Role of Small Airway Epithelial-Mesenchymal Transition and CXCL13 in Pulmonary Lymphoid Follicle Formation in Chronic Obstructive Pulmonary Disease

Overview

Journal Int J Chron Obstruct Pulmon Dis

Publisher Dove Medical Press

Specialty Pulmonary Medicine

Date 2024 Dec 4

PMID 39629182

Authors

Xia Yang

Ning Zhou

Jie Cao

Affiliations

Soon will be listed here.

Abstract

Background: Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disorder characterized by inflammation and airway remodeling. Lymphoid follicles play a crucial role in acquired immunity and the development of COPD. However, the precise mechanisms of lymphoid follicle formation in COPD and the effects of cigarette smoke (CS) exposure on this process remain unclear. Epithelial-mesenchymal transition (EMT) is implicated in the progression of COPD and may serves as a source of stromal cells that produce chemokines crucial for lymphoid follicle formation. This study aims to clarify the contributions and mechanisms of EMT in lymphoid follicle genesis in COPD, focusing specifically on the role of CXCL13.

Methods: Lung tissue samples were obtained from patients with COPD, smokers, and non-smokers. Immunohistochemistry was performed to assess the lymphoid follicles, EMT-related markers, and CXCL13 expression. In vitro experiments were conducted using CS extract (CSE)-stimulated immortalized human bronchial epithelial cells (iHBECs) to induce EMT. The expression of EMT-related markers and CXCL13 in CSE-stimulated iHBECs was analyzed using Western blotting, real-time PCR, and immunofluorescence staining. The effect of an EMT inhibitor on CXCL13 expression was also examined.

Results: Patients with COPD and lymphoid follicles exhibited significantly lower forced expiratory volume in 1 s (% predicted) values than those without lymphoid follicles. Enhanced EMT changes were observed in patients with COPD and lymphoid follicles. Increased EMT-related markers and CXCL13 expression were observed in CSE-stimulated iHBECs, and CXCL13 expression gradually increased over time. Inhibiting EMT downregulated CXCL13 expression in iHBECs.

Conclusion: Lymphoid follicles are associated with enhanced EMT in COPD. EMT may act as a key driver of the adaptive immune response in COPD by promoting a microenvironment conducive to lymphoid follicles formation through the production of CXCL13. This study provides valuable insights into the mechanisms underlying lymphoid follicle formation in COPD and identifies potential therapeutic targets.

References

Su X, Wu W, Zhu Z, Lin X, Zeng Y . The effects of epithelial-mesenchymal transitions in COPD induced by cigarette smoke: an update. Respir Res. 2022; 23(1):225. PMC: 9429334. DOI: 10.1186/s12931-022-02153-z. View

Jones G, Hill D, Jones S . Understanding Immune Cells in Tertiary Lymphoid Organ Development: It Is All Starting to Come Together. Front Immunol. 2016; 7:401. PMC: 5046062. DOI: 10.3389/fimmu.2016.00401. View

Pezzuto A, Tonini G, Ciccozzi M, Crucitti P, DAscanio M, Cosci F . Functional Benefit of Smoking Cessation and Triple Inhaler in Combustible Cigarette Smokers with Severe COPD: A Retrospective Study. J Clin Med. 2023; 12(1). PMC: 9821177. DOI: 10.3390/jcm12010234. View

Pezzuto A, Ricci A, DAscanio M, Moretta A, Tonini G, Calabro N . Short-Term Benefits of Smoking Cessation Improve Respiratory Function and Metabolism in Smokers. Int J Chron Obstruct Pulmon Dis. 2023; 18:2861-2865. PMC: 10697086. DOI: 10.2147/COPD.S423148. View

Zhou L, Le Y, Tian J, Yang X, Jin R, Gai X . Cigarette smoke-induced RANKL expression enhances MMP-9 production by alveolar macrophages. Int J Chron Obstruct Pulmon Dis. 2018; 14:81-91. PMC: 6304243. DOI: 10.2147/COPD.S190023. View

Nakashima Y, Isomoto H, Matsushima K, Yoshida A, Nakayama T, Nakayama M . Enhanced expression of CXCL13 in human Helicobacter pylori-associated gastritis. Dig Dis Sci. 2011; 56(10):2887-94. DOI: 10.1007/s10620-011-1717-8. View

Scotton C, Chambers R . Molecular targets in pulmonary fibrosis: the myofibroblast in focus. Chest. 2007; 132(4):1311-21. DOI: 10.1378/chest.06-2568. View

Mebius R . Organogenesis of lymphoid tissues. Nat Rev Immunol. 2003; 3(4):292-303. DOI: 10.1038/nri1054. View

Hogg J, Chu F, Utokaparch S, Woods R, Elliott W, Buzatu L . The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med. 2004; 350(26):2645-53. DOI: 10.1056/NEJMoa032158. View

10.

Takatori H, Kanno Y, Watford W, Tato C, Weiss G, Ivanov I . Lymphoid tissue inducer-like cells are an innate source of IL-17 and IL-22. J Exp Med. 2008; 206(1):35-41. PMC: 2626689. DOI: 10.1084/jem.20072713. View

11.

Sohal S, Reid D, Soltani A, Ward C, Weston S, Muller H . Reticular basement membrane fragmentation and potential epithelial mesenchymal transition is exaggerated in the airways of smokers with chronic obstructive pulmonary disease. Respirology. 2010; 15(6):930-8. DOI: 10.1111/j.1440-1843.2010.01808.x. View

12.

Reed H, Wang L, Sonett J, Chen M, Yang J, Li L . Lymphatic impairment leads to pulmonary tertiary lymphoid organ formation and alveolar damage. J Clin Invest. 2019; 129(6):2514-2526. PMC: 6546450. DOI: 10.1172/JCI125044. View

13.

Sohal S, Reid D, Soltani A, Ward C, Weston S, Muller H . Evaluation of epithelial mesenchymal transition in patients with chronic obstructive pulmonary disease. Respir Res. 2011; 12:130. PMC: 3198934. DOI: 10.1186/1465-9921-12-130. View

14.

Bracke K, Dhulst A, Maes T, Moerloose K, Demedts I, Lebecque S . Cigarette smoke-induced pulmonary inflammation and emphysema are attenuated in CCR6-deficient mice. J Immunol. 2006; 177(7):4350-9. DOI: 10.4049/jimmunol.177.7.4350. View

15.

Nasri A, Foisset F, Ahmed E, Lahmar Z, Vachier I, Jorgensen C . Roles of Mesenchymal Cells in the Lung: From Lung Development to Chronic Obstructive Pulmonary Disease. Cells. 2021; 10(12). PMC: 8700565. DOI: 10.3390/cells10123467. View

16.

Wang B, Xiao D, Wang C . Smoking and chronic obstructive pulmonary disease in Chinese population: a meta-analysis. Clin Respir J. 2014; 9(2):165-75. DOI: 10.1111/crj.12118. View

17.

Sohal S . Epithelial and endothelial cell plasticity in chronic obstructive pulmonary disease (COPD). Respir Investig. 2017; 55(2):104-113. DOI: 10.1016/j.resinv.2016.11.006. View

18.

Caramori G, Ruggeri P, Di Stefano A, Mumby S, Girbino G, Adcock I . Autoimmunity and COPD: Clinical Implications. Chest. 2017; 153(6):1424-1431. DOI: 10.1016/j.chest.2017.10.033. View

19.

Smedbakken L, Halvorsen B, Daissormont I, Ranheim T, Michelsen A, Skjelland M . Increased levels of the homeostatic chemokine CXCL13 in human atherosclerosis - Potential role in plaque stabilization. Atherosclerosis. 2012; 224(1):266-73. DOI: 10.1016/j.atherosclerosis.2012.06.071. View

20.

Milara J, Peiro T, Serrano A, Cortijo J . Epithelial to mesenchymal transition is increased in patients with COPD and induced by cigarette smoke. Thorax. 2013; 68(5):410-20. DOI: 10.1136/thoraxjnl-2012-201761. View