Disrupting the Btk Pathway Suppresses COPD-Like Lung Alterations in Atherosclerosis Prone ApoE−/− Mice Following Regular Exposure to Cigarette Smoke

Abstract

Chronic obstructive pulmonary disease (COPD) is associated with severe chronic inflammation that promotes irreversible tissue destruction. Moreover, the most broadly accepted cause of COPD is exposure to cigarette smoke. There is no effective cure and significantly, the mechanism behind the development and progression of this disease remains unknown. Our laboratory has demonstrated that Bruton’s tyrosine kinase (Btk) is a critical regulator of pro-inflammatory processes in the lungs and that Btk controls expression of matrix metalloproteinase-9 (MMP-9) in the alveolar compartment. For this study apolipoprotein E null (ApoE−/−) mice were exposed to SHS to facilitate study in a COPD/atherosclerosis comorbidity model. We applied two types of treatments, animals received either a pharmacological inhibitor of Btk or MMP-9 specific siRNA to minimize MMP-9 expression in endothelial cells or neutrophils. We have shown that these treatments had a protective effect in the lung. We have noted a decrease in alveolar changes related to SHS induced inflammation in treated animals. In summary, we are presenting a novel concept in the field of COPD, i.e., that Btk may be a new drug target for this disease. Moreover, cell specific targeting of MMP-9 may also benefit patients affected by this disease.

Lung Diseases: Chronic Respiratory Infections

“…The first group of articles analyzes different possible pathways of the immune and inflammatory response, before proposing possible diagnostic and treatment interventions [2][3][4][5]. Douglas et al [2] analyzed the evidence from the literature on the enhancement of upper respiratory innate immunity due to bitter taste receptors and the possible roles of individual taste differences in the clinical management of patients with upper respiratory infections.…”

“…Florence JM et al [5] Disrupting the Btk pathway suppresses COPD-like lung alterations in atherosclerosis prone ApoE −/− mice following regular exposure to cigarette smoking…”

Promoting Neutrophil Apoptosis to Treat Acute Lung Injury

“…As Harris and colleagues noted in their D iscussion , neutrophil inflammation is also an important component in chronic inflammation disorders such as chronic obstructive pulmonary disease. We have also used an atherosclerosis/chronic obstructive pulmonary disease comorbidity mouse model of apolipoprotein E–deficient mice that were regularly exposed to cigarette smoke and/or fed a proatherogenic diet, and whose treatments included ibrutinib or neutrophil-targeted siRNA to MMP-9, which we observed to have a dramatic protective effect (6, 7). Targeting either Btk or MMP-9 reduced arterial plaque growth and increased plaque stability, and furthermore ameliorated alveolar airspace enlargement as well as alveolar wall integrity and airway collagen deposition.…”

Lung Diseases: Chronic Respiratory Infections

“…The first group of articles analyzes different possible pathways of the immune and inflammatory response, before proposing possible diagnostic and treatment interventions [ 2 , 3 , 4 , 5 ].…”

“…The regulation of inflammatory processes in the lung through the new potential targets was analyzed in the original research published by Florence et al [ 5 ]. The authors demonstrate that Bruton’s tyrosine kinase (Btk) and matrix metalloproteinase-9 (MMP-9) specific siRNA can down-regulate lung inflammation in a mice model.…”