Inhibiting Bruton's tyrosine kinase rescues mice from lethal influenza-induced acute lung injury

Am J Physiol Lung Cell Mol Physiol. 2018 Jul 1;315(1):L52-L58. doi: 10.1152/ajplung.00047.2018. Epub 2018 Mar 8.

Abstract

Infection with seasonal influenza A virus (IAV) leads to lung inflammation and respiratory failure, a main cause of death in influenza-infected patients. Previous experiments in our laboratory indicate that Bruton's tyrosine kinase (Btk) plays a substantial role in regulating inflammation in the respiratory region during acute lung injury in mice; therefore, we sought to determine if blocking Btk activity has a protective effect in the lung during influenza-induced inflammation. The Btk inhibitor ibrutinib (also known as PCI-32765) was administered intranasally to mice starting 72 h after lethal infection with IAV. Our data indicate that treatment with the Btk inhibitor not only reduced weight loss and led to survival, but also had a dramatic effect on morphological changes to the lungs, in IAV-infected mice. Attenuation of lung inflammation indicative of acute lung injury, such as alveolar hemorrhage, interstitial thickening, and the presence of alveolar exudate, together with reduced levels of the inflammatory mediators TNFα, IL-1β, IL-6, KC, and MCP-1, strongly suggests amelioration of the pathological immune response in the lungs to promote resolution of the infection. Finally, we observed that blocking Btk specifically in the alveolar compartment led to significant attenuation of neutrophil extracellular traps released into the lung in vivo and neutrophil extracellular trap formation in vitro. Our innovative findings suggest that Btk may be a new drug target for influenza-induced lung injury, and, in general, that immunomodulatory treatment may be key in treating lung dysfunction driven by excessive inflammation.

Keywords: Bruton’s tyrosine kinase; acute lung injury; acute respiratory distress syndrome; influenza; neutrophil.

Publication types

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

MeSH terms

  • Acute Lung Injury / drug therapy
  • Acute Lung Injury / enzymology*
  • Acute Lung Injury / pathology
  • Acute Lung Injury / virology
  • Agammaglobulinaemia Tyrosine Kinase / antagonists & inhibitors
  • Agammaglobulinaemia Tyrosine Kinase / metabolism*
  • Animals
  • Cytokines / metabolism
  • Extracellular Traps / metabolism
  • Influenza A Virus, H1N1 Subtype / metabolism*
  • Macrophages, Alveolar / enzymology*
  • Macrophages, Alveolar / pathology
  • Mice
  • Orthomyxoviridae Infections / enzymology*
  • Orthomyxoviridae Infections / pathology
  • Protein Kinase Inhibitors / pharmacology
  • Pyrazoles / pharmacology
  • Pyrimidines / pharmacology

Substances

  • Cytokines
  • PCI 32765
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyrimidines
  • Agammaglobulinaemia Tyrosine Kinase
  • Btk protein, mouse