Cellix (Ireland)

Eosinophil accumulation in the lung is an important feature of airway inflammation in asthma. There is therefore much interest in developing novel therapies to prevent this process. Accumulating evidence suggests that statins have anti-inflammatory properties, including inhibition of leucocyte accumulation. We therefore assessed the ability of five statins to inhibit human eosinophil adhesion to recombinant human inter-cellular adhesion molecule (rhICAM)-1 under physiologically relevant flow conditions. Purified eosinophils were pre-treated with a panel of statins before elucidation of the adhesion profiles of resting and granulocyte macrophage-colony stimulating factor (GM-CSF)-stimulated cells to rhICAM-1-coated microchannels at a flow rate of 0.5 dynes/cm(2). Images were recorded in real-time at 1 min intervals and analysed using Ducocell software. Fluvastatin and lovastatin (both 10 nm) significantly inhibited GM-CSF-stimulated eosinophil adhesion to rhICAM-1 after 2 min (34.4+/-3.0% inhibition and 37.8+/-12.6% inhibition, respectively, n=4, P<0.05) but had no significant inhibitory effect on unstimulated eosinophil adhesion. Mevastatin, simvastatin, and pravastatin (all 10 nm) had no significant effect on GM-CSF-stimulated eosinophil adhesion to rhICAM-1. A concentration range of fluvastatin and lovastatin inhibited GM-CSF stimulated eosinophil adhesion with significant (P<0.05) inhibition observed at low concentrations of 1 nm for both drugs. Mevalonate (100 nm) reversed fluvastatin-mediated but not lovastatin-mediated inhibition of eosinophil adhesion. Inhibition of eosinophil adhesion to ICAM-1 by fluvastatin and lovastatin under physiological shear stress represent novel actions by these drugs that may inform the development of anti-inflammatory therapy for allergic disease.

Several studies have recognised the benefit of patients receiving statin therapy in reducing the incidence of sepsis in ICU patients. The potential protective effect of statin therapy reducing the incidence of sepsis is probably due to the immunomodulatory mechanisms of these compounds that are capable of inhibiting the inflammatory pathways. LFA‐1 is an integrin that is critical for T‐cell adhesion, T‐cell priming and cytokine secretion. Statins inhibit LFA‐1 interaction with ICAM by either directly binding to a novel site that is distant from the ICAM binding site (not pravastatin) or inhibit the prenylation of small GTPases. Our results have shown that physiologically relevant concentrations of fluva‐, meva‐, lova‐, simva‐ or pravastatin markedly inhibit T‐cell adhesion to ICAM equally, irrespective of direct LFA‐1 binding. Therefore, the reported clinical outcome of septic patients receiving statin therapy can be at least be partially associated with T‐cell‐ICAM binding activities. In conclusion the Cellix Microfluidic Platform allows for T‐cell adhesion to be accurately determined using physiological shear stress with physiologically relevant concentrations of statins.