tetano
Editor, Senior Moderator
Am J Physiol Lung Cell Mol Physiol. 2018 Mar 8. doi: 10.1152/ajplung.00047.2018. [Epub ahead of print]
[h=1]Inhibiting Bruton's Tyrosine Kinase Rescues Mice from Lethal Influenza Induced Acute Lung Injury.[/h] Florence JM[SUP]1[/SUP], Krupa A[SUP]2[/SUP], Booshehri LM[SUP]3[/SUP], Davis SA[SUP]4[/SUP], Matthay MA[SUP]5[/SUP], Kurdowska AK[SUP]6[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] 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 indicated that Bruton's tyrosine kinase (Btk) plays a substantial role in regulating inflammation in the respiratory region during acute lung injury (ALI) in mice, therefore we sought to determine if blocking Btk activity had a protective effect in the lung during influenza induced inflammation. A Btk inhibitor (Btk Inh.) Ibrutinib (also known as PCI-32765) was administered intranasally to mice starting 72h after lethal infection with IAV. Our data indicates that treatment with the Btk inhibitor not only reduced weight loss and led to survival, but had a dramatic effect on morphological changes to the lungs of IAV infected mice. Attenuation of lung inflammation indicative of ALI such as alveolar hemorrhage, interstitial thickening, and the presence of alveolar exudate, together with reduced levels of inflammatory mediators TNFα, IL-1β, IL-6, KC, and MCP-1 strongly suggest 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 (NET)s released into the lung in vivo, and NET formation in vitro. Our innovative findings suggest that Btk may be a new drug target for influenza induced lung injury, and in general immunomodulatory treatment may be key in treating lung dysfunction driven by excessive inflammation.
[h=4]KEYWORDS:[/h] Acute Lung Injury; Acute Respiratory Distress Syndrome; Bruton's Tyrosine Kinase; Influenza; Neutrophil
PMID: 29516781 DOI: 10.1152/ajplung.00047.2018
[h=1]Inhibiting Bruton's Tyrosine Kinase Rescues Mice from Lethal Influenza Induced Acute Lung Injury.[/h] Florence JM[SUP]1[/SUP], Krupa A[SUP]2[/SUP], Booshehri LM[SUP]3[/SUP], Davis SA[SUP]4[/SUP], Matthay MA[SUP]5[/SUP], Kurdowska AK[SUP]6[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] 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 indicated that Bruton's tyrosine kinase (Btk) plays a substantial role in regulating inflammation in the respiratory region during acute lung injury (ALI) in mice, therefore we sought to determine if blocking Btk activity had a protective effect in the lung during influenza induced inflammation. A Btk inhibitor (Btk Inh.) Ibrutinib (also known as PCI-32765) was administered intranasally to mice starting 72h after lethal infection with IAV. Our data indicates that treatment with the Btk inhibitor not only reduced weight loss and led to survival, but had a dramatic effect on morphological changes to the lungs of IAV infected mice. Attenuation of lung inflammation indicative of ALI such as alveolar hemorrhage, interstitial thickening, and the presence of alveolar exudate, together with reduced levels of inflammatory mediators TNFα, IL-1β, IL-6, KC, and MCP-1 strongly suggest 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 (NET)s released into the lung in vivo, and NET formation in vitro. Our innovative findings suggest that Btk may be a new drug target for influenza induced lung injury, and in general immunomodulatory treatment may be key in treating lung dysfunction driven by excessive inflammation.
[h=4]KEYWORDS:[/h] Acute Lung Injury; Acute Respiratory Distress Syndrome; Bruton's Tyrosine Kinase; Influenza; Neutrophil
PMID: 29516781 DOI: 10.1152/ajplung.00047.2018