The Aryl Hydrocarbon Receptor (AHR): A Novel Therapeutic Target for Pulmonary Diseases?

Abstract

The aryl hydrocarbon receptor (AHR) is a cytoplasmic transcription factor that is well-known for regulating xenobiotic metabolism. Studies in knockout and transgenic mice indicate that the AHR plays a vital role in the development of liver and regulation of reproductive, cardiovascular, hematopoietic, and immune homeostasis. In this focused review on lung diseases associated with acute injury and alveolar development, we reviewed and summarized the current literature on the mechanistic role(s) and therapeutic potential of the AHR in acute lung injury, chronic obstructive pulmonary disease, and bronchopulmonary dysplasia (BPD). Pre-clinical studies indicate that endogenous AHR activation is necessary to protect neonatal and adult lungs against hyperoxia- and cigarette smoke-induced injury. Our goal is to provide insight into the high translational potential of the AHR in the meaningful management of infants and adults with these lung disorders that lack curative therapies.

Keywords: acute lung injury; and bronchopulmonary dysplasia; aryl hydrocarbon receptor; chronic obstructive pulmonary disease; hyperoxia.

Figure 1

Structure of the AHR. bHLH: basic helix-loop-helix; PAS: PER-ARNT-SIM.

Figure 2

The AHR signaling pathway. Prior to ligand binding, the AHR (Aryl hydrocarbon receptor) is located in the cytoplasm as a complex comprising menu proteins, including Hsp90 (Heat shock protein 90), XAP2: (Hepatitis B virus X-associated protein 2), p23, and Src Kinase. Upon entry of the ligand-AHR into the nucleus, the associated proteins are dissociated, and the ligand-AHR complex binds to the ARNT (Aryl hydrocarbon receptor nuclear translocator,), which, in turn, binds to the AHRE (Aryl hydrocarbon receptor responsive elements) on the CYP1A1 promoter, leading to transcriptional activation of CYP1A1 and other phase II genes.

Figure 3

AHR modulates ALI in vivo via CYP1A enzymes. AHR is expressed in lungs and liver. In hyperoxic lung injury animal models, AHR deficiency potentiates the symptoms, which may be associated with AHR-regulated genes, such as CYP1A1/2, in these tissues. AHR-regulated genes may also alleviate LPS-induced lung injury. The CYP1A enzymes attenuate lung injury by detoxifying lipid hydroperoxides, such as F₂-isoprostanes [129,152,153].

Figure 4

The role of AHR in the pathogenesis of COPD. Cigarette smoke and occupational pollutants may cause COPD due to abnormal immune homeostasis in the lung, which is attenuated by activation of AHR. It suggests AHR agonists may prevent or treat COPD.

Figure 5

The role of the AHR in development of experimental BPD. Hyperoxia is one of major factors that contribute to the development of BPD. Some AHR ligands alleviate the hyperoxia-induced BPD, which may be associated with the activation of many AHR-regulated genes, such as phase I and II enzymes. However, other AHR ligands, such as environmental pollutants, potentiate the hyperoxia-induced BPD.