Air pollution and resistance to inhaled glucocorticoids: Evidence, mechanisms and gaps to fill.

Substantial evidence indicates that cigarette smoke exposure induces resistance to glucocorticoids, the primary maintenance medication in asthma treatment. Modest evidence also suggests that air pollution may reduce the effectiveness of these critical medications. Cigarette smoke, which has clear parallels with air pollution, has been shown to induce glucocorticoid resistance in asthma and it has been speculated that air pollution may have similar effects. However, the literature on an association of air pollution with glucocorticoid resistance is modest to date. In this review, we detail the evidence for, and against, the effects of air pollution on glucocorticoid effectiveness, focusing on results from epidemiology and controlled human exposure studies. Epidemiological studies indicate a correlation between increased air pollution exposure and worse asthma symptoms. But these studies also show a mix of beneficial and harmful effects of glucocorticoids on spirometry and asthma symptoms, perhaps due to confounding influences, or the induction of glucocorticoid resistance. We describe mechanisms that may contribute to reductions in glucocorticoid responsiveness following air pollution exposure, including changes to phosphorylation or oxidation of the glucocorticoid receptor, repression by cytokines, or inflammatory pathways, and epigenetic effects. Possible interactions between air pollution and respiratory infections are also briefly discussed. Finally, we detail a number of therapies that may boost glucocorticoid effectiveness or reverse resistance in the presence of air pollution, and comment on the beneficial effects of engineering controls, such as air filtration and asthma action plans. We also call attention to the benefits of improved clean air policy on asthma. This review highlights numerous gaps in our knowledge of the interactions between air pollution and glucocorticoids to encourage further research in this area with a view to reducing the harm caused to those with airways disease.