Biomolecules & Therapeutics

  • 제32권4호
  • /
  • Pages.460-466
  • /
  • 2024
  • /
  • 1976-9148(pISSN)
  • /
  • 2005-4483(eISSN)
한국응용약물학회 (The Korean Society of Applied Pharmacology)
권호 표지
DOI QR코드

DOI QR Code

Elafibranor PPARα/δ Dual Agonist Ameliorates Ovalbumin-Induced Allergic Asthma

  • Ye-Eul Lee (Department of Fundamental Pharmaceutical Sciences, Graduate School, Kyung Hee University) ;
  • Dong-Soon Im (Department of Fundamental Pharmaceutical Sciences, Graduate School, Kyung Hee University)
  • 투고 : 2023.11.05
  • 심사 : 2023.12.20
  • 발행 : 2024.07.01
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Asthma is characterized by chronic inflammation and respiratory tract remodeling. Peroxisome proliferator-activated receptors (PPARs) play important roles in the pathogenesis and regulation of chronic inflammatory processes in asthma. The role of PPARγ has been studied using synthetic PPARγ agonists in patients with asthma. However, involvement of PPARα/δ has not been studied in asthma. In the present study, we investigated if elafibranor, a PPARα/δ dual agonist, can modulate ovalbumin (OVA)-induced allergic asthma, which is a potential drug candidate for non-alcoholic fatty liver in obese patients. Elafibranor suppresses antigen-induced degranulation in RBL-2H3 mast cells without inducing cytotoxicity in vitro. In mice with OVA-induced allergic asthma, the administration of elafibranor suppressed OVA-induced airway hyper-responsiveness at a dose of 10 mg/kg. Elafibranor also suppressed the OVA-induced increase in immune cells and pro-inflammatory cytokine production in the bronchoalveolar lavage fluid (BALF). Histological studies suggested that elafibranor suppressed OVA-induced lung inflammation and mucin hyper-production in the bronchial airways. In addition, elafibranor suppressed OVA-induced increases in serum immunoglobulin E and IL-13 levels in BALF. Conversely, the present study suggests that elafibranor has the potential for use in patients with allergic asthma.

키워드

과제정보

This research was supported by the Basic Science Research Program of the Korean National Research Foundation funded by the Korean Ministry of Science, ICT, and Future Planning (NRF-2023R1A2C2002380).

참고문헌

  1. Anderson, J. R., Mortimer, K., Pang, L., Smith, K. M., Bailey, H., Hodgson, D. B., Shaw, D. E., Knox, A. J. and Harrison, T. W. (2016) Evaluation of the PPAR-γ agonist pioglitazone in mild asthma: a double-blind randomized controlled trial. PLoS One 11, e0160257.
  2. Ando, T. and Kitaura, J. (2021) Tuning IgE: IgE-associating molecules and their effects on ige-dependent mast cell reactions. Cells 10, 1697.
  3. Cariou, B., Hanf, R., Lambert-Porcheron, S., Zair, Y., Sauvinet, V., Noel, B., Flet, L., Vidal, H., Staels, B. and Laville, M. (2013) Dual peroxisome proliferator-activated receptor α/δ agonist GFT505 improves hepatic and peripheral insulin sensitivity in abdominally obese subjects. Diabetes Care 36, 2923-2930.
  4. Cariou, B., Zair, Y., Staels, B. and Bruckert, E. (2011) Effects of the new dual PPAR α/δ agonist GFT505 on lipid and glucose homeostasis in abdominally obese patients with combined dyslipidemia or impaired glucose metabolism. Diabetes Care 34, 2008-2014.
  5. Cheng, Y., Li, S., Wang, M., Cheng, C. and Liu, R. (2018) Peroxisome proliferator activated receptor gamma (PPARγ) agonist rosiglitazone ameliorate airway inflammation by inhibiting toll-like receptor 2 (TLR2)/nod-like receptor with pyrin domain containing 3 (NLRP3) inflammatory corpuscle activation in asthmatic mice. Med. Sci. Monit. 24, 9045-9053.
  6. Chung, K. F., Caramori, G. and Adcock, I. M. (2009) Inhaled corticosteroids as combination therapy with beta-adrenergic agonists in airways disease: present and future. Eur. J. Clin. Pharmacol. 65, 853-871.
  7. Contreras, A. V., Torres, N. and Tovar, A. R. (2013) PPAR-α as a key nutritional and environmental sensor for metabolic adaptation. Adv. Nutr. 4, 439-452.
  8. Dharmage, S. C., Perret, J. L. and Custovic, A. (2019) Epidemiology of asthma in children and adults. Front. Pediatr. 7, 246.
  9. Dixon, A. E., Subramanian, M., DeSarno, M., Black, K., Lane, L. and Holguin, F. (2015) A pilot randomized controlled trial of pioglitazone for the treatment of poorly controlled asthma in obesity. Respir. Res. 16, 143.
  10. Fehrenbach, H., Wagner, C. and Wegmann, M. (2017) Airway remodeling in asthma: what really matters. Cell Tissue Res. 367, 551-569.
  11. Hamelmann, E., Schwarze, J., Takeda, K., Oshiba, A., Larsen, G. L., Irvin, C. G. and Gelfand, E. W. (1997) Noninvasive measurement of airway responsiveness in allergic mice using barometric plethysmography. Am. J. Respir. Crit. Care Med. 156, 766-775.
  12. Hou, Y., Moreau, F. and Chadee, K. (2012) PPARγ is an E3 ligase that induces the degradation of NFκB/p65. Nat. Commun. 3, 1300.
  13. Kaler, M., Barochia, A. V., Weir, N. A., Cuento, R. A., Stylianou, M., Roth, M. J., Filie, A. C., Vaughey, E. C., Nathan, S. D. and Levine, S. J. (2017) A randomized, placebo-controlled, double-blinded, crossover trial of pioglitazone for severe asthma. J. Allergy Clin. Immunol. 140, 1716-1718.
  14. Khan, R. S., Bril, F., Cusi, K. and Newsome, P. N. (2019) Modulation of insulin resistance in nonalcoholic fatty liver disease. Hepatology 70, 711-724.
  15. Lee, J.-H. and Im, D.-S. (2021) 4-CMTB ameliorates ovalbumin-induced allergic asthma through FFA2 activation in mice. Biomol. Ther. (Seoul) 29, 427-433.
  16. Luo, W., Hu, J., Xu, W. and Dong, J. (2022) Distinct spatial and temporal roles for Th1, Th2, and Th17 cells in asthma. Front. Immunol. 13, 974066.
  17. Neels, J. G. and Grimaldi, P. A. (2014) Physiological functions of peroxisome proliferator-activated receptor β. Physiol. Rev. 94, 795-858.
  18. Nobs, S. P., Natali, S., Pohlmeier, L., Okreglicka, K., Schneider, C., Kurrer, M., Sallusto, F. and Kopf, M. (2017) PPARγ in dendritic cells and T cells drives pathogenic type-2 effector responses in lung inflammation. J. Exp. Med. 214, 3015-3035.
  19. Ratziu, V., Harrison, S. A., Francque, S., Bedossa, P., Lehert, P., Serfaty, L., Romero-Gomez, M., Boursier, J., Abdelmalek, M., Caldwell, S., Drenth, J., Anstee, Q. M., Hum, D., Hanf, R., Roudot, A., Megnien, S., Staels, B. and Sanyal, A. (2016) Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology 150, 1147-1159.e5.
  20. Richards, D. B., Bareille, P., Lindo, E. L., Quinn, D. and Farrow, S. N. (2010) Treatment with a peroxisomal proliferator activated receptor gamma agonist has a modest effect in the allergen challenge model in asthma: a randomised controlled trial. Respir. Med. 104, 668-674.
  21. Rujitharanawong, C., Yoodee, S., Sueksakit, K., Peerapen, P., Tuchinda, P., Kulthanan, K. and Thongboonkerd, V. (2022) Systematic comparisons of various markers for mast cell activation in RBL-2H3 cells. Cell Tissue Res. 390, 413-428.
  22. Su, X., Zhou, G., Wang, Y., Yang, X., Li, L., Yu, R. and Li, D. (2014) The PPARβ/δ agonist GW501516 attenuates peritonitis in peritoneal fibrosis via inhibition of TAK1-NFκB pathway in rats. Inflammation 37, 729-737.
  23. Tacke, F. and Weiskirchen, R. (2021) Non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH)-related liver fibrosis: mechanisms, treatment and prevention. Ann. Transl. Med. 9, 729.
  24. Westerouen Van Meeteren, M. J., Drenth, J. P. H. and Tjwa, E. (2020) Elafibranor: a potential drug for the treatment of nonalcoholic steatohepatitis (NASH). Expert Opin. Investig. Drugs 29, 117-123.