Abstract: 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.

Abstract: 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.