Significance
Repetitive and chronic viral upper respiratory tract infections trigger toll-like receptor (TLR)3-NFκB/RelA mediated airway remodeling which is linked to a progressive decline in pulmonary function in patients with asthma and chronic obstructive pulmonary disease. Small molecule inhibitors of the epigenetic regulator bromodomain-containing protein 4 (BRD4) are potential therapeutics for viral and allergen-induced airway remodeling. A limitation of their preclinical advancement is the lack of detailed understanding of mechanisms of action and biomarkers of effect. Our study revealed that the activation of (TLR)3-NFκB/RelA pathway in the lung induced an elevation in coagulation, complement, and platelet factors, indicating the increased vascular leak during airway remodeling. The mechanism of vascular leakage was chronic inflammation-induced pericyte-myofibroblast transition, which was blocked by BRD4 inhibitors. Finally, proteomics analysis of the bronchoalveolar lavage fluid samples from humans with severe asthma demonstrated similar findings that we observed in the animal model.