Role of the Arylhydrocarbon Receptor in Lung Disease

Abstract

Ubiquitous environmental contaminants such as dioxins have long been implicated in cellular toxicity, but only recently have various biological effects been linked to immune regulation. These plentiful noxious agents exert their effects through the arylhydrocarbon receptor (AhR) recognized as a ligand-activated transcription factor. AhR activation mediates gene alteration, cell-cell adhesion interaction, cytokine expression, and mucin production, which are involved in the induction of cancer or inflammation. We have reported that human bronchial epithelial cells express AhR, and AhR activation induces mucin production through reactive oxygen species. This review discusses the role of AhR in lung disease, focusing in particular on airway epithelial cells. In addition, although it is not yet clear how the activation of AhR modifies carcinogenesis or airway inflammation, we mention a potent therapeutic target for AhR activation in the prevention/treatment of lung cancer, allergic asthma, and chronic obstructive pulmonary disease.

The Aryl Hydrocarbon Receptor Modulates Acute and Late Mast Cell Responses

“…Conflicting results have been also reported for the role of AhR in immunological responses in the airways. Chiba et al (43) have reported that AhR activation in airway epithelial cells induces mucin secretion through production of ROS, suggesting that antioxidant treatments may be appropriate for patients with respiratory symptoms related to dioxin exposure. On the contrary, Baglole et al (44) have shown that AhR activation by cigarette smoke extracts has a protective effect on airway inflammation by inducing the production of the cytoprotective enzyme heme-oxygenase-1 by lung fibroblasts.…”

Aryl hydrocarbon receptor agonists upregulate VEGF secretion from bronchial epithelial cells

“…This concept is supported by many epidemiological studies, which link air pollution exposure to both the risk of asthma and COPD and the need of emergency department visit or hospitalization [13][14][15][16][17][18]. Because many inhaled toxicants, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and polycyclic aromatic hydrocarbons (PAH), are aryl hydrocarbon receptor (AhR) agonists, it is not surprising that the role of AhR pathway in these pulmonary diseases has been gradually recognized in recent years [19,20]. For example, a long-term epidemiological study revealed that dioxin exposure increased COPD incidence and mortality from COPD [21].…”

Analysis of the AHR gene proximal promoter GGGGC-repeat polymorphism in lung, breast, and colon cancer

“…The AhR thus appears to be involved in both toxification and detoxification events of several exogenous carcinogens. While there may be other pathways involved in lung carcinogenesis (Chiba et al, 2011), metabolic activation of smoke-borne carcinogens is almost universally accepted as a causative, initiating event.…”