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Dive Deeper into COPD and IL-33

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Frequently asked questions

IL-33 is a cytokine that is released upon epithelial damage at the top of the inflammatory cascade. There are 2 forms of IL-33 (reduced and oxidized) that each distinctly contribute to many symptom manifestations. Dysregulation of the dual IL-33 pathways is associated with airway inflammation and mucus and epithelial dysfunction, and can contribute to the pathophysiology of COPD.1-6

References: 1. Strickson S, et al. Eur Respir J. 2023;62(3):2202210. doi:10.1183/13993003.02210-2022 2. Rabe KF, et al. Am J Respir Crit Care Med. 2023;208(4):395-405. doi:10.1164/rccm.202303-0455CI 3. Calderon AA, et al. Eur Respir Rev. 2023;32(167):220144. doi:10.1183/16000617.0144-2022 4. Hiemstra PS, et al. Eur Respir J. 2023;62(3):2301301. doi:10.1183/13993003.01301-2023 5. Gabryelska A, et al. Front Immunol. 2019;10:692. doi:10.3389/fimmu.2019.00692 6. Donovan C, et al. ACS Pharmacol Transl Sci. 2020;3(1):56-62. doi:10.1021/acsptsci.9b00099

Data suggest IL-33 RED activates inflammation through the ST2 pathway, while IL-33 OX triggers mucus hypersecretion and impairs epithelial repair via the RAGE/EGFR pathway.1-4

References: 1. Strickson S, et al. Eur Respir J. 2023;62(3):2202210. doi:10.1183/13993003.02210-2022 2. Rabe KF, et al. Am J Respir Crit Care Med. 2023;208(4):395-405. doi:10.1164/rccm.202303-0455CI 3. Gabryelska A, et al. Front Immunol. 2019;10:692. doi:10.3389/fimmu.2019.00692 4. Donovan C, et al. ACS Pharmacol Transl Sci. 2020;3(1):56-62. doi:10.1021/acsptsci.9b00099

IL-33 can increase the risk of COPD exacerbations. IL-33 is associated with a twofold increased risk of exacerbations over 1 year.1,2

References: 1. Kim SW, et al. Int J Chron Obstruct Pulmon Dis. 2017;12:395-402. doi:10.2147/COPD.S120445 2. Joo H, et al. BMC Pulm Med. 2021;21(1):86. doi:10.1186/s12890-021-01423-8

Common symptoms in COPD include1-6:

  • Dyspnea
  • Cough
  • Wheezing
  • Fatigue
  • Excess mucus

In addition to dyspnea, serious risks in COPD are driven by mucus.

References: 1. Global Initiative for Chronic Obstructive Lung Disease. Accessed July 2026. https://goldcopd.org/2026-gold-report-and-pocket-guide/ 2. World Health Organization. Accessed July 2026. https://www.who.int/news-room/fact-sheets/detail/chronic-obstructive-pulmonary-disease-(copd) 3. Strickson S, et al. Eur Respir J. 2023;62(3):2202210. doi:10.1183/13993003.02210-2022 4. Jin KN, et al. Arch Bronconeumol. 2025;61(3):138-146. doi:10.1016/j.arbres.2024.07.017 5. Mettler SK, et al. N Engl J Med. 2025;392(19):1973-1975. doi:10.1056/NEJMc2502456 6. Mettler SK, et al. Chest. 2024;166(5):1010-1019. doi:10.1016/j.chest.2023.11.033

IL-33 is associated with mucus dysfunction—hypersecretion, impaired clearance, and mucus plugs—increasing airflow obstruction and exacerbation risk. Data
suggest IL-33 OX triggers mucus hypersecretion and impairs epithelial repair.1-8

References: 1. Strickson S, et al. Eur Respir J. 2023;62(3):2202210. doi:10.1183/13993003.02210-2022 2. Jin KN, et al. Arch Bronconeumol. 2025;61(3):138-146. doi:10.1016/j.arbres.2024.07.017 3. Mettler SK, et al. N Engl J Med. 2025;392(19):1973-1975. doi:10.1056/NEJMc2502456 4. Mettler SK, et al. Chest. 2024;166(5):1010-1019. doi:10.1016/j.chest.2023.11.033 5. Wei Y, et al. Int J Chron Obstruct Pulmon Dis. 2025;20:2581-2587. doi:10.2147/COPD.S514152 6. Borger JG, et al. Front Immunol. 2019;10:1597. doi:10.3389/fimmu.2019.01597 7. Shah BK, et al. Mediators Inflamm. 2023;2023:8840594. doi:10.1155/2023/8840594 8. Washko G, et al. Poster presented at: American Thoracic Society (ATS) International Conference 2026; May 15–20, 2026; Orlando, FL, USA. Poster D96-08.

 

Exacerbations can contribute to repeated OCS and antibiotic use. In a study of patients with COPD over a 1-year baseline period*1-4:

  • 90% of patients received ≥1 OCS prescription with an average exposure of 73 days
  • ~90% of patients had ≥1 prescription for antibiotics corresponding to a mean annual exposure of 45 days

* Data from follow-up period (mean duration 21.2 months) of SIRIUS, a US retrospective cohort study of patients with COPD (N=4920) with 1 year of continuous triple therapy and a history of frequent exacerbations, defined as ≥2 moderate or ≥1 severe exacerbation per year during 12-month baseline period. Study used Optum integrated claims and electronic health record database (study period: 2015-2019).

References: 1. Kim SW, et al. Int J Chron Obstruct Pulmon Dis. 2017;12:395-402. doi:10.2147/COPD.S12044 2. Riera-Martínez L, et al. Int J Mol Sci. 2023;24(10):8702. doi:10.3390/ijms24108702 3. Nordon C, et al. Int J Chron Obstruct Pulmon Dis. 2025;20:1851-1864. doi:10.2147/COPD.S513573 4. Nordon C, et al. Poster presented at: European Respiratory Society (ERS) Congress 2024; September 7-11, 2024; Vienna, Austria. Poster PA1287.

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ATS=American Thoracic Society; COPD=chronic obstructive pulmonary disease; EGFR=epidermal growth factor receptor; IL=interleukin; MSL=medical science liaison; OCS=oral corticosteroid; OX=oxidized; RAGE=receptor for advanced glycation end-products; RED=reduced; ST2=suppression of tumorigenicity 2 (also known as serum stimulation-2).