At a Glance
Recent research has shed light on the pivotal role of Cullin4A (CUL4A) in the progression of Chronic Obstructive Pulmonary Disease (COPD). High expression of CUL4A has been observed in the lung epithelium of patients with COPD, and its link with the epithelial-mesenchymal transition (EMT) in small airway epithelium unveils new potential therapeutic targets to combat this debilitating respiratory disease. This article delves into the findings of a study that explored the implication of CUL4A in promoting EMT and contributing to airway remodeling in COPD.
Introduction
Chronic Obstructive Pulmonary Disease (COPD) is a widespread respiratory ailment characterized by persistent airflow limitation that is not fully reversible. The World Health Organization ranks COPD as the third leading cause of death worldwide, posing a significant public health challenge [Lopez-Campos JL, Tan W, Soriano JB. 2016]. In the quest to understand the pathophysiology behind this disease, researchers are investigating the underlying molecular mechanisms. A notable discovery in the respiratory research field is the association of the E3 ubiquitin ligase, Cullin4A (CUL4A), with EMT, a cellular process implicated in airway remodeling in COPD patients [Ren Yidan et al. 2019].
The Connection Between CUL4A and COPD
COPD arises from chronic inflammation due to noxious particles or gases, particularly tobacco smoke, which leads to irreversible changes in the small airways and lung parenchyma [Negewo NA, Gibson PG, VM MD. 2015]. Airway remodeling, a hallmark of COPD, is characterized by structural changes that consist of epithelial thickening, fibrosis, and increased smooth muscle mass. The EMT plays a crucial role in the remodeling process, where epithelial cells lose their characteristics and gain a mesenchymal phenotype, leading to enhanced migratory capacity, invasiveness, and resistance to apoptosis [Jolly MK et al. 2018].
Recent studies indicate that CUL4A mediates degradation of various proteins and is implicated in several biological processes, including cell cycle progression, DNA repair, and embryonic development [Komander D. 2009]. Overexpression of CUL4A has been linked to cancer progression as it facilitates EMT, thereby contributing to metastasis [Mahmood MQ et al. 2017]. The novel study by Ren Yidan Y and colleagues is groundbreaking as it systematically examines CUL4A’s role in COPD for the first time, indicating that it potentially contributes to small airway epithelial cell remodeling via the induction of EMT [Ren Yidan et al. 2019].
Small Airway Epithelium and EMT in COPD
In COPD, small airway epithelium is the primary site affected, where pathological changes contribute to disease progression. Cigarette smoke, recognized as a high-risk factor for COPD, promotes inflammation, and tissue damage, leading to EMT [Jiang B et al. 2018]. The study by Ren and colleagues focused on determining the presence and effect of CUL4A in small airway epithelial cells from COPD patients exposed to cigarette smoke extract (CSE). Using immunohistochemistry, they found that CUL4A was significantly up-regulated in the small airway epithelium of COPD patients, implicating a negative correlation with forced expiratory volume in one second (FEV1), an essential clinical indicator of airflow obstruction.
The CUL4A Mechanism in EMT
To further dissect the role of CUL4A in EMT during COPD, the researchers performed in vitro experiments by silencing or overexpressing CUL4A in human small airway epithelial cells (HSAEpiCs) [Ren Yidan et al. 2019]. The in vitro results substantiated the in vivo findings; cigarette smoke extract (CSE)-induced EMT was regulated by the levels of CUL4A. This suggests that the overexpression of CUL4A may drive the progression of EMT, contributing to the structural alterations observed in the small airways of COPD patients.
These findings are in line with previous cancer research where CUL4A was seen to promote cancer metastasis by regulating the expression of EMT-related transcription factors such as ZEB1 and Snail [Wang Y et al. 2014]. Given the similarity in EMT behavior in COPD and cancer, the implication of CUL4A in both conditions underscores the potential of targeting this protein to reverse or attenuate the EMT process, thereby impeding airway remodeling in COPD.
Ethical Considerations of the Study
The study was conducted in accordance with the ethical standards of the Medical Ethics Committees of the Qilu Hospital, Shandong University, ensuring the highest ethical conduct. Such research is pivotal as it provides a foundation for future clinical studies and potential therapeutic interventions aimed at decelerating the progression of COPD.
Future Perspectives and Conclusion
The research by Ren Yidan and colleagues marks a critical step in understanding the molecular intricacies of COPD. By demonstrating the up-regulation of CUL4A and its regulatory role in EMT in the small airway epithelium, the study paves the way for new therapeutic approaches that might involve targeting CUL4A to prevent or reverse airway remodeling in COPD. However, further studies are needed to investigate the precise mechanisms by which CUL4A influences the EMT process and to evaluate the potential clinical benefits of modulating CUL4A expression in COPD treatment.
References
1. Ren Yidan, et al. “The cullin4A is up-regulated in chronic obstructive pulmonary disease patient and contributes to epithelial-mesenchymal transition in small airway epithelium.” Respiratory Research, vol. 20, no. 1, 2019, p. 84. DOI: 10.1186/s12931-019-1048-4.
2. Lopez-Campos JL, Tan W, Soriano JB. “Global burden of COPD.” Respirology, 2016;21(1):14–23. DOI: 10.1111/resp.12660.
3. Negewo NA, Gibson PG, VM MD. “COPD and its comorbidities: impact, measurement and mechanisms.” Respirology, 2015;20(8):1160–1171. DOI: 10.1111/resp.12642.
4. Jolly MK, Ward C, Eapen MS, et al. “Epithelial-mesenchymal transition, a spectrum of states: role in lung development, homeostasis, and disease.” Developmental Dynamics, 2018;247(3):346–358. DOI: 10.1002/dvdy.24541.
5. Wang Y et al. “CUL4A induces epithelial-mesenchymal transition and promotes cancer metastasis by regulating ZEB1 expression.” Cancer Research, 2014;74(2):520–531. DOI: 10.1158/0008-5472.CAN-13-2182.
Keywords
1. Chronic Obstrctive Pulmonary Disease COPD
2. Cullin4A (CUL4A) Expression
3. Airway Remodeling in COPD
4. Epithelial-Mesenchymal Transition (EMT)
5. Cigarette Smoke Extract (CSE) Impact