Role of the Arylhydrocarbon Receptor (AhR) in the Pathology of Asthma and COPD

Abstract

The dioxins and dioxin-like compounds in cigarette smoke and environmental pollutants modulate immunological responses. These environmental toxicants are known to cause lung cancer but have also recently been implicated in allergic and inflammatory diseases such as bronchitis, asthma, and chronic obstructive pulmonary disease (COPD). In a novel pathway of this response, the activation of a nuclear receptor, arylhydrocarbon receptor (AhR), mediates the effects of these toxins through the arachidonic acid cascade, cell differentiation, cell-cell adhesion interactions, cytokine expression, and mucin production that are implicated in the pathogenesis and exacerbation of asthma/COPD. We have previously 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 asthma and COPD, focusing in particular on inflammatory and resident cells in the lung. We describe the important impact that AhR activation may have on the inflammation phase in the pathology of asthma and COPD. In addition, crosstalk of AhR signaling with other ligand-activated transcription factors such as peroxisome proliferator-activated receptors (PPARs) has been well documented.

Figure 1

Effects of AhR agonist B[a]P on MUC5AC mRNA level in NCI-H₂₉₂ after 12 h of incubation. MUC5AC was measured by real-time RT-PCR. B[a]P induced MUC5AC mRNA expression in dose-dependent manner. Pretreatment with AhR antagonist, resveratrol, inhibited AhR-induced MUC5AC upregulation. Data are expressed as means ± SD (n = 6). *P < 0.05 versus control (medium alone). **P < 0.05 versus B[a]P 1 μM.

Figure 2

Normal human epidermal keratinocytes (NHEKs) were exposed to B[a]P at various concentrations for 24 h, and IL-8 production in the culture supernatant was measured. B[a]P induced IL-8 production in a dose-dependent manner. Data are expressed as means ± SD (n = 3). *P < 0.05 versus control (medium alone).

Figure 3

Schematic diagram of the proposed crosstalk AhR-signaling pathway and inflammatory effects in airway epithelial cells.

Figure 4

(a) Effect of PPARγ agonist troglitazone on eosinophil chemotaxis stimulated with eotaxin. Purified eosinophils were preincubated with increasing concentrations of troglitazone for 1 h. Migration assays were performed using Boyden chambers. Chemotactic response to eotaxin alone was considered to be 100%, and reactions to lower concentrations are presented relative to eotaxin alone. Data are expressed as mean ± SD. Troglitazone inhibited the eotaxin-directed eosinophil chemotaxis in a dose-dependent manner (n = 4). *P < 0.05 versus eotaxin alone. (b) Effect of troglitazone on eosinophil survival determined by staining with Annexin V-FITC and propidium iodine. Eosinophils were incubated with and without troglitazone in the presence of 1 ng/mL IL-5 for 48 h. Eosinophils were treated with Annexin V to stain early-phase apoptotic cells and with propidium iodine (PI) to stain the late-phase cells. The bar graph shows a dose-dependent effect of troglitazone on IL-5-induced eosinophil survival (n = 4). Data are expressed as mean ± SD. *P < 0.05 versus without troglitazone.