-modifying activity. Statins are used to help reduce cardiovascular risk, which is high in many patients with COPD. Their use has been associated with improvements in some respiratory manifestations of disease and reduction in all-cause mortality, with greatest reductions seen in patients with the highest inflammatory burden. The mechanism for these effects is poorly understood. Neutrophils are key effector cells in COPD, and correlate with disease severity and inflammation. Recent in vitro studies have shown neutrophil functions are dysregulated in COPD and this is thought to contribute both to the destruction of lung parenchyma and to the poor responses seen in infective exacerbations. In this article, we will discuss the potential utility of statins in COPD, with a particular emphasis on their immune-modulatory effects as well as presenting new data regarding the effects of statins on neutrophil function in vitro.

Keywords: COPD; chemotaxis; inflammation; neutrophil; simvastatin; statins.

Figure 1

The HMG-CoA reductase pathway. Statins act by competitively inhibiting HMG-CoA reductase, reducing the rate by which HMG Co-A reductase is able to produce mevalonate, the next molecule in the pathway that produces cholesterol. This pathway is also responsible for isoprenoid formation, these are required to modify and activate small GTPases.

Figure 2

Shared inflammatory mechanisms in COPD and CVD. Chronic cigarette smoke exposure or other toxic inhalants in susceptible people leads to (1) the sustained activation of airway macrophages and epithelial cells; (2) The release of inflammatory cytokines causes endothelial activation and neutrophils recruitment to the airways, however COPD poor migratory accuracy and increased reactive oxygen species release leads to (3) increased systemic inflammation. This activates endothelial cells further, recruiting more neutrophils and as well as causing (4) bystander tissue damage to both blood vessels and the lung parenchyma; (5) Neutrophil proteinases degrade elastin fibres both in the lung and large blood vessels, causing emphysema and arterial stiffness as well as increasing the activity of macrophage proteinases such as MMP12. Neutrophil netosis (6) adds to the inflammatory burden, and promotes platelet aggregation in small vessels due to endothelial damage (7). Atherosclerotic plaques form over areas of endothelial damage, which are infiltrated by immune cells including neutrophils during plaque rupture.

Figure 3

Neutrophil migratory accuracy is improved in COPD following in vitro exposure to simvastatin. Neutrophil migratory chemotaxis (A,B) (accuracy of movement towards a chemoattractant) and chemokinesis (C,D) (random speed of movement in any direction) from n = 8 patients with COPD and n = 10 age-matched healthy controls towards 100 nm CXCL8 (A,C) or 10 nm fMLP (B,D) were compared. White bars represent healthy controls (HC) and gray bars represent patients with COPD. “NC” is migration towards CXCL8 or fMLP when neutrophils were incubated with buffer alone, “VC” is migration towards the chemoattractants when neutrophils were incubated in vehicle control. “Sim” is migration towards the chemoattractants when neutrophils were incubated with simvastatin (concentrations as shown). Data presented as mean and standard error of the mean. * represents p value < 0.05. Data was compared using Mann-Whitney-U or Kruskal Wallis tests. Neutrophils from patients with COPD were faster than those from healthy controls, but less accurate when migrating towards fMLP and CXCL8. Simvastatin improved accuracy of migration (chemotaxis) towards CXCL8 and fMLP in patients with COPD, and towards healthy controls towards CXCL8. Simvastatin did not affect the speed of migration in either group.

Figure 3

Neutrophil migratory accuracy is improved in COPD following in vitro exposure to simvastatin. Neutrophil migratory chemotaxis (A,B) (accuracy of movement towards a chemoattractant) and chemokinesis (C,D) (random speed of movement in any direction) from n = 8 patients with COPD and n = 10 age-matched healthy controls towards 100 nm CXCL8 (A,C) or 10 nm fMLP (B,D) were compared. White bars represent healthy controls (HC) and gray bars represent patients with COPD. “NC” is migration towards CXCL8 or fMLP when neutrophils were incubated with buffer alone, “VC” is migration towards the chemoattractants when neutrophils were incubated in vehicle control. “Sim” is migration towards the chemoattractants when neutrophils were incubated with simvastatin (concentrations as shown). Data presented as mean and standard error of the mean. * represents p value < 0.05. Data was compared using Mann-Whitney-U or Kruskal Wallis tests. Neutrophils from patients with COPD were faster than those from healthy controls, but less accurate when migrating towards fMLP and CXCL8. Simvastatin improved accuracy of migration (chemotaxis) towards CXCL8 and fMLP in patients with COPD, and towards healthy controls towards CXCL8. Simvastatin did not affect the speed of migration in either group.