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Aryl hydrocarbon receptor deficiency causes the development of chronic obstructive pulmonary disease through the integration of multiple pathogenic mechanisms
Author(s) -
Guerriecola,
Traboulsi Hussein,
Rico de Souza Angela,
Bossé Yohan,
Thatcher Thomas H.,
Robichaud Annette,
Ding Jun,
Li Pei Z.,
Simon Leora,
Pareek Swati,
Bourbeau Jean,
Tan Wan C.,
Benedetti Andrea,
Obeidat Ma’en,
Sin Don D.,
Brandsma CorryAnke,
Nickle David C.,
Sime Patricia J.,
Phipps Richard P.,
Nair Parameswaran,
Zago Michela,
Hamid Qutayba,
Smith Benjamin M.,
Eidelman David H.,
Baglole Carolyn J.
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.202002350r
Subject(s) - aryl hydrocarbon receptor , copd , pathogenesis , medicine , lung , immunology , pulmonary function testing , biomarker , transcription factor , pathology , biology , biochemistry , gene
Abstract 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.