Am J Physiol Lung Cell Mol Physiol. 2014 Sep 15;307(6):L435-48. doi: 10.1152/ajplung.00234.2013. Epub 2014 Aug 1.

Silencing Bruton's tyrosine kinase in alveolar neutrophils protects mice from LPS/immune complex-induced acute lung injury.

Krupa A1, Fol M2, Rahman M3, Stokes KY4, Florence JM3, Leskov IL4, Khoretonenko MV4, Matthay MA5, Liu KD5, Calfee CS5, Tvinnereim A3, Rosenfield GR3,Kurdowska AK6.

Author information

• 1Department of Cellular and Molecular Biology, University of Texas Health Science Center at Tyler, Tyler, Texas; Institute of Medical Biology, Polish Academy of Sciences, Lodz, Poland;
• 2Department of Cellular and Molecular Biology, University of Texas Health Science Center at Tyler, Tyler, Texas; Department of Immunology and Infectious Biology, University of Lodz, Lodz, Poland.
• 3Department of Cellular and Molecular Biology, University of Texas Health Science Center at Tyler, Tyler, Texas;
• 4Department of Molecular and Cellular Physiology and Center for Molecular and Tumor Virology, Louisiana State University Health Sciences Center, Shreveport, Louisiana;
• 5Departments of Medicine and Anesthesia, University of California, San Francisco, California; and.
• 6Department of Cellular and Molecular Biology, University of Texas Health Science Center at Tyler, Tyler, Texas; anna.kurdowska@uthct.edu.

Abstract

Previous observations made by our laboratory indicate that Bruton's tyrosine kinase (Btk) may play an important role in the pathophysiology of local inflammation in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). We have shown that there is cross talk between FcγRIIa and TLR4 in alveolar neutrophils from patients with ALI/ARDS and that Btk mediates the molecular cooperation between these two receptors. To study the function of Btk in vivo we have developed a unique two-hit model of ALI: LPS/immune complex (IC)-induced ALI. Furthermore, we conjugated F(ab)2 fragments of anti-neutrophil antibodies (Ly6G1A8) with specific siRNA for Btk to silence Btk specifically in alveolar neutrophils. It should be stressed that we are the first group to perform noninvasive transfections of neutrophils, both in vitro and in vivo. Importantly, our present findings indicate that silencing Btk in alveolar neutrophils has a dramatic protective effect in mice with LPS/IC-induced ALI, and that Btk regulates neutrophil survival and clearance of apoptotic neutrophils in this model. In conclusion, we put forward a hypothesis that Btk-targeted neutrophil specific therapy is a valid goal of research geared toward restoring homeostasis in lungs of patients with ALI/ARDS.