The Airway Epithelium-A Central Player in Asthma Pathogenesis

Abstract

Asthma is a chronic inflammatory airway disease characterized by variable airflow obstruction in response to a wide range of exogenous stimuli. The airway epithelium is the first line of defense and plays an important role in initiating host defense and controlling immune responses. Indeed, increasing evidence indicates a range of abnormalities in various aspects of epithelial barrier function in asthma. A central part of this impairment is a disruption of the airway epithelial layer, allowing inhaled substances to pass more easily into the submucosa where they may interact with immune cells. Furthermore, many of the identified susceptibility genes for asthma are expressed in the airway epithelium. This review focuses on the biology of the airway epithelium in health and its pathobiology in asthma. We will specifically discuss external triggers such as allergens, viruses and alarmins and the effect of type 2 inflammatory responses on airway epithelial function in asthma. We will also discuss epigenetic mechanisms responding to external stimuli on the level of transcriptional and posttranscriptional regulation of gene expression, as well the airway epithelium as a potential treatment target in asthma.

Keywords: airway epithelium; alarmins; allergen; asthma; barrier; miRNA; type 2 inflammation; virus.

Figure 1

The structure and protective functions of the human airway epithelium in the lower respiratory tract.

Figure 2

The epithelial-derived cytokines TSLP, IL-33, and IL-25 are released in response to various insults, including allergens and respiratory viruses, and act as key upstream drivers of type 2 inflammation in the airways through effects on both innate and adaptive immune cells.

Figure 3

Proposed effects of miRNAs in the airway epithelium that may influence barrier functions and host response to respiratory virus infections. miRNAs that are up- or downregulated in bronchial epithelial cells from asthmatic individuals are depicted in red color with upward arrow and blue color with downward arrow, respectively. Black lines ending with a perpendicular line indicate an inhibitory effect. Dotted lines illustrate regulated miRNAs or processes (orange color), where up- and downward arrows indicate stimulation and suppression, respectively.