Novel regulators of airway epithelial barrier function during inflammation: potential targets for drug repurposing

ABSTRACT

Introduction

Endogenous inflammatory signaling molecules resulting from deregulated immune responses can impair airway epithelial barrier function and predispose individuals with airway inflammatory diseases to exacerbations and lung infections. Therapeutically targeting the specific endogenous factors disrupting the airway barrier therefore has the potential to prevent disease exacerbations without affecting the protective immune responses.

Areas covered

Here, we review the endogenous factors and specific mechanisms disrupting airway epithelial barrier during inflammation and reflect on whether these factors can be specifically targeted by repurposing the existing drugs. Literature search was conducted using PubMed, drug database of US FDA and European Medicines Agency until and including September 2021.

Expert opinion

IL-4 and IL-13 signaling are the major pathways disrupting the airway epithelial barrier during airway inflammation. However, blocking IL-4/IL-13 signaling may adversely affect protective immune responses and increase susceptibility of host to infections. An alternate approach to modulate airway epithelial barrier function involves therapeutically targeting specific downstream component of IL-4/IL-13 signaling or different inflammatory mediators responsible for regulation of airway epithelial barrier. Airway epithelium-targeted therapy using inhibitors of HDAC, HSP90, MIF, mTOR, IL-17A and VEGF may be a potential strategy to prevent airway epithelial barrier dysfunction in airway inflammatory diseases.

KEYWORDS:

• Adherens junction
• airway epithelial barrier
• drug repurposing
• inflammation
• tight junction
• immune signaling targets

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosure

One reviewer is affiliated with a company which is developing IFN beta for the treatment of viral infections in respiratory diseases. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose

Article highlights

• Preserving inter-epithelial adhesion and intact airway epithelial barrier is crucial for preventing exacerbations and recurrent infections in airway inflammatory diseases.

• IL-4 and IL-13 signaling are the major pathways disrupting the airway epithelial barrier during airway inflammatory diseases.

• Blocking the entire IL-4 and IL-13 signaling pathways carry adverse effects such as increased susceptibility to infections, cardiovascular events and malignancy.

• HDAC, HSP90, MIF, mTOR, IL-17A, and VEGF are novel signaling factors regulating airway epithelial barrier function during inflammation.

• HDAC, HSP90, MIF, mTOR, IL-17A, and VEGF can be inhibited by dugs currently approved for treating diseases other than airway inflammatory conditions.

• Airway epithelium-targeted therapy with inhibitors of HDAC, HSP90, MIF, mTOR, IL-17A and VEGF may be a potential therapeutic strategy to prevent airway epithelial barrier dysfunction in airway inflammatory diseases.

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Additional information

Funding

This paper was not funded.