Pharmacoproteomics reveal novel protective activity of bromodomain containing 4 inhibitors on vascular homeostasis in TLR3-mediated airway remodeling

Autor: Jing Zhang, Maxim V. Ivannikov, Massoud Motamedi, Hong Sun, Bing Tian, Yingxin Zhao, Lata Kaphalia, Jia Zhou, Allan R. Brasier, William J. Calhoun, Zhiqing Liu, Rosario Maroto, Yueqing Zhang
Rok vydání: 2019
Předmět:
Male
Proteomics
0301 basic medicine
Proteome
Cell Cycle Proteins
Biochemistry
Biomarkers
Pharmacological
Mice
Idiopathic pulmonary fibrosis
Homeostasis
Receptor
Sulfonamides
medicine.diagnostic_test
Azepines
respiratory system
medicine.anatomical_structure
Airway Remodeling
medicine.symptom
Bronchoalveolar Lavage Fluid
Biophysics
Inflammation
Respiratory Mucosa
Exosome
Article
Bleomycin
03 medical and health sciences
medicine
Animals
Humans
Lung
030102 biochemistry & molecular biology
business.industry
Triazoles
medicine.disease
Asthma
Idiopathic Pulmonary Fibrosis
Toll-Like Receptor 3
respiratory tract diseases
Bromodomain
Mice
Inbred C57BL
Disease Models
Animal
Poly I-C
030104 developmental biology
Bronchoalveolar lavage
Cytoprotection
Case-Control Studies
TLR3
Cancer research
Blood Vessels
Endothelium
Vascular
business
Transcription Factors
Zdroj: J Proteomics
ISSN: 1874-3919
DOI: 10.1016/j.jprot.2019.103415
Popis: 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. 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.
Databáze: OpenAIRE
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