The Aryl Hydrocarbon Receptor Suppresses Chronic Smoke-Induced Pulmonary Inflammation.

Necola Guerrina,David H Eidelman,Hussein Traboulsi,Carolyn J Baglole

doi:10.3389/ftox.2021.653569

Necola Guerrina, David H Eidelman + Show 2 more

Open Access

https://doi.org/10.3389/ftox.2021.653569

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Abstract

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor expressed in the lungs that is activated by numerous xenobiotic, endogenous and dietary ligands. Although historically the AhR is known for mediating the deleterious response to the environmental pollutant dioxin, emerging evidence supports a prominent role for the AhR in numerous biological process including inflammation. We have shown that the AhR suppresses pulmonary neutrophilia in response to acute cigarette smoke exposure. Whether the AhR can also prevent lung inflammation from chronic smoke exposure is not known but highly relevant, given that people smoke for decades. Using our preclinical smoke model, we report that exposure to chronic cigarette smoke for 8-weeks or 4 months significantly increased pulmonary inflammation, the response of which was greater in Ahr−/− mice. Notably, there was an increased number of multinucleated giant cells (MNGCs) in smoke-exposed Ahr−/− mice without a change in cytokine levels. These data support a protective role for the AhR against the deleterious effects of cigarette smoke, warranting continued investigation into its therapeutic potential for chronic lung diseases.

Highlights

The aryl hydrocarbon receptor (AhR) is a transcription factor that is activated in response a multitude of low molecular weight compounds of both exogenous and endogenous origins; these include dioxins, polycyclic aromatic hydrocarbons (PAHs), plant polyphenols and tryptophan metabolites (Abel and Haarmann-Stemmann, 2010; Quintana, 2013)
To assess if the absence of the AhR was associated with an increase in inflammation from chronic smoke exposure, we first chose an 8-week cigarette smoke exposure, a timeframe that precedes the development of lung structural and functional alterations
Neutrophil numbers were significantly elevated as a consequence of an 8-week cigarette smoke-exposure, there was no significant difference in Bronchoalveolar Lavage (BAL) neutrophils between the smoke-exposed Ahr−/− and Ahr+/− mice (Figure 1C)

Summary

Introduction

The aryl hydrocarbon receptor (AhR) is a transcription factor that is activated in response a multitude of low molecular weight compounds of both exogenous and endogenous origins; these include dioxins, polycyclic aromatic hydrocarbons (PAHs), plant polyphenols and tryptophan metabolites (Abel and Haarmann-Stemmann, 2010; Quintana, 2013). These bind to the ligandbinding domain located on the amino terminal of the cytoplasmic AhR. The AhR dissociates from its chaperone proteins prior to heterodimerization with the aryl hydrocarbon receptor nuclear translocator (ARNT).

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