Epithelial damage in the cystic fibrosis lung: the role of host and microbial factors

ABSTRACT

Introduction

The airway epithelium is a key system within the lung. It acts as a physical barrier to inhaled factors, and can actively remove unwanted microbes and particles from the lung via the mucociliary escalator. On a physiological level, it senses the presence of pathogens and initiates innate immune responses to combat their effects. Hydration of the airways is also controlled by the epithelium. Within the cystic fibrosis (CF) lung, these properties are suboptimal and contribute to the pulmonary manifestations of CF.

Areas covered

In this review, we discuss how various host and microbial factors can contribute to airway epithelium dysfunction in the CF lung focusing on mechanisms relating to the mucociliary escalator and protease expression and function. We also explore how alterations in microRNA expression can impact the behavior of the airway epithelium.

Expert opinion

Notwithstanding the unprecedented benefits that CFTR modulator drugs now provide to the health of CF sufferers, it will be important to delve more deeply into additional mechanisms underpinning CF lung disease such as those illustrated here in an attempt to counteract these aberrant processes and further enhance quality of life for people with CF.

KEYWORDS:

• Cystic fibrosis
• airway epithelial cells
• mucociliary escalator
• protease
• microRNA

Article highlights

• Pathogenic colonization of bacteria in the CF lung with classical and emerging pathogens negatively affects epithelial barrier integrity and function. Virulence factors expressed by Pseudomonas aeruginosa or Stenotrophomonas maltophilia, for example, include proteases that can interfere directly with the pulmonary epithelium.

• Host serine, cysteine, and metalloproteases are present at higher than normal levels in the CF lung and can deleteriously affect various processes. Degradation of extracellular matrix proteins, antimicrobial peptides, and cell surface receptors, as well as transcriptional upregulation of mucin and chemokine expression are among these harmful effects.

• Altered microRNA expression in the CF airway epithelium affects various processes central to epithelial barrier integrity, ion transport, and innate immunity.

• Specific microRNAs could represent new targets for novel adjunct CF therapy development. In particular, nebulized biopolymer-encapsulated miRNA modulators could augment the effectiveness of CFTR modulators for improved patient care.

• Antimicrobial, antiprotease, or miRNA-targeted medicines are likely to have even greater relevance as personalized treatments for people with CF who do not respond to CFTR modulator drugs or those in rare mutation classes for which there are no currently approved therapies

Declaration of interest

CM Greene’s research is funded by grants from Vertex Pharmaceuticals and the National Institutes of Health. AMA Glasgow’s research is funded by grants from Vertex Pharmaceuticals and the US Alpha One Foundation. The authors have 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

This paper was not funded.