Fig. 8

Schematic summary of the effects of ODSH on attenuating lung injury in cystic fibrosis by targeting airway HMGB1. Deficiency or dysfunction in CFTR gene or protein leads to an elevation of airway level of HMGB1. High levels of airway HMGB1 can compromise host defense in bacterial clearance by impairing the ability of macrophages to phagocytose the invading bacteria, resulting in increased bacterial loads in the lung and subsequently causing lung injury. Increased bacterial load in the lung and lung injury can further stimulate the release of proinflammatory mediators, including HMGB1, into the airways, establishing a deleterious cycle to cause sustained pulmonary infections and severe lung injury. Nitric oxide (NO) also plays a critical role in host defense to clear invading bacteria. However, CFTR deficiency leads to a decrease of bacterial infection-induced NO production in the lung, which can contribute to impairing host defense in clearing the invading PA. Administration of ODSH to CF mice can improve the bacterial clearing by (1) attenuating CF-suppressed NO production induced by bacterial infection in the lung, (2) decreasing the airway accumulation of extracellular HMGB1 released by necrotic cells of the injured lung as well as actively secreted by macrophages and (3) decreasing the HMGB1-mediated macrophage dysfunction. Importantly, ODSH can bind directly to HMGB1, inducing its conformational changes which might be responsible for the reduced HMGB1 binding to its receptors (e.g. TLR2 and TLR4) on macrophages. Together, ODSH protects the CF lung upon bacterial infection by attenuating HMGB1-induced innate immune dysfunction. Thus, ODSH ultimately enhances host defense in bacterial clearance by augmenting macrophage phagocytic ability, which leads to attenuating lung injury in CF