ToxPoint: Mucus matters: pollution alters mucus pathophysiology

Air pollution is known to cause and worsen muco-obstructive pulmonary diseases (MOPDs) such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), non-cystic fibrosis bronchiectasis, and primary ciliary dyskinesia, as well as lung cancer in adults (Kurt et al. 2016; Loaiza-Ceballos et al. 2022). Lacking is a mechanistic understanding of how pollution affects pulmonary function. The airways are protected from inhaled pollutants by a viscoelastic mucus layer that traps irritants and facilitates their removal from the lung via mucociliary clearance (MCC) (Linssen et al. 2021; Hill et al. 2022). The viscoelastic properties of mucus, such as the storage (resistance to elastic deformation) and loss moduli (resistance to viscous deformation), as well as viscosity (resistance to flow), arise from the entanglements and interactions of polymeric, secreted mucin glycoproteins MUC5B and MUC5AC. Due to this polymeric nature, the physical properties of mucus are highly dependent on concentration. In MOPDs, the concentration, composition, and physical properties of mucus are altered (Linssen et al. 2021). Likewise, the mucus layer is altered by exposure to particulate matter (PM) (Huff et al. 2019). Although a link between pollution and pulmonary pathophysiology is broadly accepted, the specific influence of pollution on the biochemical composition and biophysical properties of mucus is poorly understood. Although our focus in this article is on the effects of air pollution in fully formed adult lungs, it is important to note that air pollution also has pronounced effects on the development of the lung (Voynow and Auten 2015).

A unifying feature of MOPDs is mucus hyperconcentration, which has been shown to lead to decreased MCC rates, declining lung function, and worsening patient outcomes (Hill et al. 2022). The compositional changes to mucus in MOPDs include increased concentrations of MUC5B and MUC5AC, as well as increased concentrations of extracellular DNA (Hill et al. 2022). The increased concentrations of MUC5AC, which is scantly present in health, have been highly correlated with worsening lung function in COPD (Bonser and Erle 2017; Hill et al. 2022). Although environmental challenges, including PM, ozone, and indoor air pollutants, increase mucin production (Loaiza-Ceballos et al. 2022), the specific effects of altered MUC5B and MUC5AC concentrations and interactions in the context of inhaled pollutants have not yet been interrogated. Our present understanding of the role of mucus pathology in MOPDs can be used as a roadmap to elucidate the effect of environmental pollutants on pulmonary mucus and its link to pathology, which may help inform public health policies aimed at curbing the effects of pollution.

Chronic inflammation is associated with increased DNA and mucin concentrations, which increase mucus viscoelastic properties and impede MCC (Linssen et al. 2021; Hill et al. 2022). The inflammatory processes exacerbating CF and COPD can be triggered by a host of factors, including air pollutants such as ozone, PM, and combustion products (Huff et al. 2019; Loaiza-Ceballos et al. 2022). Neutrophilic-dominated inflammation in response to inhaled pathogens or PM facilitates the formation of neutrophil extracellular traps, which have been shown to increase mucus viscoelasticity, thereby decreasing MCC (Kurt et al. 2016; Linssen et al. 2021). Thus, pollutant-induced airway inflammation in pathological mucus, with increased MUC5AC concentrations, may result in further decreased MCC. Additionally, independent of existing respiratory disease, air pollutants trigger the inflammatory response, which increases mucus concentration, alters mucus composition, and compromises MCC (Huff et al. 2019; Loaiza-Ceballos et al. 2022). Multiple studies have shown that airborne contaminants cause increased expression of pro-inflammatory responses (Huff et al. 2019; Loaiza-Ceballos et al. 2022) that upregulate mucin production (Chen et al. 2019; Hill et al. 2022). Understanding how environmental challenges affect mucus, and ultimately influence pathology, is critical for improving the treatment and prevention of MOPDs. As transport is already compromised by hyperconcentration, we hypothesize that increasing the residence time of inhaled PM in the airway will further promote inflammation. Investigating the degree to which pollution promotes inflammation both in healthy individuals and those with existing airway disease will require multidisciplinary studies like those that have been employed to understand MOPDs (Bonser and Erle 2017; Hill et al. 2022).

Although animal models and observational studies demonstrate that pollutants increase host susceptibility to respiratory infection (Loaiza-Ceballos et al. 2022), these studies do not interrogate changes in the mucus that may contribute to the modified host defense functions after environmental challenges. In addition, pollutant-induced activation of oxidative stress pathways including increased generated reactive oxygen species (ROS), can have catastrophic effects on mucus structure and function, including mucin cross-linking, which cause increasing viscoelastic properties and compromised transport (Hill et al. 2022). Pollutant-induced generation of ROS stimulates the upregulation of proteins/molecules involved in inflammation and antioxidant systems (Huff et al. 2019). Although the relationship between air pollution, mucus protein content, and biophysical properties has not yet been systematically characterized, it is likely that pollutant-induced increase in ROS and subsequent alterations in inflammatory and antioxidant pathways results in mucus hyperconcentration, compromised MCC, and airway obstruction.

The need to develop a mechanistic understanding of the effect of air pollution on mucus in both healthy and pathological airways is a critical public health charge. Characterizing how inhaled pollutants alter mucus structure and function will establish the foundation for restoring the mucus defect. Additionally, identifying how chronic respiratory infections develop and behave and/or are caused by pollution-induced hyperconcentrated mucus will be invaluable when selecting treatment strategies. This effort will benefit from a wide breath of expertise being brought to bear, including both epigenetic and toxicological studies into effects of air pollution on cell viability and differentiation (Kurt et al. 2016), epigenetic understanding of how air pollution effects mucin secretion, and developmental consideration (Voynow and Auten 2015), in addition to those addressed herein. As airborne pollutants continue to present a significant threat to public health, understanding their impact on pulmonary health is critical. Future studies focusing on the intersection between air pollution and mucus dysfunction will improve our understanding of pulmonary pathophysiology and provide novel targets for respiratory diseases.

Funding

This work was funded by the Cystic Fibrosis Foundation (ROUILL22F0, HILL20Y2-OUT), the National Institutes of Health (P01HL164320, P30DK065988), and the US Environmental Protection Agency (CR 84033801). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or EPA.

Conflicts of interest

None declared.