A retinoid X receptor partial agonist attenuates pulmonary emphysema and airway inflammation

Daisuke Morichika, Nobuaki Miyahara, Utako Fujii, Akihiko Taniguchi, Naohiro Oda, Satoru Senoo, Mikio Kataoka, Mitsune Tanimoto, Hiroki Kakuta, Katsuyuki Kiura, Yoshinobu Maeda, Arihiko Kanehiro

Research output: Contribution to journalArticle

Abstract

Background: Retinoid X receptors (RXRs) are members of the nuclear receptor (NR) superfamily that mediate signalling by 9-cis retinoic acid, a vitamin A derivative. RXRs play key roles not only as homodimers but also as heterodimeric partners, e.g., for retinoic acid receptors, vitamin D receptors, and peroxisome proliferator-activated receptors. The NR family may also play important roles in the development of emphysema. However, the role of RXRs in the pathogenesis of emphysema is not well defined. Methods: We developed a novel RXR partial agonist (NEt-4IB) and investigated its effect and mechanism compared to a full agonist (bexarotene) in a murine model of emphysema. For emphysema induction, BALB/c mice received intraperitoneal cigarette smoke extract (CSE) or intratracheal porcine pancreas elastase (PPE). Treatment with RXR agonists was initiated before or after emphysema induction. Results: Treatment with NEt-4IB significantly suppressed the increase in static lung compliance and emphysematous changes in CSE-induced emphysema and PPE-induced established and progressive emphysema. NEt-4IB significantly suppressed PPE-induced neutrophilic airway inflammation and the levels of keratinocyte chemoattractant (KC), C-X-C motif ligand5 (CXCL5), interferon (IFN)-γ and IL-17. NEt-4IB also improved the matrix metalloproteinase-9 (MMP-9)/tissue inhibitor of metalloproteinase-1 (TIMP-1) imbalance and the reduced anti-oxidant activity in bronchoalveolar lavage (BAL) fluid. NEt-4IB suppressed PPE-induced vascular endothelial growth factor (VEGF) expression in the airway. Treatment with NEt-4IB and bexarotene significantly suppressed the increase in static lung compliance and emphysematous changes. However, adverse effects of RXR agonists, including hypertriglyceridemia and hepatomegaly, were observed in bexarotene-treated mice but not in NEt-4IB-treated mice. Conclusion: These data suggest that RXRs play crucial roles in emphysema and airway inflammation, and novel partial RXR agonists could be potential therapeutic strategies for the treatment of PPE- and CSE-induced emphysema.

Original languageEnglish
Article number2
JournalRespiratory Research
Volume20
Issue number1
DOIs
Publication statusPublished - Jan 3 2019

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Retinoid X Receptors
Pulmonary Emphysema
Emphysema
Inflammation
Pancreatic Elastase
Pancreas
Swine
Smoke
Tobacco Products
Lung Compliance
Cytoplasmic and Nuclear Receptors
Therapeutics
Retinoic Acid Receptors
Calcitriol Receptors
Peroxisome Proliferator-Activated Receptors
Tissue Inhibitor of Metalloproteinase-1
Hepatomegaly
Interleukin-17
Hypertriglyceridemia
Chemotactic Factors

Keywords

  • Anti-oxidant activity
  • Emphysema
  • Matrix metalloproteinase-9
  • Neutrophilic airway inflammation
  • Retinoid X receptor
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

A retinoid X receptor partial agonist attenuates pulmonary emphysema and airway inflammation. / Morichika, Daisuke; Miyahara, Nobuaki; Fujii, Utako; Taniguchi, Akihiko; Oda, Naohiro; Senoo, Satoru; Kataoka, Mikio; Tanimoto, Mitsune; Kakuta, Hiroki; Kiura, Katsuyuki; Maeda, Yoshinobu; Kanehiro, Arihiko.

In: Respiratory Research, Vol. 20, No. 1, 2, 03.01.2019.

Research output: Contribution to journalArticle

Morichika, Daisuke ; Miyahara, Nobuaki ; Fujii, Utako ; Taniguchi, Akihiko ; Oda, Naohiro ; Senoo, Satoru ; Kataoka, Mikio ; Tanimoto, Mitsune ; Kakuta, Hiroki ; Kiura, Katsuyuki ; Maeda, Yoshinobu ; Kanehiro, Arihiko. / A retinoid X receptor partial agonist attenuates pulmonary emphysema and airway inflammation. In: Respiratory Research. 2019 ; Vol. 20, No. 1.
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abstract = "Background: Retinoid X receptors (RXRs) are members of the nuclear receptor (NR) superfamily that mediate signalling by 9-cis retinoic acid, a vitamin A derivative. RXRs play key roles not only as homodimers but also as heterodimeric partners, e.g., for retinoic acid receptors, vitamin D receptors, and peroxisome proliferator-activated receptors. The NR family may also play important roles in the development of emphysema. However, the role of RXRs in the pathogenesis of emphysema is not well defined. Methods: We developed a novel RXR partial agonist (NEt-4IB) and investigated its effect and mechanism compared to a full agonist (bexarotene) in a murine model of emphysema. For emphysema induction, BALB/c mice received intraperitoneal cigarette smoke extract (CSE) or intratracheal porcine pancreas elastase (PPE). Treatment with RXR agonists was initiated before or after emphysema induction. Results: Treatment with NEt-4IB significantly suppressed the increase in static lung compliance and emphysematous changes in CSE-induced emphysema and PPE-induced established and progressive emphysema. NEt-4IB significantly suppressed PPE-induced neutrophilic airway inflammation and the levels of keratinocyte chemoattractant (KC), C-X-C motif ligand5 (CXCL5), interferon (IFN)-γ and IL-17. NEt-4IB also improved the matrix metalloproteinase-9 (MMP-9)/tissue inhibitor of metalloproteinase-1 (TIMP-1) imbalance and the reduced anti-oxidant activity in bronchoalveolar lavage (BAL) fluid. NEt-4IB suppressed PPE-induced vascular endothelial growth factor (VEGF) expression in the airway. Treatment with NEt-4IB and bexarotene significantly suppressed the increase in static lung compliance and emphysematous changes. However, adverse effects of RXR agonists, including hypertriglyceridemia and hepatomegaly, were observed in bexarotene-treated mice but not in NEt-4IB-treated mice. Conclusion: These data suggest that RXRs play crucial roles in emphysema and airway inflammation, and novel partial RXR agonists could be potential therapeutic strategies for the treatment of PPE- and CSE-induced emphysema.",
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author = "Daisuke Morichika and Nobuaki Miyahara and Utako Fujii and Akihiko Taniguchi and Naohiro Oda and Satoru Senoo and Mikio Kataoka and Mitsune Tanimoto and Hiroki Kakuta and Katsuyuki Kiura and Yoshinobu Maeda and Arihiko Kanehiro",
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AU - Morichika, Daisuke

AU - Miyahara, Nobuaki

AU - Fujii, Utako

AU - Taniguchi, Akihiko

AU - Oda, Naohiro

AU - Senoo, Satoru

AU - Kataoka, Mikio

AU - Tanimoto, Mitsune

AU - Kakuta, Hiroki

AU - Kiura, Katsuyuki

AU - Maeda, Yoshinobu

AU - Kanehiro, Arihiko

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N2 - Background: Retinoid X receptors (RXRs) are members of the nuclear receptor (NR) superfamily that mediate signalling by 9-cis retinoic acid, a vitamin A derivative. RXRs play key roles not only as homodimers but also as heterodimeric partners, e.g., for retinoic acid receptors, vitamin D receptors, and peroxisome proliferator-activated receptors. The NR family may also play important roles in the development of emphysema. However, the role of RXRs in the pathogenesis of emphysema is not well defined. Methods: We developed a novel RXR partial agonist (NEt-4IB) and investigated its effect and mechanism compared to a full agonist (bexarotene) in a murine model of emphysema. For emphysema induction, BALB/c mice received intraperitoneal cigarette smoke extract (CSE) or intratracheal porcine pancreas elastase (PPE). Treatment with RXR agonists was initiated before or after emphysema induction. Results: Treatment with NEt-4IB significantly suppressed the increase in static lung compliance and emphysematous changes in CSE-induced emphysema and PPE-induced established and progressive emphysema. NEt-4IB significantly suppressed PPE-induced neutrophilic airway inflammation and the levels of keratinocyte chemoattractant (KC), C-X-C motif ligand5 (CXCL5), interferon (IFN)-γ and IL-17. NEt-4IB also improved the matrix metalloproteinase-9 (MMP-9)/tissue inhibitor of metalloproteinase-1 (TIMP-1) imbalance and the reduced anti-oxidant activity in bronchoalveolar lavage (BAL) fluid. NEt-4IB suppressed PPE-induced vascular endothelial growth factor (VEGF) expression in the airway. Treatment with NEt-4IB and bexarotene significantly suppressed the increase in static lung compliance and emphysematous changes. However, adverse effects of RXR agonists, including hypertriglyceridemia and hepatomegaly, were observed in bexarotene-treated mice but not in NEt-4IB-treated mice. Conclusion: These data suggest that RXRs play crucial roles in emphysema and airway inflammation, and novel partial RXR agonists could be potential therapeutic strategies for the treatment of PPE- and CSE-induced emphysema.

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KW - Anti-oxidant activity

KW - Emphysema

KW - Matrix metalloproteinase-9

KW - Neutrophilic airway inflammation

KW - Retinoid X receptor

KW - Vascular endothelial growth factor

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