Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지
DOI QR코드

DOI QR Code

Selonsertib, an ASK1 Inhibitor, Ameliorates Ovalbumin-Induced Allergic Asthma during Challenge and Sensitization Periods

  • So-Young Han (Department of Fundamental Pharmaceutical Sciences, Graduate School, Kyung Hee University) ;
  • Dong-Soon Im (Department of Fundamental Pharmaceutical Sciences, Graduate School, Kyung Hee University)
  • Received : 2023.11.16
  • Accepted : 2024.02.20
  • Published : 2024.07.01
Download PDF
⟨ Previous Next ⟩

Abstract

Apoptosis signal-regulating kinase 1 (ASK1) is an upstream signaling molecule in oxidative stress-induced responses. Because oxidative stress is involved in asthma pathogenesis, ASK1 gene deficiency was investigated in animal models of allergic asthma. However, there is no study to investigate whether ASK1 inhibitors could be applied for asthma to date. Selonsertib, a potent and selective ASK1 inhibitor, was applied to BALB/c mice of an ovalbumin (OVA)-induced allergic asthma model. Selonsertib suppressed antigen-induced degranulation of RBL-2H3 mast cells in a concentration-dependent manner. The administration of selonsertib both before OVA sensitization and OVA challenge significantly reduced airway hyperresponsiveness, and suppressed eosinophil numbers and inflammatory cytokine levels in the bronchoalveolar lavage fluid. Histopathologic examination elucidated less inflammatory responses and reduced mucin-producing cells around the peribronchial regions of the lungs. Selonsertib also suppressed the IgE levels in serum and the protein levels of IL-13 in the bronchoalveolar lavage fluid. These results suggest that selonsertib may ameliorate allergic asthma by suppressing immune responses and be applicable to allergic asthma.

Keywords

Acknowledgement

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).

References

  1. Deo, S. S., Mistry, K. J., Kakade, A. M. and Niphadkar, P. V. (2010) Role played by Th2 type cytokines in IgE mediated allergy and asthma. Lung India 27, 66-71. https://doi.org/10.4103/0970-2113.63609
  2. Eapen, M. S., Kota, A., Vindin, H., McAlinden, K. D., Xenaki, D., Oliver, B. G., Deshpande, D. A., Sohal, S. S. and Sharma, P. (2018) Apoptosis signal-regulating kinase 1 inhibition attenuates human airway smooth muscle growth and migration in chronic obstructive pulmonary disease. Clin. Sci. 132, 1615-1627. https://doi.org/10.1042/CS20180398
  3. Holgate, S. T. (2008) Pathogenesis of asthma. Clin. Exp. Allergy 38, 872-897. https://doi.org/10.1111/j.1365-2222.2008.02971.x
  4. Holgate, S. T. (2011) The sentinel role of the airway epithelium in asthma pathogenesis. Immunol. Rev. 242, 205-219. https://doi.org/10.1111/j.1600-065X.2011.01030.x
  5. Hoshino, T., Okamoto, M., Takei, S., Sakazaki, Y., Iwanaga, T. and Aizawa, H. (2008) Redox-regulated mechanisms in asthma. Antioxid. Redox Signal. 10, 769-784. https://doi.org/10.1089/ars.2007.1936
  6. Ichiki, H., Hoshino, T., Kinoshita, T., Imaoka, H., Kato, S., Inoue, H., Nakamura, H., Yodoi, J., Young, H. A. and Aizawa, H. (2005) Thioredoxin suppresses airway hyperresponsiveness and airway inflammation in asthma. Biochem. Biophys. Res. Commun. 334, 1141-1148. https://doi.org/10.1016/j.bbrc.2005.07.007
  7. Imaoka, H., Hoshino, T., Takei, S., Sakazaki, Y., Kinoshita, T., Okamoto, M., Kawayama, T., Yodoi, J., Kato, S., Iwanaga, T. and Aizawa, H. (2007) Effects of thioredoxin on established airway remodeling in a chronic antigen exposure asthma model. Biochem. Biophys. Res. Commun. 360, 525-530. https://doi.org/10.1016/j.bbrc.2007.06.019
  8. Lee, J.-H. and Im, D.-S. (2021a) 4-CMTB ameliorates ovalbumininduced allergic asthma through FFA2 activation in mice. Biomol. Ther. (Seoul) 29, 427-433. https://doi.org/10.4062/biomolther.2020.176
  9. Lee, J.-H., Son, S.-H., Kim, N.-J. and Im, D.-S. (2022) NJK14047 suppression of the p38 MAPK ameliorates OVA-induced allergic asthma during sensitization and challenge periods. Biomol. Ther. (Seoul) 31, 183-192.
  10. Lee, J. E. and Im, D. S. (2021b) Suppressive effect of carnosol on ovalbumin-induced allergic asthma. Biomol. Ther. (Seoul) 29, 58-63. https://doi.org/10.4062/biomolther.2020.050
  11. Lee, Y.-J. and Im, D.-S. (2022) Efficacy comparison of LPA2 antagonist H2L5186303 and agonist GRI977143 on ovalbumin-induced allergic asthma in BALB/c mice. Int. J. Mol. Sci. 23, 9745.
  12. Loomba, R., Lawitz, E., Mantry, P. S., Jayakumar, S., Caldwell, S. H., Arnold, H., Diehl, A. M., Djedjos, C. S., Han, L., Myers, R. P., Subramanian, G. M., McHutchison, J. G., Goodman, Z. D., Afdhal, N. H. and Charlton, M. R. (2018) The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: a randomized, phase 2 trial. Hepatology 67, 549-559. https://doi.org/10.1002/hep.29514
  13. Maruoka, S., Gon, Y., Mizumura, K., Okamoto, S., Tsuya, K., Shikano, S., Soda, K., Naguro, I., Ichijo, H. and Hashimoto, S. (2017) Involvement of apoptosis signal-regulating kinase-1 in house dust miteinduced allergic asthma in mice. Allergol. Int. 66, S50-S52. https://doi.org/10.1016/j.alit.2017.05.007
  14. Matsuzawa, A., Saegusa, K., Noguchi, T., Sadamitsu, C., Nishitoh, H., Nagai, S., Koyasu, S., Matsumoto, K., Takeda, K. and Ichijo, H. (2005) ROS-dependent activation of the TRAF6-ASK1-p38 pathway is selectively required for TLR4-mediated innate immunity. Nat. Immunol. 6, 587-592. https://doi.org/10.1038/ni1200
  15. O'Byrne, P. M., Gauvreau, G. M. and Murphy, D. M. (2009) Efficacy of leukotriene receptor antagonists and synthesis inhibitors in asthma. J. Allergy Clin. Immunol. 124, 397-403. https://doi.org/10.1016/j.jaci.2009.05.029
  16. Pawankar, R. (2014) Allergic diseases and asthma: a global public health concern and a call to action. World Allergy Organ. J. 7, 12.
  17. Pelaia, G., Cuda, G., Vatrella, A., Gallelli, L., Caraglia, M., Marra, M., Abbruzzese, A., Caputi, M., Maselli, R. and Costanzo, F. S. (2005) Mitogen-activated protein kinases and asthma. J. Cell. Physiol. 202, 642-653. https://doi.org/10.1002/jcp.20169
  18. Psenakova, K., Hexnerova, R., Srb, P., Obsilova, V., Veverka, V. and Obsil, T. (2020) The redox-active site of thioredoxin is directly involved in apoptosis signal-regulating kinase 1 binding that is modulated by oxidative stress. FEBS J. 287, 1626-1644. https://doi.org/10.1111/febs.15101
  19. Rouillard, M. M. (2022) The role of ASK1 in allergen-mediated mast cell signaling and activation-dependent inflammatory responses. Master thesis. Brock University, St. Catharines, ON.
  20. Saitoh, M., Nishitoh, H., Fujii, M., Takeda, K., Tobiume, K., Sawada, Y., Kawabata, M., Miyazono, K. and Ichijo, H. (1998) Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. EMBO J. 17, 2596-2606. https://doi.org/10.1093/emboj/17.9.2596
  21. Sibilano, R., Frossi, B. and Pucillo, C. E. (2014) Mast cell activation: a complex interplay of positive and negative signaling pathways. Eur. J. Immunol. 44, 2558-2566. https://doi.org/10.1002/eji.201444546
  22. Son, S.-E., Koh, J.-M. and Im, D.-S. (2022) Activation of free fatty acid receptor 4 (FFA4) ameliorates ovalbumin-induced allergic asthma by suppressing activation of dendritic and mast cells in mice. Int. J. Mol. Sci. 23, 5270.
  23. Sujitha, S., Dinesh, P. and Rasool, M. (2018) Berberine modulates ASK1 signaling mediated through TLR4/TRAF2 via upregulation of miR-23a. Toxicol. Appl. Pharmacol. 359, 34-46. https://doi.org/10.1016/j.taap.2018.09.017
  24. Takada, E., Furuhata, M., Nakae, S., Ichijo, H., Sudo, K. and Mizuguchi, J. (2013) Requirement of apoptosis-inducing kinase 1 for the induction of bronchial asthma following stimulation with ovalbumin. Int. Arch. Allergy Immunol. 162, 104-114. https://doi.org/10.1159/000353240
  25. Valenca, S. S., Dong, B. E., Gordon, E. M., Sun, R. C. and Waters, C. M. (2022) ASK1 regulates bleomycin-induced pulmonary fibrosis. Am. J. Respir. Cell Mol. Biol. 66, 484-496. https://doi.org/10.1165/rcmb.2021-0465OC
  26. Warner, J. and Kroegel, C. (1994) Pulmonary immune cells in health and disease: mast cells and basophils. Eur. Respir. J. 7, 1326-1341. https://doi.org/10.1183/09031936.94.07071326