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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. We report a systems-level pharmacoproteomics in a standardized murine model of toll-like receptor TLR3-NFκB/RelA innate inflammation in the absence or presence of a highly selective BRD4 inhibitor (ZL0454) or nonselective bromodomain and extraterminal domain inhibitor (JQ1). Proteomics of bronchoalveolar lavage fluid (BALF) secretome and exosomal proteins from this murine model revealed increased, selective, capillary leak associated with pericyte-myofibroblast transition, a phenomenon blocked by BRD4 inhibitors. BALF proteomics also suggested that ZL0454 better reduced the vascular leakage and extracellular matrix deposition than JQ1. A significant subset of inflammation-mediated remodeling factors was also identified in a mouse model of idiopathic pulmonary fibrosis produced by bleomycin. BALF exosome analysis indicated that BRD4 inhibitors reduced the induction of exosomes enriched in coagulation factors whose presence correlated with interstitial fibrin deposition. Finally, BALF samples from humans with severe asthma demonstrated similar upregulations of ORM2, APCS, SPARCL1, FGA, and FN1, suggesting their potential as biomarkers for early detection of airway remodeling and/or monitoring of therapy response.
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.
This article was published in the following journal.
Name: Journal of proteomics
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Specialized clothing or equipment worn for protection against health hazards. Personal Protective Equipment may include MASKS; RESPIRATORY PROTECTIVE DEVICES; HEAD PROTECTIVE DEVICES; EYE PROTECTIVE DEVICES; EAR PROTECTIVE DEVICES; PROTECTIVE CLOTHING; and protective footwear.
Compounds that inhibit the activity of DNA TOPOISOMERASES.
Drugs that inhibit the transport of neurotransmitters into axon terminals or into storage vesicles within terminals. For many transmitters, uptake determines the time course of transmitter action so inhibiting uptake prolongs the activity of the transmitter. Blocking uptake may also deplete available transmitter stores. Many clinically important drugs are uptake inhibitors although the indirect reactions of the brain rather than the acute block of uptake itself is often responsible for the therapeutic effects.
Drugs that mimic the effects of parasympathetic nervous system activity. Included here are drugs that directly stimulate muscarinic receptors and drugs that potentiate cholinergic activity, usually by slowing the breakdown of acetylcholine (CHOLINESTERASE INHIBITORS). Drugs that stimulate both sympathetic and parasympathetic postganglionic neurons (GANGLIONIC STIMULANTS) are not included here.
Compounds that inhibit the activity of DNA TOPOISOMERASE II.
Vascular relates to blood vessels (Oxford Medical Dictionary) and can be used to describe the supply of blood, a disease affecting the blood vessels or molecules associated with these structures. For example, <!--LGfEGNT2Lhm-->atherosclerosis ...
The development and maintenance of an organism is orchestrated by a set of chemical reactions that switch parts of the genome off and on at strategic times and locations. Epigenetics is the study of these reactions and the factors that influence them. ...
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