Small Airway Susceptibility to Chemical and Particle Injury

Small airways (SA) in humans are commonly defined as those conducting airways <2 mm in diameter. They are susceptible to particle- and chemical-induced injury and play a major role in the development of airway disease such as COPD and asthma. Susceptibility to injury can be attributed in part to structural features including airflow dynamics and tissue architecture, but recent evidence may indicate a more prominent role for cellular composition in directing toxicological responses. Animal studies support the hypothesis that inherent cellular differences across the tracheobronchial tree, including metabolic CYP450 expression in the distal conducting airways, can influence SA susceptibility to injury. Currently, there is insufficient information in humans to make similar conclusions, prompting further necessary work in this area. An understanding of why the SA are more susceptible to certain chemical and particle exposures than other airway regions is fundamental to our ability to identify hazardous materials, their properties, and accompanying exposure scenarios that compromise lung function. It is also important for the ability to develop appropriate models for toxicity testing. Moreover, it is central to our understanding of SA disease aetiology and how interventional strategies for treatment may be developed. In this review, we will document the structural and cellular airway regional differences that are likely to influence airway susceptibility to injury, including the role of secretory club cells. We will also describe recent advances in single-cell sequencing of human airways, which have provided unprecedented details of cell phenotype, likely to impact airway chemical and particle injury.