Therapeutic targets for inflammation-mediated airway remodeling in chronic lung disease

ABSTRACT

Introduction: Acute exacerbations of chronic lung disease account for substantial morbidity and health costs. Repeated inflammatory episodes and attendant bronchoconstriction cause structural remodeling of the airway. Remodeling is a multicellular response to mucosal injury that results in epithelial cell-state changes, enhanced extracellular deposition, and expansion of pro-fibrotic myofibroblast populations.

Areas covered: This manuscript overviews mechanistic studies identifying key sentinel cell populations in the airway and how pattern recognition signaling induces maladaptive mucosal changes and airway remodeling. Studies elucidating how NFκB couples with an atypical histone acetyltransferase, bromodomain-containing protein 4 (BRD4) that reprograms mucosal fibrogenic responses, are described. The approaches to development and characterization of selective inhibitors of epigenetic reprogramming on innate inflammation and structural remodeling in preclinical models are detailed.

Expert commentary: Bronchiolar cells derived from Scgb1a1-expressing progenitors function as major sentinel cells of the airway, responsible for initiating antiviral and aeroallergen responses. In these sentinel cells, activation of innate inflammation is coupled to neutrophilic recruitment, mesenchymal transition and myofibroblast expansion. Therapeutics targeting the NFkB-BRD4 may be efficacious in reducing pathological effects of acute exacerbations in chronic lung disease.

KEYWORDS:

• Airway remodeling
• bromodomain-containing protein 4 (BRD4)
• mesenchymal transition
• myofibroblast
• epigenetics

Declaration of interest

The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

Division of Allergy and Immunology (DAIT), National Institute of Allergy and Infectious Diseases (NIAID) 2P01AI062885, National Center for Advancing Translational Research NCATS UL1TR00237