A recent study published in Frontiers in Immunology discussed how injury and abnormal repair of the airway epithelium drive chronic obstructive pulmonary disease (COPD) and asthma.
Study: Mechanisms of airway epithelial injury and abnormal repair in asthma and COPD. Image Credit: Andrey_Popov/Shutterstock.com
The airway epithelium is a complex system of cells working with the immune system, forming a barrier to pathogens or foreign particles. This whole system collectively functions as the first-line defense to protect and minimize damage due to stress.
However, loss of barrier function and defects in interlinked processes can cause asthma and COPD. The present study discussed the mechanisms of airway epithelial injury and repair that drive asthma and COPD.
Crosstalk between immune and airway epithelial cells
Epithelial cells have pattern recognition receptors (PRRs) that recognize irritants and trigger the secretion of cytokines, alarmins, and chemokines, resulting in acute inflammation.
The immune-epithelial cell interaction is crucial for tissue homeostasis. The immune response depends upon the coordinated activation and response of damage-associated molecular patterns (DAMPs) and PRRs.
The activation and resolution of repair mechanisms are effective in a healthy airway; the immune-epithelial cell interactions indicate the influence of the airway epithelium on immune cells and vice versa. The release of epithelial alarmins is the primary defense mechanism induced by DAMPs and PRRs.
Asthma and epithelial dysfunction
The airway epithelium in asthma exhibits functional and structural abnormalities, such as exaggerated secretion of chemokines, cytokines, and alarmins. These activate and recruit eosinophils, neutrophils, macrophages, and T helper 2 (Th2) cells.
Neutrophils and macrophages produce reactive oxygen species (ROS) and proteases, while eosinophils secrete cationic proteins that exacerbate epithelial damage.
Activated innate immune and epithelial cells also secrete pro-remodeling factors such as transforming growth factor-β and epidermal growth factor ligands, which trigger fibroblast activation, goblet cell hyperplasia, epidermal-to-mesenchymal transition (EMT), and proliferation and hypertrophy of smooth muscle cells in the airway.
Cytokine activation due to the release of chemokines and alarmins in the asthmatic airway is an established mechanism driving asthma. Specifically, alarmin releases primes cluster of differentiation 4 (CD4) Th2 cell response through dendritic cells (DCs).
These DCs trigger an uncontrolled Th2 response and enhance the functionality of type 2 innate lymphoid cells, mast cells, and basophils.
The epithelial response to injury amplifies the release of pro-inflammatory cytokines from basophils and mast cells.
This increases interleukin (IL)-5 and immunoglobulin E (IgE) levels to activate or mature eosinophils and IL-13 levels that induce hyperresponsive smooth muscle contraction, macrophage activation, and goblet cell hyperplasia.
COPD and epithelial dysfunction
Chronic inflammation is a critical factor in the pathogenesis of COPD that causes senescence, abnormal differentiation and function of cells, and cell death. Cigarette smoke is a common risk factor for COPD. It contains ROS that is cytotoxic to the epithelium and triggers acute inflammation.
Epithelial cells secrete pro-inflammatory cytokines leading to the recruitment of neutrophils, monocytes, and macrophages that secrete tumor necrosis factor (TNF)-α and IL-6.
Oxidative stress and chronic inflammation lead to apoptosis and necrosis. In response, adjacent cells dedifferentiate and form squamous epithelium. In healthy scenarios, basal cells and stem cells differentiate and form pseudo-stratified epithelium when toxic exposure of the epithelium ceases.
On the contrary, chronic inflammation and persistent exposure to COPD prevent normal epithelium formation.
Furthermore, predisposing factors are also likely to contribute to COPD pathogenesis. Non-coding RNAs, epigenetic changes, and gene polymorphisms might be involved in abnormal repair in COPD. Cigarette smoking alters DNA methylation at gene promoters.
For instance, in COPD airway epithelial cells exposed to cigarette smoke extracts, hypomethylation of a gene promoter increased the expression of the repressor of the aryl hydrocarbon receptor (AHR).
This increased inhibition of AHR expression elevates the susceptibility to epithelial cell apoptosis and necroptosis. An imbalance between histone acetylation-deacetylation has been observed in the lungs in COPD that is also associated with higher expression of inflammatory genes.
Further, the expression of many micro RNAs (miRNAs) has been reported to be abnormal in COPD airways.
The epithelium protects airways from irritants and pathogens as a physical barrier blocking their entry into the sub-mucosal compartments.
In COPD and asthma, intrinsic defects in the mechanisms of protection and repair, accompanied by repeated injuries, result in epithelial abnormalities. Targeting the mechanisms underlying damage susceptibility and abnormal repair may lead to more effective therapies.