Aryl hydrocarbon receptor is essential for the pathogenesis of pulmonary arterial hypertension

Tomita, Masaki; Okazawa, Makoto; Asano, Ryotaro; Ishibashi, Tatsuro; Yamagishi, Akiko; Umeki-Mizushima, Saori; Nishimura, Motoi; Manabe, Yusuke; Ishibashi‐Ueda, Hatsue; Shirai, Makoto; Tsuchimochi, Hirotsugu; Pearson, James T.; Kumanogoh, Atsushi; Sakata, Yasushi; Ogo, Takeshi; Kishimoto, Tadamitsu; Nakaoka, Yoshikazu

doi:10.1073/pnas.2023899118

Cited by 36 publications

(23 citation statements)

References 45 publications

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“…recently reported that activation of AHR caused PAH by activating a focal inflammatory response in the lungs and promoting infiltration of immune cells from the bone marrow. 44 Thus, both albumin and bilirubin may associate with the development of PoPH through reduction of anti-oxidative ability and activation of AHR, respectively.…”

Section: Discussionmentioning

confidence: 99%

Association between the albumin–bilirubin (ALBI) score and severity of portopulmonary hypertension (PoPH): A data‐mining analysis

Kawaguchi

Honda

Sugiyama

et al. 2021

Hepatology Research

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Introduction: Portopulmonary hypertension (PoPH) is a severe complication of chronic liver disease. We aimed to investigate the etiology of chronic liver disease and the factors associated with the severity of PoPH. Subjects and Methods: Echocardiography was undergone in 833 patients with chronic liver disease during 2005-2019 and 13 patients (1.6%) were diagnosed with PoPH in this observational study. At the diagnosis of PoPH, liver function was evaluated by albumin-bilirubin (ALBI) score. Severe PoPH was defined as (1) mean pulmonary arterial pressure (mPAP) ≥50 mmHg or (2) mPAP: 35-49 mmHg and pulmonary vascular resistance ≥400 dyne/s/cm 5 . Factors associated with severe PoPH were evaluated by decision-tree analysis.Results: In patients with PoPH, the leading etiology of chronic liver disease was hepatitis C virus (HCV) (46.2% [sustained virological response (SVR): 23.1% and non-SVR: 15.4%]). Severe PoPH was observed in 53.8% of patients and the 5-year survival rate was 48.1%. There was a significant correlation of mPAP with ALBI score (r = 0.6456, p = 0.0171). In the decision-tree and random forest analyses, the most impacted classifier for severe PoPH was the ALBI score. In patients with ALBI score ≥−1.45, all patients showed severe PoPH, while the prevalence of severe PoPH was 25.0% in patients with ALBI score <−1.45. Conclusions:We found that HCV including SVR was the major etiology of chronic liver disease in patients with PoPH. Moreover, we revealed that the ALBI score was the most impacted factor associated with severe PoPH. Thus, ALBI score may be useful for the estimation of pulmonary vascular resistance.

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Section: Discussionmentioning

confidence: 99%

Association between the albumin–bilirubin (ALBI) score and severity of portopulmonary hypertension (PoPH): A data‐mining analysis

Kawaguchi

Honda

Sugiyama

et al. 2021

Hepatology Research

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“…While the exact mechanism responsible for this phenomenon remains unclear, it has been hypothesized that tobacco carcinogens such as BAP may be responsible for upregulating PD-L1 expression [ 19 ]. BAP activation is mediated by aryl hydrocarbon receptors (AhR), that detoxify xenobiotics and regulate immune cell function [ 22 ]. Wang et al observed that silencing AhR in mice decreased PD-L1 expression and prolonged survival [ 19 ].…”

Section: Tobacco Smoking and The Immune Systemmentioning

confidence: 99%

Tobacco Use and Response to Immune Checkpoint Inhibitor Therapy in Non-Small Cell Lung Cancer

Corke

Leighl

et al. 2022

Current Oncology

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Tobacco is a known risk factor for lung cancer, and continued tobacco use is associated with poorer outcomes across multiple lung cancer treatment modalities including surgery, chemotherapy and radiation therapy. Less is known about the association of tobacco use and outcomes with immune checkpoint inhibitors (ICIs), which are becoming an important part of the treatment landscape in lung cancer, both in metastatic and curative settings. We reviewed the literature on the association of tobacco and tumor biology as it relates to immunotherapy. We also reviewed the association of tobacco use on outcomes among phase III randomized clinical trials involving ICIs in non-small cell lung cancer (NSCLC). We identified that patients with a smoking history may have a greater benefit with ICI treatment compared to never smokers in both treatment-naïve (HR 0.82, 95% CI 0.69–0.97, vs. HR 1.06, 95% CI 0.81–1.38) and pre-treated (HR 0.79, 95% CI 0.70–0.90 vs. 1.03, 95% CI 0.74–1.43) settings. In trials where smoking status was further defined, ex-smokers appear to demonstrate greater benefit with ICI therapy compared to current smokers (HR 0.78, 95% CI 0.59–1.01 vs. 0.91, 95% CI 0.72–1.14). We conclude by offering our perspective on future directions in this area of research, including implementation of standardized collection and analysis of tobacco use in clinical trials involving ICI therapy in lung cancer and other disease sites, and also evaluating how tobacco may affect toxicities related to ICI therapy. Based on our review, we believe that a patient’s history of tobacco smoking does have a role to play in guiding treatment decision making in patients with lung cancer.

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“…40 41 Activation of AhR has been suggested as a possible mechanism in the pathobiology of IN-induced PAH. [42][43][44] As a natural product, the composition of IN varies widely among sources, 45 making batch-to-batch consistency difficult to control. To mitigate these risks, a single molecule AhR agonist that achieves the same therapeutic effect as IN could improve quality control.…”

Section: Discussionmentioning

confidence: 99%

Treatment-refractory ulcerative colitis responsive to indigo naturalis

Saiki

Andreasson

Grimes

et al. 2021

BMJ Open Gastroenterol

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BackgroundIndigo naturalis (IN) is an herbal medicine that has been used for ulcerative colitis with an unclear mechanism of action. Indigo and indirubin, its main constituents, are ligands of the aryl hydrocarbon receptor (AhR). We assessed the safety, efficacy, and colon AhR activity of IN given orally to patients with treatment-refractory ulcerative colitis. The role of AhR in IN benefit was further evaluated with an AhR antagonist in a murine colitis model.MethodsThis open-label, dose-escalation study sequentially treated 11 patients with ulcerative colitis with either IN 500 mg/day or 1.5 g/day for 8 weeks, followed by a 4-week non-treatment period. The primary efficacy endpoint was clinical response at week 8, assessed by total Mayo score. Secondary endpoints included clinical remission, Ulcerative Colitis Endoscopic Index of Severity, quality of life, and colon AhR activity measured by cytochrome P450 1A1 (CYP1A1) RNA expression.ResultsTen of 11 (91%) patients, including 8/9 (89%) with moderate-to-severe disease, achieved a clinical response. Among these 10 patients, all had failed treatment with 5-aminosalicylic acid, 8 patients with a tumour necrosis factor (TNF)-alpha inhibitor, and 6 patients with TNF-alpha inhibitor and vedolizumab. Five patients were corticosteroid dependent. Clinical response was observed in all five patients who had been recommended for colectomy. Three patients achieved clinical remission. All patients experienced improved endoscopic severity and quality of life. Four weeks after treatment completion, six patients had worsened partial Mayo scores. Four patients progressed to colectomy after study completion. Colon CYP1A1 RNA expression increased 12 557-fold at week 8 among six patients evaluated. No patient discontinued IN due to an adverse event. Concomitant administration of 3-methoxy-4-nitroflavone, an AhR antagonist, in a murine colitis model abrogated the benefit of IN.ConclusionIN is a potentially effective therapy for patients with treatment-refractory ulcerative colitis. This benefit is likely through AhR activation.Trial registration numberNCT02442960.

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Aryl hydrocarbon receptor is essential for the pathogenesis of pulmonary arterial hypertension

Cited by 36 publications

References 45 publications

Association between the albumin–bilirubin (ALBI) score and severity of portopulmonary hypertension (PoPH): A data‐mining analysis

Association between the albumin–bilirubin (ALBI) score and severity of portopulmonary hypertension (PoPH): A data‐mining analysis

Tobacco Use and Response to Immune Checkpoint Inhibitor Therapy in Non-Small Cell Lung Cancer

Treatment-refractory ulcerative colitis responsive to indigo naturalis

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