Abstract
Background: Lung inflammation, cell death and extensive lung tissue remodeling characterize COPD. Regulation of the activity of potentially harmful extracellular histones released from necrotic cells is important for the prevention of excessive tissue damage and disease progression in COPD. Osteopontin (OPN) is an anionic glycoprotein upregulated during a number of physiological and pathological processes has been involved in the regulation of inflammation. In recent studies high levels of OPN have been detected in the airways of patients with COPD. However contribution of OPN to the host response during COPD has not been well characterized.
Objective: Investigate if OPN binds to extracellular histones and modulate their cytotoxic effects.
Methods: The binding affinity and kinetics of histones with OPN was measured utilizing SPR BIAcore. The cytotoxic effects of extracellular histones in presence and absence of OPN was determined by measuring lysis of erythrocytes, epithelial and endothelial cells and antimicrobial activities of histones in presence of OPN were determined.
Results: OPN binds to all subclasses of histones with varying affinities. Functional analysis has revealed that OPN neutralizes the cytotoxic effects of extracellular histones, which is evidenced by low levels of LDH release from epithelial and endothelial cells and complete inhibition of erythrocyte lysis. In addition the antimicrobial activities of histones was suppressed in presence of OPN.
Conclusions: These findings suggest a possible protective mechanism of OPN in modulating host immune response by neutralizing extracellular histones, thereby presenting a novel treatment strategy to preventexcessive tissue damage and disease progression in COPD.
- Copyright ©ERS 2015