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

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


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.

Keywords: ALI; Btk; LPS; immune complex; neutrophil.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Lung Injury / chemically induced*
  • Acute Lung Injury / enzymology*
  • Acute Lung Injury / genetics
  • Acute Lung Injury / pathology
  • Agammaglobulinaemia Tyrosine Kinase
  • Animals
  • Antigen-Antibody Complex / toxicity*
  • Female
  • Gene Silencing*
  • Humans
  • Lipopolysaccharides / toxicity*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Neutrophils / enzymology*
  • Neutrophils / pathology
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • Pulmonary Alveoli / enzymology*
  • Pulmonary Alveoli / pathology
  • Receptors, IgG / genetics
  • Receptors, IgG / metabolism
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism


  • Antigen-Antibody Complex
  • FCGR2A protein, human
  • Lipopolysaccharides
  • Receptors, IgG
  • TLR4 protein, human
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Protein-Tyrosine Kinases
  • Agammaglobulinaemia Tyrosine Kinase
  • BTK protein, human
  • Btk protein, mouse