Blood CDC42 overexpression is associated with an increased risk of acute exacerbation, inflammation and disease severity in patients with chronic obstructive pulmonary disease

Ming,Xiaoyan; Ming,Xiaoyan; Yang,Fan; Yang,Fan; Zhu,Hong; Zhu,Hong

doi:10.3892/etm.2022.11481

Blood CDC42 overexpression is associated with an increased risk of acute exacerbation, inflammation and disease severity in patients with chronic obstructive pulmonary disease

Authors:
- Xiaoyan Ming
- Fan Yang
- Hong Zhu
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Affiliations: Department of General Practice, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430014, P.R. China, Department of Thyroid and Breast Surgery, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430014, P.R. China
Published online on: June 30, 2022 https://doi.org/10.3892/etm.2022.11481
Article Number: 544
Copyright: © Ming et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

It has been previously reported that cell division control 42 (CDC42) protein can regulate macrophage recruitment, T cell‑associated inflammation and lung injury. However, its role in chronic obstructive pulmonary disease (COPD) remain poorly understood. Therefore, the present study aimed to investigate the possible association among CDC42 expression, the risk of acute exacerbation and disease features in patients with COPD. Peripheral blood mononuclear cells (PBMCs) and serum samples were collected from 60 patients with acute exacerbation COPD (AE‑COPD), 60 patients with stable COPD (S‑COPD) and 60 healthy control (HCs) individuals. The mRNA expression levels of CDC42 in PBMCs were then measured using reverse transcription‑quantitative PCR. The serum levels of TNF‑α, IL‑1β, IL‑6 and IL‑17 were measured using ELISA. The results showed that the expression of CDC42 was dysregulated among patients with AE‑COPD and S‑COPD compared with that in HCs. Specifically, the expression level of CDC42 was the highest in patients with AE‑COPD, followed by those with S‑COPD and the lowest in HCs (P<0.001). Furthermore, receiver operating characteristic curve analysis demonstrated that CDC42 expression was associated with an increased risk of acute exacerbation in COPD with an area under curve of 0.690 (95% confidence interval=0.595‑0.785). CDC42 was found to be positively associated with Global Initiative for Chronic Obstructive Lung Disease staging in patients with AE‑COPD (P<0.01) and S‑COPD (P<0.05). Additionally, CDC42 expression associated positively with the serum levels of TNF‑α, IL‑1β, IL‑6 and IL‑17 in patients with AE‑COPD (all P<0.05). However, this association was weaker in patients with S‑COPD and became negligible in HCs. In conclusion, data from the present study suggest that CDC42 is associated with an increased risk of acute exacerbation, inflammation and disease severity in patients with COPD, implicating its application as a potential biomarker for COPD.

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1	Hattab Y, Alhassan S, Balaan M, Lega M and Singh AC: Chronic obstructive pulmonary disease. Crit Care Nurs Q. 39:124–130. 2016.PubMed/NCBI View Article : Google Scholar
2	Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, Abraham J, Adair T, Aggarwal R, Ahn SY, et al: Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: A systematic analysis for the global burden of disease study 2010. Lancet. 380:2095–2128. 2012.PubMed/NCBI View Article : Google Scholar
3	GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the global burden of disease study 2017. Lancet. 392:1789–1858. 2018.PubMed/NCBI View Article : Google Scholar
4	Ming X, Duan W and Yi W: Long non-coding RNA NEAT1 predicts elevated chronic obstructive pulmonary disease (COPD) susceptibility and acute exacerbation risk, and correlates with higher disease severity, inflammation, and lower miR-193a in COPD patients. Int J Clin Exp Pathol. 12:2837–2848. 2019.PubMed/NCBI
5	Heaney LG and McGarvey LP: Personalised medicine for asthma and chronic obstructive pulmonary disease. Respiration. 93:153–161. 2017.PubMed/NCBI View Article : Google Scholar
6	Lowe KE, Regan EA, Anzueto A, Austin E, Austin JHM, Beaty TH, Benos PV, Benway CJ, Bhatt SP, Bleecker ER, et al: COPDGene((R)) 2019: Redefining the diagnosis of chronic obstructive pulmonary disease. Chronic Obstr Pulm Dis. 6:384–399. 2019.PubMed/NCBI View Article : Google Scholar
7	Zheng C, Wang Y, Yang L, Zhou S, Gao Y, Li F, Feng Y, Wang Z, Zhan L, Yan Q, et al: Cell division cycle 42 plays a cell type-specific role in lung tumorigenesis. Sci Rep. 7(10407)2017.PubMed/NCBI View Article : Google Scholar
8	Zhang B, Zhang J, Xia L, Luo J, Zhang L, Xu Y, Zhu X and Chen G: Inhibition of CDC42 reduces macrophage recruitment and suppresses lung tumorigenesis in vivo. J Recept Signal Transduct Res. 41:504–510. 2020.PubMed/NCBI View Article : Google Scholar
9	Zhou J, Dehne N and Brüne B: Nitric oxide causes macrophage migration via the HIF-1-stimulated small GTPases Cdc42 and Rac1. Free Radic Biol Med. 47:741–749. 2009.PubMed/NCBI View Article : Google Scholar
10	Nikolic DM, Gong MC, Turk J and Post SR: Class A scavenger receptor-mediated macrophage adhesion requires coupling of calcium-independent phospholipase A(2) and 12/15-lipoxygenase to Rac and Cdc42 activation. J Biol Chem. 282:33405–33411. 2007.PubMed/NCBI View Article : Google Scholar
11	Shiraishi A, Uruno T, Sanematsu F, Ushijima M, Sakata D, Hara T and Fukui Y: DOCK8 protein regulates macrophage migration through Cdc42 protein activation and LRAP35a protein interaction. J Biol Chem. 292:2191–2202. 2017.PubMed/NCBI View Article : Google Scholar
12	Kalim KW, Yang JQ, Li Y, Meng Y, Zheng Y and Guo F: Reciprocal regulation of glycolysis-driven Th17 pathogenicity and regulatory T cell stability by Cdc42. J Immunol. 200:2313–2326. 2018.PubMed/NCBI View Article : Google Scholar
13	Chen L, Collado K and Rastogi D: Contribution of systemic and airway immune responses to pediatric obesity-related asthma. Paediatr Respir Rev. 37:3–9. 2021.PubMed/NCBI View Article : Google Scholar
14	Lv J, Zeng J, Guo F, Li Y, Xu M, Cheng Y, Zhang L, Cai S, Chen Y, Zheng Y and Hu G: Endothelial Cdc42 deficiency impairs endothelial regeneration and vascular repair after inflammatory vascular injury. Respir Res. 19(27)2018.PubMed/NCBI View Article : Google Scholar
15	Hu GD, Chen YH, Tong WC, Cheng YX, Zhang L, Zhang L and Cai SX: The comparison between the vascular endothelial cells special cdc42-deficient heterozygous mice and the non-knockout mice on lung tissue pathological change and vasopermeability in acute lung injury. Nan Fang Yi Ke Da Xue Xue Bao. 31:995–998. 2011.PubMed/NCBI(In Chinese).
16	Xing J, Wang Q, Coughlan K, Viollet B, Moriasi C and Zou MH: Inhibition of AMP-activated protein kinase accentuates lipopolysaccharide-induced lung endothelial barrier dysfunction and lung injury in vivo. Am J Pathol. 182:1021–1030. 2013.PubMed/NCBI View Article : Google Scholar
17	Tang S and Gong F: Cdc42 participates in the occurrence of chronic obstructive pulmonary disease by regulating migration of inflammatory cells. Minerva Med. 110:477–480. 2019.PubMed/NCBI View Article : Google Scholar
18	Vogelmeier CF, Criner GJ, Martinez FJ, Anzueto A, Barnes PJ, Bourbeau J, Celli BR, Chen R, Decramer M, Fabbri LM, et al: Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report. GOLD executive summary. Am J Respir Crit Care Med. 195:557–582. 2017.PubMed/NCBI View Article : Google Scholar
19	Cho O, Oh YT, Chun M, Noh OK and Heo JS: Prognostic implication of FEV1/FVC ratio for limited-stage small cell lung cancer. J Thorac Dis. 10:1797–1805. 2018.PubMed/NCBI View Article : Google Scholar
20	Sun N, Ye L, Chang T and Li X and Li X: microRNA-195-Cdc42 axis acts as a prognostic factor of esophageal squamous cell carcinoma. Int J Clin Exp Pathol. 7:6871–6879. 2014.PubMed/NCBI
21	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001.PubMed/NCBI View Article : Google Scholar
22	Hu ST, Xia Q, Zeng XL, Bao HR and Liu XJ: Effects of PI3Kδ-RhoA pathway on phagocytosis defect of alveolar macrophages in a mouse model of chronic obstructive pulmonary disease. Zhonghua Jie He He Hu Xi Za Zhi. 40:520–526. 2017.PubMed/NCBI View Article : Google Scholar : (In Chinese).
23	Yu Y, Jing L, Zhang X and Gao C: Simvastatin attenuates acute lung injury via regulating CDC42-PAK4 and endothelial microparticles. Shock. 47:378–384. 2017.PubMed/NCBI View Article : Google Scholar
24	Theodorakopoulou MP, Alexandrou ME, Bakaloudi DR, Pitsiou G, Stanopoulos I, Kontakiotis T and Boutou AK: Endothelial dysfunction in COPD: A systematic review and meta-analysis of studies using different functional assessment methods. ERJ Open Res. 7:2021.PubMed/NCBI View Article : Google Scholar
25	Rushton L: Chronic obstructive pulmonary disease and occupational exposure to silica. Rev Environ Health. 22:255–272. 2007.PubMed/NCBI View Article : Google Scholar
26	Dinarello CA: The IL-1 family of cytokines and receptors in rheumatic diseases. Nat Rev Rheumatol. 15:612–632. 2019.PubMed/NCBI View Article : Google Scholar
27	Chang SH: T helper 17 (Th17) cells and interleukin-17 (IL-17) in cancer. Arch Pharm Res. 42:549–559. 2019.PubMed/NCBI View Article : Google Scholar
28	Liu P, Jia S, Lou Y, He K and Xu LX: Cryo-thermal therapy inducing MI macrophage polarization created CXCL10 and IL-6-rich pro-inflammatory environment for CD4⁺ T cell-mediated anti-tumor immunity. Int J Hyperthermia. 36:408–420. 2019.PubMed/NCBI View Article : Google Scholar
29	Katz S, Zsiros V and Kiss AL: Under inflammatory stimuli mesenteric mesothelial cells transdifferentiate into macrophages and produce pro-inflammatory cytokine IL-6. Inflamm Res. 68:525–528. 2019.PubMed/NCBI View Article : Google Scholar