Aryl hydrocarbon receptor deficiency causes the development of chronic obstructive pulmonary disease through the integration of multiple pathogenic mechanisms

Necola Guerrina, Hussein Traboulsi, Angela Rico de Souza, Yohan Bosse, Thomas H. Thatcher, Annette Robichaud, Jun Ding, Pei Z. Li, Leora Simon, Swati Pareek, Jean Bourbeau, Wan C. Tan, Andrea Benedetti, Ma'en Obeidat, Don D. Sin, Corry-Anke Brandsma, David C. Nickle, Patricia J. Sime, Richard P. Phipps, Parameswaran NairMichela Zago, Qutayba Hamid, Benjamin M. Smith, David H. Eidelman, Carolyn J. Baglole*

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

2 Citaten (Scopus)

Samenvatting

Emphysema, a component of chronic obstructive pulmonary disease (COPD), is characterized by irreversible alveolar destruction that results in a progressive decline in lung function. This alveolar destruction is caused by cigarette smoke, the most important risk factor for COPD. Only 15%-20% of smokers develop COPD, suggesting that unknown factors contribute to disease pathogenesis. We postulate that the aryl hydrocarbon receptor (AHR), a receptor/transcription factor highly expressed in the lungs, may be a new susceptibility factor whose expression protects against COPD. Here, we report that Ahr-deficient mice chronically exposed to cigarette smoke develop airspace enlargement concomitant with a decline in lung function. Chronic cigarette smoke exposure also increased cleaved caspase-3, lowered SOD2 expression, and altered MMP9 and TIMP-1 levels in Ahr-deficient mice. We also show that people with COPD have reduced expression of pulmonary and systemic AHR, with systemic AHR mRNA levels positively correlating with lung function. Systemic AHR was also lower in never-smokers with COPD. Thus, AHR expression protects against the development of COPD by controlling interrelated mechanisms involved in the pathogenesis of this disease. This study identifies the AHR as a new, central player in the homeostatic maintenance of lung health, providing a foundation for the AHR as a novel therapeutic target and/or predictive biomarker in chronic lung disease.

Originele taal-2English
Artikelnummer21376
Pagina's (van-tot)e21376
Aantal pagina's17
TijdschriftFASEB Journal
Volume35
Nummer van het tijdschrift3
DOI's
StatusPublished - mrt-2021

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