Inhibition of Bruton's Tyrosine Kinase (Btk) in the Lung to Treat Severe Lung Inflammation and Lung Injury

摘要

Bruton's tyrosine kinase (Btk) plays an important role in the pathophysiology of local inflammation in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). A unique two hit model of ALI induced by lipopolysaccharide (LPS)/immune complex (IC)—was developed, along with viral-induced ALI caused by influenza virus and COPD caused by second hand smoke. Two types or therapeutics (i) Anti-neutrophil antibodies, and specifically their F(ab′)₂ fragments conjugated to Btk-specific siRNA or (ii) small molecule Btk inhibitors were administered to lungs and silenced or inhibited Btk specifically in alveolar neutrophils. Such silencing/inhibition had a dramatic protective effect lung damage induced by LPS/IC, influenza virus and on COPD. Btk regulates neutrophil survival and clearance of apoptotic neutrophils in these diseases. Btk-targeted neutrophil-specific therapy restores homeostasis in lungs of patients with ALI/ARDS, acute lung infection, COPD and other lung diseases.