Chronic obstructive pulmonary disease (COPD) continues to be a major cause of disability and is one of the leading causes of mortality worldwide. While there are numerous treatment options for the lung disease, the available treatments focus on symptoms secondary to inflammation, and are not curative. In a review published in the American Journal of Physiology – Lung Cellular and Molecular Physiology, experts focus on potential disease-relevant pathways and emphasize the important of developing new treatments for patients with COPD.1

The objective of the review was to summarize COPD pathology, available treatment options and additional potential pathways and targets for new therapeutic development.

Cigarette smoke contains thousands of injurious agents and is the key cause of COPD worldwide as these induce tissue damage and inflammatory process leading to destruction of alveolar tissue, loss of extracellular matrix and alveolar cells, along with airway remodeling.2 As COPD may progress in patients despite smoking cessation it was suggested that persistent airway inflammation in these patients is related to repair of smoke-induced tissue damage in the airways.3 Failure to achieve normal lung function in early adulthood followed by age-appropriate rates of decline causes up to half of COPD cases.4

The 2020 Global Initiative for Chronic Obstructive Lung Disease guidelines recommend that the management strategy of COPD should be based on the assessment of symptoms and future risk of exacerbations and the main goals of pharmacological therapy for COPD are to reduce symptoms and frequency and severity of exacerbations, as well as to improve exercise tolerance and health status. However, at this point there is no evidence that any of the available medications can modify the long-term decline in lung function.5


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The commonly used maintenance medications in COPD are short- and long-acting beta-2 agonists and anti-cholinergics, methylxanthines, inhaled or systemic corticosteroids, phosphodiesterase (PDE)-4 inhibitors and mucolytic agents.5 As these medications are mainly focused on relieving symptoms and reducing the risk for exacerbations, more effective treatment strategies are needed. COPD is a complex disease and precision medicine strategy, that considers biologic and psychosocial factors, may improve disease outcomes.4

New Treatment Targets

There is a real need to uncover new biology in order to advance more precision-based therapeutic strategies for patients with COPD. New disease-specific strategies in development are focusing on inflammatory pathways, hoping this will help to address disease onset. Early reports suggest there are several promising targets that can address inflammatory complications, including oxidative stress, kinase-mediates pathways, phosphodiesterase inhibitors, interleukins and chemokines.

Oxidative Stress – a common denominator for aging and cellular senescence, resulting in macromolecular damage and DNA damage.2 With cigarette smoke exposure there is an increased oxidative stress, associated with an increase in Nrf2 activity which declines with the progression of COPD.6 As several studies have implicated Nrf2 in COPD pathology, this pathway is a potential important therapeutic target. Several agents may change Nrf2 expression and activity in airway cell, including aspirin-triggered resolvin D1, crocin, sulforaphane, and schisandrin B.1,6  

Kinase-mediated Pathwaysas various kinases, including MAPK, receptor-tyrosine kinases, phosphoinositide-3-kinases, JAK, and NF-κB, may induce chronic inflammation, they may serve as new targets for COPD treatment. There are several drugs that target different kinases but these are not approved for clinical use. Drugs with a more specific action, such as RV568 that inhibits p38α, was well tolerated in a 14-day clinical trial and showed promising results with potent anti-inflammatory effects on cell and animal models relevant to COPD, with evidence for improvement in lung function and anti-inflammatory effects on sputum biomarkers.7

Phosphodiesterase Inhibitors – inhibiting PDE leads to an increase in intracellular cAMP levels that may have anti-inflammatory effects. Roflumilast is an oral PDE-4 inhibitor already in use for more severe cases of COPD, but more potent medications are being developed, including several inhaled formulations, such as CHF6001, which was reported to have significant anti-inflammatory properties in the lungs of patients with COPD already receiving triple inhaled therapy (8). Ensifentrine is a PDE3/PDE4 inhibitor with anti-inflammatory and bronchodilator properties and when combined with short-acting bronchodilators or tiotropium caused additional improvement in lung function, reduced gas trapping, and improved airway conductance.9

Inflammatory Mediators – exposure to inhaled irritants and tobacco smoke results in an increase in various interleukins (IL) that increase the number of immune cells and induce inflammatory responses. Hence, treatment directed against these mediators may reduce inflammation.1 Mepolizumab, reslizumab, and benralizumab are antibodies directed against IL-5 and its receptor and reduced eosinophil-related inflammation. These medications are approved for use for asthma, and were not effective in COPD, but may be valuable for patients with COPD with eosinophilia. Dupilumab, a monoclonal antibody directed against IL-4 and IL-13 receptor, is another potential candidate for future use. microRNAs are also involved in inflammation regulation, and miR-155 expression was shown to be increased in COPD, but at this point there are no available miRNA-based therapeutics for COPD.10

Additional Potential Treatment Targets

While multiple medications under development for COPD are focusing on the inflammatory pathways, they are not expected to reverse the lung damage. For this reason, it is important to study the upstream pathways that may help to identify strategies to reverse exiting lung damage, including targets that can lead to lung repair and regeneration.

These potential breakthrough targets may include treatments directed against mitochondrial dysfunction; structural integrity of airway epithelium such as proteins that comprise tight junctions or the extracellular matrix; various ion channels that are responsible for airway hydration; and pro-regenerative strategies, including stem cell and tissue-engineering treatments to repair lung damage.1

Animal models and 3D human-based disease models have an important role in the efforts to better understand disease process and identify specific therapeutic targets and pathways.11,12 These models improve our knowledge about the basic mechanisms underlying COPD physiology, pathophysiology and treatment. Although they can only mimic some of the features of the disease, they are valuable for further investigation of mechanisms involved in human COPD.11

Several different types of 3D cell culture models have been developed in recent years, and these have gained increasing interest in drug discovery and tissue engineering due to their evident advantages in providing more physiologically relevant information and more predictive data. Ex vivo modeling using primary human material can improve translational research activities by fostering the mechanistic understanding of human lung diseases while reducing animal usage. It is believed that using new model organisms may allow exploring new avenues and treatments approached for human disease, and these are especially promising.12  

“COPD is a major public health concern, and as it continues to be a global burden, the importance of developing new treatments is apparent. Current treatments are not curative, and while new strategies and drugs are in the pipeline, they still address mostly secondary inflammatory pathways of the disease. An additional major complication in COPD drug development likely comes from the essential dependency on surrogate endpoints like FEV1 to assess the impact of a therapeutic strategy. Thus, any new therapeutic strategy will ultimately require long-term studies to confirm that the surrogate endpoints accurately reflect efficacy on disease outcome,” concluded the researchers.

References

1. Nguyen JMK, Robinson DN, Sidhaye VK. Why new biology must be uncovered to advance therapeutic strategies for chronic obstructive pulmonary disease. Am J Physiol Lung Cell Mol Physiol. 2021;320(1):L1-L11. doi:10.1152/ajplung.00367.2020

2. Tuder RM, Petrache I. Pathogenesis of chronic obstructive pulmonary disease. J Clin Invest. 2012;122(8):2749-55. doi:10.1172/JCI60324

3. Willemse BW, ten Hacken NH, Rutgers B, Lesman-Leegte IG, Postma DS, Timens W. Effect of 1-year smoking cessation on airway inflammation in COPD and asymptomatic smokers. Eur Respir J. 2005;26(5):835-45. doi:10.1183/09031936.05.00108904

4. Sidhaye VK, Nishida K, Martinez FJ. Precision medicine in COPD: where are we and where do we need to go? Eur Respir Rev. 2018;27(149):180022. doi:10.1183/16000617.0022-2018

5. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease 2020 report [Online]. Global Initiative for Chronic Obstructive Lung Disease. https://goldcopd.org/wp-content/uploads/2019/11/GOLD-2020-REPORT-ver1.1wms.pdf. Accessed January 25, 2021.

6. Cuadrado A, Rojo AI, Wells G, et al. Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nat Rev Drug Discov. 2019;18(4):295-317. doi:10.1038/s41573-018-0008-x

7. Charron CE, Russell P, Ito K, et al. RV568, a narrow-spectrum kinase inhibitor with p38 MAPK-α and -γ selectivity, suppresses COPD inflammation. Eur Respir J. 2017;50(4):1700188. doi:10.1183/13993003.00188-2017

8. Singh D, Beeh KM, Colgan B, et al. Effect of the inhaled PDE4 inhibitor CHF6001 on biomarkers of inflammation in COPD. Respir Res. 2019;20(1):180. doi:10.1186/s12931-019-1142-7

9. Singh D, Abbott-Banner K, Bengtsson T, Newman K. The short-term bronchodilator effects of the dual phosphodiesterase 3 and 4 inhibitor RPL554 in COPD. Eur Respir J. 2018;52(5):1801074. doi:10.1183/13993003.01074-2018

10. Barnes PJ. Targeting cytokines to treat asthma and chronic obstructive pulmonary disease. Nat Rev Immunol. 2018;18(7):454-466. doi:10.1038/s41577-018-0006-6

11. Ghorani V, Boskabady MH, Khazdair MR, Kianmeher M. Experimental animal models for COPD: a methodological review. Tob Induc Dis. 2017;15:25. doi:10.1186/s12971-017-0130-2

12. Zscheppang K, Berg J, Hedtrich S, et al. Human pulmonary 3D models For translational research. Biotechnol J. 2018;13(1):1700341. doi:10.1002/biot.201700341