Chronic Obstructive Pulmonary Disease

Outline

Think About COPD
- Is it time to think differently about COPD?
- Partnering to Support Healthcare Providers
Exacerbation Consequences
COPD Pathobiology
Scientific Resources

Think About COPD
Exacerbation Consequences
COPD Pathobiology
Scientific Resources

Think About COPD

Is it time to think differently about COPD?

Icons of people overlaid on a map of the United States

COPD remains a major healthcare burden and a leading cause of death in the United States^1-5

~11.7 million people are diagnosed with COPD in the US, representing ~4.6% of the adult population.^,a

Picture of an elderly man with oxygen sitting on a bench

Why don't we think about COPD Exacerbations the same way as heart attacks?

The consequences of COPD exacerbations can be severe, yet delays in care and proactive management remain. Experts note that despite the negative impacts on morbidity and mortality, the term "COPD exacerbation" does not confer the same urgency as terms used for acute events in other diseases.

Picture of two people at a table having a discussion with a healthcare provider

COPD is a complex and heterogeneous disease⁸

Take a deeper dive into COPD pathobiology, including how IL-33 dysregulation may play a role in COPD.

Partnering to Support Healthcare Providers

The AstraZeneca Medical Team is Committed to Supporting the Improvement of COPD Care

Explore our Resources

Browse resources for healthcare providers, including slide decks, infographics, videos, and more

Icon of two people having a conversation

Connect with an MSL

Contact the Medical Science Liaison in your region to learn more about COPD.

Next: Exacerbation Consequences

Exacerbation Consequences

"Many exacerbations are not reported to healthcare professionals, and yet these events, although often shorter in duration, have a significant impact on health status"

Icon of the lungs with a magnifying glass

Disease Activity and Stability Are Now Recognized by the GOLD Report⁸

The GOLD report recommends that a key objective of COPD management should be to reduce disease activity with the aim that patients have:

NO exacerbations
NO worsening of symptoms
NO accelerated loss of lung function

COPD Exacerbations and Lung Function

Line Graph showing the mean change in FEV1 from -8 to 8 weeks after an exacerbation illustrating an FEV1 loss of approx. 32 mL

Exacerbations can irreversibly reduce lung function¹¹^,a

Following an exacerbation, lung function may not recover to pre-exacerbation levels¹¹
In some patients, there was still a loss of lung function 8 weeks following an exacerbation¹¹

Associations Between COPD Symptoms, Exacerbations, Cardiovascular Events, and Mortality

Image showing the relationship between symptoms, COPD exacerbations, cardiovascular event(s) and early death

COPD Exacerbations can Lead to Cardiopulmonary Events, Including Premature Death¹²

Click the labels below to explore data behind each association

Increasing symptoms have been associated with an increased risk of exacerbations^13,14

Moderate-to-severe exacerbation frequency during 12 months follow-up¹³^,a

^aRetrospective observational cohort study that evaluated risk factors associated with exacerbation frequency in 58,589 patients with COPD identified from primary care in the UK Clinical Practice Research Datalink.¹³

Exacerbation history can predict future events¹⁵

Baseline Exacerbations and Risks for Future Events¹⁵^,a,b

^aRetrospective cohort study of Medicare FFS claims data in ~1.5 million patients with COPD that quantified the type and frequency of COPD exacerbations over three years by prior exacerbation history.

^bRate of moderate or severe exacerbations expressed as per patient-year.

Increased Risk of CV Events May Persist for Up to a Year After an Exacerbation¹⁶

Risk of CV Events in Patients With COPD and Existing or Risk Factors for CVD¹⁶

^aPost-hoc analysis of the SUMMIT trial (n=16,485) was performed to determine whether the risk for CV events increases after a moderate/severe COPD exacerbation.

^bSevere COPD exacerbation.

Risk of All-cause Mortality Was Greatest in the First Month After an Exacerbation

The 30-day risk of all-cause mortality was ~3.4-fold higher following 2^nd and 3^rd exacerbations compared to those with one or two, respectively.¹⁷

Hazard Ratios of All-Cause Mortality by Duration of Follow-up¹⁷

Retrospective cohort study of just over 395,000 patients with newly diagnosed COPD between January 1, 2012 and December 31, 2019 using the US Healthcare Integrated Research Database to estimate the incidence of acute CV events and all-cause mortality following an exacerbation compared to the incidence in the absence of an exacerbation. Patients were excluded if they had an acute CV event within 6 months of their index date.
^aAdjusted for baseline demographics, comorbidities, and medications.

COPD-driven Cardiopulmonary Risk

Cardiopulmonary Risk

The risk of serious respiratory and/or CV events in patients with COPD include but are not limited to:

COPD exacerbation
MI
Stroke
HF decompensation
Arrhythmia
Death owing to any of these events

Potential Core Mechanisms of COPD-driven Cardiopulmonary Risk

EXACERBATIONS can be a...

Inflammation

Lung inflammation can trigger systemic inflammation, resulting in atherothrombosis in the heart and vasculature

Hyperinflation

Hyperinflation compresses the heart, hinders blood pumping and oxygenation

Hypoxemia

Hypoxic vasoconstriction in the lungs can cause pulmonary hypertension, which can result in right heart failure and reduced cardiac output

Featured Resource

Learn From Our Medical Team

Listen to a Medical Science Liaison discuss the concept of COPD‑driven cardiopulmonary risk.

Time to Raise the Standards of Care for Patients With COPD

Identify At-Risk Patients^12,24

Symptomatic patients or patients with a recent history of exacerbations¹³

Optimize Management^8,24

Prevent exacerbations, CV complications, and decrease risk of mortality²⁴

Timing of Care⁸

Help improve outcomes with a more proactive disease management approach⁸

Previous: Think About COPD

Next: COPD Pathobiology

COPD Pathobiology

COPD is characterized by Chronic Inflammation, Airway Remodeling and Mucus Dysfunction^25-28

Inflammation

Environmental insults and epithelial damage can result in chronic inflammation and airway narrowing. This can lead to worsening COPD symptoms and increased exacerbation risk.

Mucus Dysfunction

Mucus dysfunction includes mucus hypersecretion, impaired airway clearance, and mucus plugging. This can result in airway obstruction, structural damage, and increased exacerbation risk.

IL-33 in COPD

IL-33 is a cytokine produced by epithelial, endothelial, and other structural cells. IL-33 can drive inflammation, mucus and epithelial dysfunction.

Inflammation in COPD

In the majority of patients with COPD, inflammation is predominantly non-eosinophilic. While a subset of patients can exhibit eosinophilic inflammation, the immunology of inflammation in COPD is complex.^26,31,32

Explore the diagrams below to learn more about inflammation in COPD

Multiple Inflammatory Processes Contribute to the Heterogeneous Pathology of COPD^26,31

Figure adapted from Calderon AA, et al. Eur Respir Rev. 2023;32(167):220144 and Brightling C, Greening N. Eur Respir J. 2019;54(2):1900651.

Please note that the proposed inflammatory pathways in COPD shown here have been simplified for illustration purposes only and do not align with specific disease pathology or clinical manifestations, nor do they imply clinical benefit or relevance.

Alarmins are Key Drivers of Inflammatory Responses in Disease Pathogenesis^33-42

Figure adapted from Calderon AA, et al. Eur Respir Rev. 2023;32(167):220144.

IL-33 May Drive COPD Pathophysiology by Affecting a Variety of Downstream Cell Types^{26,28,31-33,39,43-47}

Figure adapted from Calderon AA, et al. Eur Respir Rev. 2023;32(167):220144.

Multiple Inflammatory Processes Contribute to the Heterogeneous Pathology of COPD^26,31

Figure adapted from Calderon AA, et al. Eur Respir Rev. 2023;32(167):220144 and Brightling C, Greening N. Eur Respir J. 2019;54(2):1900651.

Please note that the proposed inflammatory pathways in COPD shown here have been simplified for illustration purposes only and do not align with specific disease pathology or clinical manifestations, nor do they imply clinical benefit or relevance.

Alarmins are Key Drivers of Inflammatory Responses in Disease Pathogenesis^33-42

Figure adapted from Calderon AA, et al. Eur Respir Rev. 2023;32(167):220144.

IL-33 May Drive COPD Pathophysiology by Affecting a Variety of Downstream Cell Types^{26,28,31-33,39,43-47}

Figure adapted from Calderon AA, et al. Eur Respir Rev. 2023;32(167):220144.

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Featured Resource

Learn From Our Medical Team

Immunology diagrams can be confusing. Listen to our Medical team discuss the science behind inflammation in COPD to simplify the complexity.

Mucus Dysfunction in COPD

Image of the airway epithelial with mucus

Mucus dysfunction is central to the pathology of COPD.²⁷

Click each tab below to explore the 3 elements of mucus dysfunction

Mucus Hypersecretion is associated with

COPD symptoms such as productive cough and dyspnea^48,49
Disrupted basal cell differentiation⁵⁰
Impaired ciliary clearance, infection, and microbial growth⁵¹

Impaired Airway Clearance

Repeated epithelial injury, particularly from cigarette smoke, can result in impaired ciliary function^50,52
Defective mucociliary clearance allows mucus to accumulate in the airways and may form luminal plugs, contributing to airflow obstruction⁵²

Mucus Plugging

Mucus plugs have been observed in up to 67% of CT scans of patients with COPD and increase in prevalence with GOLD staging^53-55
Mucus plug formation may persist in patients with COPD over a 5-year period⁵⁴
Viscous mucus obstructs the airways and causes airway occlusion^55,56
High mucus plug scores are associated with accelerated lung function decline and increased all-cause mortality^54,57

Representative CT image of a patient with COPD who showed a mucus plug in the airway⁵⁸

Image from Computed tomography mucus plugs and airway tree structure in patients with chronic obstructive pulmonary disease: associations with airflow limitation, health-related independence and mortality by Tanabe N, et al. Respirology. 2024;29:951-961.

Licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/)

Mucus Hypersecretion
Impaired Airway Clearance
Mucus Plugging

Mucus Hypersecretion is associated with

COPD symptoms such as productive cough and dyspnea^48,49
Disrupted basal cell differentiation⁵⁰
Impaired ciliary clearance, infection, and microbial growth⁵¹

Impaired Airway Clearance

Repeated epithelial injury, particularly from cigarette smoke, can result in impaired ciliary function^50,52
Defective mucociliary clearance allows mucus to accumulate in the airways and may form luminal plugs, contributing to airflow obstruction⁵²

Mucus Plugging

Mucus plugs have been observed in up to 67% of CT scans of patients with COPD and increase in prevalence with GOLD staging^53-55
Mucus plug formation may persist in patients with COPD over a 5-year period⁵⁴
Viscous mucus obstructs the airways and causes airway occlusion^55,56
High mucus plug scores are associated with accelerated lung function decline and increased all-cause mortality^54,57

Representative CT image of a patient with COPD who showed a mucus plug in the airway⁵⁸

Image from Computed tomography mucus plugs and airway tree structure in patients with chronic obstructive pulmonary disease: associations with airflow limitation, health-related independence and mortality by Tanabe N, et al. Respirology. 2024;29:951-961.

Licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/)

Featured Resource

Mucus Dysfunction in COPD Infographic

This resource explores the role of mucus dysfunction in COPD. It discusses the clinical impacts as well as the mechanisms underlying mucus dysfunction.

IL-33 in COPD

Image of the reduced IL-33 and oxidized IL-33 pathways

There are two forms of IL‑33 which contribute to a cycle of downstream inflammation, mucus dysfunction, and impaired epithelial repair.^28,34,59

Dysregulation of IL‑33 RED and IL‑33 OX triggers dual pathways, which may drive distinct manifestations.

Increased IL-33 expression has been observed in both sputum and serum samples from patients with COPD relative to healthy controls⁶⁰
Increased levels of circulating IL-33 in patients with COPD were found to be associated with chronic bronchitis and COPD exacerbations^61,62

IL-33 and Associated Features in COPD^61,62

^aThis study defined chronic bronchitis as phlegm for ≥3 months per year.⁶¹

^bIn this analysis of 307 patients from the COPD Korean Obstructive Lung Disease cohort, IL-33 levels above the median IL-33 level of the cohort were defined as high, with all values below the median defined as low. At baseline, the median IL-33 level was 11.9 pg/mL (interquartile range 7.9-30.6).⁶¹

^cIn this analysis of 62 patients with COPD based in Korea, levels of IL-33 in the upper quartile of the cohort were defined as high, with all levels below this value defined as low. Patients were prospectively followed for 1 year and monitored for exacerbation.⁶²

^dNumber of exacerbations per year (±SD): Low IL-33 group = 0.40 (±0.62) and High IL-33 group = 1.00 (±1.16)⁶²

Featured Resource

Interested to Learn Even More about IL-33?

Unpack the Burden of IL-33 in COPD at dualcopdburden.com

Previous: Exacerbation Consequences

Next: Scientific Resources

Scientific Resources

This page offers scientific resources related to COPD, including videos, slide decks, and infographics. Our AstraZeneca Medical team has created this content as an information service for healthcare professionals and is not intended for patient education. Updates are made as new content becomes available.

Featured Resources

Infographic

Transition of Care Discharge Checklist

Transition of care discharge checklist for patients with COPD discharged after a COPD hospitalization

Slide Deck

Overview of COPD and the GOLD 2026 Report

This presentation reviews the pathophysiology and management of COPD, including an overview of the updated GOLD 2026 Report

Website

dualCOPDburden.com

This resource helps unpack the burden of IL‑33 in COPD and explores the dual pathways of inflammation and mucus dysfunction.

Slide Decks

Icon of a person pointing to a presentation

PRIMUS Study Overview Slide Deck

This presentation provides an overview of the analysis of triple therapy initiation following a disease exacerbation among patients with chronic obstructive pulmonary disease (PRIMUS)

COPD Pathophysiology and Management of Disease-GOLD 2026

This presentation reviews the pathophysiology of COPD and the updated GOLD 2026 Report

Infographics

GOLD 2026 Quick Reference

This infographic provides a 2 page overview of key figures from the GOLD 2026 report

Achieving Health Equity Through Race-Neutral Spirometry

2-page infographic illustrates the evolution of race-based spirometry and its implications for COPD diagnosis across diverse patient populations

Transition of Care Discharge Checklist

Transition of care discharge checklist for patients with COPD discharged after a COPD hospitalization

Mucus Dysfunction in COPD

This resource explores the role of mucus dysfunction in COPD. It discusses the clinical impacts as well as the mechanisms underlying mucus dysfunction.

The Dual Role of IL-33 in COPD

This infographic provides an overview of the role of IL-33 in driving inflammation, mucus dysfunction, and epithelial dysfunction in COPD.

Videos

An Animated Exploration of the PRIMUS Study

This video is a brief overview of the PRIMUS study in a whiteboard-style animation

Exploring the Science Behind IL-33

Hear from two experts at AstraZeneca as they discuss the biology of IL‑33 and the history of discoveries in IL‑33 Science.

COPD Immunology Explained

Learn From the AZMedical Team about the different types of inflammation in COPD.

The Dual Role of IL-33 in COPD

This video provides an overview of the role of IL-33 in driving inflammation, mucus dysfunction, and epithelial dysfunction in COPD.

COPD-Driven Cardiopulmonary Risk

Learn From the AZMedical Team about the concept of COPD-driven cardiopulmonary risk

Publications

This section provides links to AstraZeneca publications that present data and real-world evidence from studies on COPD. Each link directs to the publisher's website. Your ability to access the full text of these publications at these links may be dependent on whether you or your institution subscribes to this content.

Cardiopulmonary Risk Review Paper

Implications of Cardiopulmonary Risk for the Management of COPD: A Narrative Review

PRIMUS

Prompt Initiation of Maintenance Therapy in the US: A Real-World Analysis of Clinical and Economic Outcomes Among Patients Initiating Triple Therapy Following a COPD Exacerbation

CONQUEST 1

CONQUEST Quality Standards: For the Collaboration on Quality Improvement Initiative for Achieving Excellence in Standards of COPD Care

CONQUEST 2

CONQUEST: A Quality Improvement Program for Defining and Optimizing Standards of Care for Modifiable High-Risk COPD Patients

EXACOS-CV US Study

Risk of Death and Cardiovascular Events Following an Exacerbation of COPD: The EXACOS-CV US Study

Websites

goldcopd.org

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) works with healthcare professionals and public health officials around the world to raise awareness of Chronic Obstructive Pulmonary Disease (COPD) and to improve prevention and treatment of this lung disease.

COPDfoundation.org

The COPD Foundation is a patient-centered organization committed to preventing COPD, bronchiectasis, and nontuberculous mycobacterial (NTM) lung disease, and to seeking cures while improving lives and advocating for all affected.

dualcopdburden.com

This resource unpacks the burden of IL-33 in COPD and explores the dual pathways of inflammation and mucus dysfunction.

Previous: COPD Pathobiology

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B cells B lymphocytes

CD cluster differentiation

CI confidence interval

CONQUEST Collaboration on Quality Improvement Initiative for Achieving Excellence in Standards of COPD Care

COPD chronic obstructive pulmonary disease

CRS cytokine release syndrome

CT computed tomography

CV cardiovascular

CVD cardiovascular disease

EGFR epidermal growth factor receptor

EoE eosinophilic esophagitis

EXACOS-CV EXAcerbations of COPD and their OutcomeS in CardioVascular diseases

FEV₁ forced expiratory volume in 1 second

FFS fee-for-service

GOLD Global Initiative for Chronic Obstructive Lung Disease

HF heart failure

HR hazard ratio

IFN-γ interferon gamma

IgE immunoglobulin E

IL interleukin

IL-33 OX oxidized interleukin-33

IL-33 RED reduced interleukin-33

ILC innate lymphoid cell

LRTD lower respiratory tract disease

MCP-1 monocyte chemoattractant protein-1

MI myocardial infarction

MMP-9 matrix metalloproteinase-9

MRC Medical Research Council

MSL medical science liaison

NK natural killer

PRIMUS Prompt Initiation of Maintenance Therapy in the US

RAGE receptor for advanced glycation end products

SD standard deviation

SE standard error

SUMMIT Study to Understand Mortality and Morbidity in COPD

Tc1 type 1 cytotoxic T cell(s)

Th T helper cell(s)

TNF-α tumor necrosis factor alpha

TSLP thymic stromal lymphopoietin

UK United Kingdom

US United States

WISDOM Withdrawal of Inhaled Steroids During Optimized bronchodilator Management

1. American Lung Association. COPD Trends Brief: Prevalence. American Lung Association Website. https://www.lung.org/research/trends-in-lung-disease/copd-trends-brief/copd-prevalence

2. Centers for Disease Control and Prevention. Deaths and mortality. CDC website. https://www.cdc.gov/nchs/fastats/deaths.htm

3. GBD 2021 US Burden of Disease and Forecasting Collaborators. Burden of disease scenarios by state in the USA, 2022-50: a forecasting analysis for the Global Burden of Disease Study 2021. Lancet. 2024;404(10469):2341-2370. doi:10.1016/S0140-6736(24)02246-3

4. American Lung Association. COPD trends brief: burden. American Lung Association website. https://www.lung.org/research/trends-in-lung-disease/copd-trends-brief/copd-burden

5. American Lung Association. COPD trends brief: mortality. American Lung Association website. https://www.lung.org/research/trends-in-lung-disease/copd-trends-brief/copd-mortality

6. Patel D, Pollack M, Tang F, et al. Healthcare utilization burden, treatment patterns, and cardiopulmonary outcomes in patients following hospital discharge for a COPD exacerbation in a United States administrative database [abstract]. Am J Respir Crit Care Med. 2024;209:A5970.

7. Lindenauer PK, Dharmarajan K, Qin L, et al. Risk trajectories of readmission and death in the first year after hospitalization for chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2018;197(8):1009-1017. https://doi.org/10.1164/rccm.201709-1852OC

8. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: 2026 report. Published December 8, 2025. https://goldcopd.org/2026-gold-report-and-pocket-guide/

9. Locke ER, Young JP, Battaglia C, et al. Care-seeking and delay of care during COPD exacerbations. NPJ Prim Care Respir Med. 2022;32(1):7. doi:10.1038/s41533-022-00269-9

10. Bafadhel M, Criner G, Dransfield MT, et al. Exacerbations of chronic obstructive pulmonary disease: time to rename. Lancet Respir Med. 2020;8(2):133-135. doi:10.1016/S2213-2600(19)30414-X

11. Watz H, Tetzlaff K, Magnussen H, et al. Spirometric changes during exacerbations of COPD: a post hoc analysis of the WISDOM trial. Respir Res. 2018;19(1):251. https://doi.org/0.1186/s12931-018-0944-3

12. Singh D, Han MK, Hawkins NM, et al. Implications of cardiopulmonary risk for the management of COPD: a narrative review. Adv Ther. 2024;41(6):2151-2167. doi:10.1007/s12325-024-02855-4

13. Müllerová H, Shukla A, Hawkins A, et al. Risk factors for acute exacerbations of COPD in a primary care population: a retrospective observational cohort study. BMJ Open. 2014;4(12):e006171. https://doi.org/10.1136/bmjopen-2014-006171

14. Lindberg A, Sawalha S, Hedman L, et al. Subjects with COPD and productive cough have an increased risk for exacerbations and death. Respir Med. 2015;109(1):88-95. https://doi.org/10.1016/j.rmed.2014.12.001

15. Sethi S, Make BJ, Robinson SB, et al. Relationship of COPD exacerbation severity and frequency on risks for future events and economic burden in the Medicare fee-for-service population. Int J Chron Obstruct Pulmon Dis. 2022;17:593-608. doi:10.2147/COPD.S350248

16. Kunisaki KM, Dransfield MT, Anderson JA, et al. Exacerbations of chronic obstructive pulmonary disease and cardiac events. A post hoc cohort analysis from the SUMMIT randomized clinical trial. Am J Respir Crit Care Med. 2018;198(1):51-57.

17. Daniels K, Lanes S, Tave A, et al. Risk of death and cardiovascular events following an exacerbation of COPD: the EXACOS-CV US study [Article and supplemental tables]. Int J Chron Obstruct Pulmon Dis. 2024;19:225-241.

18. Van Eeden S, Leipsic J, Paul Man SF, et al. The relationship between lung inflammation and cardiovascular disease. Am J Respir Crit Care Med. 2012;186(1):11-16. doi:10.1164/rccm.201203-0455PP

19. Crisan L, Wong N, Sin DD, et al. Karma of cardiovascular disease risk factors for prevention and management of major cardiovascular events in the context of acute exacerbations of chronic obstructive pulmonary disease. Front Cardiovasc Med. 2019;6:79. https://doi.org/10.3389/fcvm.2019.00079

20. Calderón Montero A. El eje cardiopulmonar y la mortalidad cardiovascular en el paciente EPOC [Cardiopulmonary axis and cardiovascular mortality in patients with COPD]. Semergen. 2023;49(4):101928.

21. Rabe KF, Hurst JR, Suissa S. Cardiovascular disease and COPD: dangerous liaisons?. Eur Respir Rev. 2018;27(149):180057. doi:10.1183/16000617.0057-2018

22. Kent BD, Mitchell PD, McNicholas WT. Hypoxemia in patients with COPD: cause, effects, and disease progression. Int J Chron Obstruct Pulmon Dis. 2011;6:199-208. https://doi.org/10.2147/COPD.S10611

23. Aisanov Z, Khaltaev N. Management of cardiovascular comorbidities in chronic obstructive pulmonary disease patients. J Thorac Dis. 2020;12(5):2791-2802. https://doi.org/10.21037/jtd.2020.03.60

24. Pullen R, Miravitlles M, Sharma A, et al. CONQUEST quality standards: for the collaboration on quality improvement initiative for achieving excellence in standards of COPD care. Int J Chron Obstruct Pulmon Dis. 2021;16:2301-2322. https://doi.org/10.2147/COPD.S313498

25. Wang Y, Xu J, Meng Y, et al. Role of inflammatory cells in airway remodeling in COPD. Int J Chron Obstruct Pulmon Dis. 2018;13:3341-3348. doi:10.2147/COPD.S176122

26. Brightling C, Greening N. Airway inflammation in COPD: progress to precision medicine. Eur Respir J. 2019;54(2):1900651. doi:10.1183/13993003.00651-2019

27. Tian PW, Wen FQ. Clinical significance of airway mucus hypersecretion in chronic obstructive pulmonary disease. J Transl Int Med. 2015;3(3):89-92. doi:10.1515/jtim-2015-0013

28. Strickson S, Houslay KF, Negri VA, et al. Oxidised IL-33 drives COPD epithelial pathogenesis via ST2-independent RAGE/EGFR signalling complex. Eur Respir J. 2023;62(3):2202210. doi:10.1183/13993003.02210-2022

29. Moussion C, Ortega N, Girard JP. The IL-1-like cytokine IL-33 is constitutively expressed in the nucleus of endothelial cells and epithelial cells in vivo: a novel 'alarmin'? PLoS One. 2008;3(10):e3331.

30. Cayrol C, Girard JP. Interleukin-33 (IL-33): A critical review of its biology and the mechanisms involved in its release as a potent extracellular cytokine. Cytokine. 2022;156:155891. doi:10.1016/j.cyto.2022.155891

31. Calderon AA, Dimond C, Choy DF, et al. Targeting interleukin-33 and thymic stromal lymphopoietin pathways for novel pulmonary therapeutics in asthma and COPD. Eur Respir Rev. 2023;32(167):220144. doi:10.1183/16000617.0144-2022

32. Celli BR, Anzueto A, Singh D, et al. The emerging role of alarmin-targeting biologics in the treatment of patients with COPD. Chest. 2025;167(5):1346-1355. doi:10.1016/j.chest.2024.09.049

33. Rabe KF, Rennard S, Martinez FJ, et al. Targeting type 2 inflammation and epithelial alarmins in chronic obstructive pulmonary disease: a biologics outlook. Am J Respir Crit Care Med. 2023;208(4):395-405. doi:10.1164/rccm.202303-0455CI

34. Roan F, Obata-Ninomiya K, Ziegler SF. Epithelial cell-derived cytokines: more than just signaling the alarm. J Clin Invest. 2019;129(4):1441-1451. https://doi.org/10.1172/JCI124606

35. Mitchell PD, O’Byrne PM. Epithelial-derived cytokines in asthma. Chest. 2017;151(6):1338-1344. https://doi.org/10.1016/j.chest.2016.10.042

36. Stanbery AG, Shuchi Smita, Jakob von Moltke, et al. TSLP, IL-33, and IL-25: Not just for allergy and helminth infection. J Allergy Clin Immunol. 2022;150(6):1302-1313. doi:10.1016/j.jaci.2022.07.003

37. Annunziato F, Romagnani C, Romagnani S. The 3 major types of innate and adaptive cell-mediated effector immunity. J Allergy Clin Immunol. 2015;135(3):626-635. doi:10.1016/j.jaci.2014.11.001

38. Bertuccio FR, Baio N, Montini S, et al. Potential new inflammatory markers in bronchiectasis: a literature review. Curr Issues Mol Biol. 2024;46(7):6675-6689. doi:10.3390/cimb46070398

39. Drake LY, Prakash YS. Contributions of IL-33 in non-hematopoietic lung cells to obstructive lung disease. Front Immunol. 2020;11:1798. doi:10.3389/fimmu.2020.01798

40. Scott IC, Zuydam NV, Cann JA, et al. IL-33 is associated with alveolar dysfunction in patients with viral lower respiratory tract disease. Mucosal Immunol. 2025;18(2):312-325. doi:10.1016/j.mucimm.2024.12.001

41. Petersen BC, Dolgachev V, Rasky A, et al. IL-17E (IL-25) and IL-17RB promote respiratory syncytial virus-induced pulmonary disease. J Leukoc Biol. 2014;95(5):809-815. doi:10.1189/jlb.0913482

42. Headley MB, Zhou B, Shih WX, et al. TSLP conditions the lung immune environment for the generation of pathogenic innate and antigen-specific adaptive immune responses. J Immunol. 2009;182(3):1641-1647. doi:10.4049/jimmunol.182.3.1641

43. An G, Zhang X, Wang W, et al. The effects of interleukin-33 on airways collagen deposition and matrix metalloproteinase expression in a murine surrogate of asthma. Immunology. 2018;154(4):637-650. doi:10.1111/imm.12911

44. Guo Z, Wu J, Zhao J, et al. IL-33 promotes airway remodeling and is a marker of asthma disease severity. J Asthma. 2014;51(8):863-869. doi:10.3109/02770903.2014.921196

45. Wu L, Luo Z, Zheng J, et al. IL-33 can promote the process of pulmonary fibrosis by inducing the imbalance between MMP-9 and TIMP-1. Inflammation. 2018;41(3):878-885. doi:10.1007/s10753-018-0742-6

46. Zhang Y, Li S, Huang S, et al. IL33/ST2 contributes to airway remodeling via p-JNK MAPK/STAT3 signaling pathway in OVA-induced allergic airway inflammation in mice. Exp Lung Res. 2019;45(3-4):65-75. doi:10.1080/01902148.2019.1611972

47. Kaur D, Gomez E, Doe C, et al. IL-33 drives airway hyper-responsiveness through IL-13-mediated mast cell: airway smooth muscle crosstalk. Allergy. 2015;70(5):556-567. doi:10.1111/all.12593

48. Stott-Miller M, Müllerová H, Miller B, et al. Defining chronic mucus hypersecretion using the CAT in the SPIROMICS cohort. Int J Chron Obstruct Pulmon Dis. 2020;15:2467-2476. doi:10.2147/COPD.S267002

49. Hughes R, Rapsomaniki E, Janson C, et al. Frequent productive cough: symptom burden and future exacerbation risk among patients with asthma and/or COPD in the NOVELTY study. Respir Med. 2022;200:106921. doi:10.1016/j.rmed.2022.106921

50. Raby KL, Michaeloudes C, Tonkin J, et al. Mechanisms of airway epithelial injury and abnormal repair in asthma and COPD. Front Immunol. 2023;14:1201658. doi:10.3389/fimmu.2023.1201658

51. Kotlyarov S. Involvement of the innate immune system in the pathogenesis of chronic obstructive pulmonary disease. Int J Mol Sci. 2022;23(2):985. doi:10.3390/ijms23020985

52. Diaz AA. Beyond bronchodilation and airway inflammation: mucus plugs as a therapeutic target in COPD. Chest. 2025;167(1):34-36. doi:10.1016/j.chest.2024.08.017

53. Dunican EM, Elicker BM, Henry T, et al. Mucus plugs and emphysema in the pathophysiology of airflow obstruction and hypoxemia in smokers. Am J Respir Crit Care Med. 2021;203(8):957-968. doi:10.1164/rccm.202006-2248OC

54. Okajima Y, Come CE, Nardelli P, et al. Luminal plugging on chest CT scan: association with lung function, quality of life, and COPD clinical phenotypes. Chest. 2020;158(1):121-130. doi:10.1016/j.chest.2019.12.046

55. Diaz AA, Orejas JL, Grumley S, et al. Airway-occluding mucus plugs and mortality in patients with chronic obstructive pulmonary disease. JAMA. 2023;329(21):1832-1839.

56. Fahy JV, Dickey BF. Airway mucus function and dysfunction. N Engl J Med. 2010;363(23):2233-2247. doi:10.1056/NEJMra0910061

57. Jin KN, Lee HJ, Park H, et al. Mucus plugs as precursors to exacerbation and lung function decline in COPD patients. Arch Bronconeumol. 2025;61(3):138-146. doi:10.1016/j.arbres.2024.07.017

58. Tanabe N, Shimizu K, Shima H, et al. Computed tomography mucus plugs and airway tree structure in patients with chronic obstructive pulmonary disease: associations with airflow limitation, health-related independence and mortality. Respirology. 2024;29(11):951-961. doi:10.1111/resp.14776

59. Cohen ES, Scott IC, Majithiya JB, et al. Oxidation of the alarmin IL-33 regulates ST2-dependent inflammation. Nat Commun. 2015;6:8327. doi:10.1038/ncomms9327

60. Tworek D, Majewski S, Szewczyk K, et al. The association between airway eosinophilic inflammation and IL-33 in stable non-atopic COPD. Respir Res. 2018;19(1):108.

61. Kim SW, Rhee CK, Kim KU, et al. Factors associated with plasma IL-33 levels in patients with chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2017;12:395-402.

62. Joo H, Park SJ, Min KH, et al. Association between plasma interleukin-33 level and acute exacerbation of chronic obstructive pulmonary disease. BMC Pulm Med. 2021;21(1):337. doi:10.1186/s12890-021-01703-3