CTRP3 regulates NF-κB and TGFβ1/Smad3 pathways to alleviate airway inflammation and remodeling in asthmatic mice induced by OVA
Main Article Content
Keywords
Asthma, airway inflammation, airway remodeling, CTRP3, NF-κB, TGFβ1/Smad3
Abstract
Background: Asthma is a common illness with chronic airway inflammation. C1q/tumor necrosis factor (TNF)-related protein 3 (CTRP3) plays a vital role ininflammatory response, but its effect on asthma is imprecise. Herein, we analyzed the functions of CTRP3 in asthma.
Methods: The BALB/c mice were randomized into four groups: control, ovalbumin (OVA), OVA+vector, and OVA+CTRP3. The asthmatic mice model was established by OVA stimulation. Overexpression of CTRP3 was implemented by the transfection of corresponding adeno-associated virus 6 (AAV6). The contents of CTRP3, E-cadherin, N-cadherin, smooth muscle alpha-actin (α-SMA), phosphorylated (p)-p65/p65, transforming growth factor-beta 1 (TGFβ1), and p-Smad3/Smad3 were determined by Western blot analysis. The quantity of total cells, eosinophils, neutrophils, and lymphocytes in bronchoalveolar lavage fluid (BALF) was assessed by using a hemocytometer. The contents of tumor necrosis factor-α and interleukin-1β in BALF were examined by enzyme-linked immunesorbent serologic assay. The lung function indicators and airway resistance (AWR) were measured. The bronchial and alveolar structures were evaluated by hematoxylin and eosin staining and sirius red staining.
Results: The CTRP3 was downregulated in mice of OVA groups; however, AAV6-CTRP3 treatment markedly upregulated the expression of CTRP3. Upregulation of CTRP3 diminished asthmatic airway inflammation by decreasing the number of inflammatory cells and the contents of proinflammatory factors. CTRP3 markedly lessened AWR and improved lung function in OVA-stimulated mice. Histological analysis found that CTRP3 alleviated OVA-induced airway remodeling in mice. Moreover, CTRP3 modulated NF-κB and TGFβ1/Smad3 pathways in OVA-stimulated mice.
Conclusion: CTRP3 alleviated airway inflammation and remodeling in OVA-induced asthmatic mice via regulating NF-κB and TGFβ1/Smad3 pathways.
References
2. Poddighe D, Brambilla I, Licari A, Marseglia GL. Omalizumab in the therapy of pediatric asthma. Recent Pat Inflamm Allergy Drug Discov. 2018;12(2):103–9. 10.2174/1872213X12666180430161351
3. Dong L, Wang Y, Zheng T, Pu Y, Ma Y, Qi X, et al. Hypoxic hUCMSC-derived extracellular vesicles attenuate allergic airway inflammation and airway remodeling in chronic asthma mice. Stem Cell Res Ther. 2021;12(1):4. 10.1186/s13287-020-02072-0
4. Bousquet J, Schunemann HJ, Togias A, Bachert C, Erhola M, Hellings PW, et al. Next-generation allergic rhinitis and its impact on asthma (ARIA) guidelines for allergic rhinitis based on grading of recommendations assessment, development and evaluation (GRADE) and real-world evidence. J Allergy Clin Immunol. 2020;145(1):70–80.e3. 10.1046/j.1472-9725.2003.00063.x
5. Cardona V, Ansotegui IJ, Ebisawa M, El-Gamal Y, Fernandez Rivas M, Fineman S, et al. World allergy organization anaphylaxis guidance 2020. World Allergy Organ J. 2020;13(10):10047210.1016/j.waojou.2020.100472
6. Patel SJ, Teach SJ. Asthma. Pediatr Rev. 2019;40(11):549–67. 10.1542/pir.2018-0282
7. Gans MD, Gavrilova T. Understanding the immunology of asthma: Pathophysiology, biomarkers, and treatments for asthma endotypes. Paediatr Respir Rev. 2020;36:118–27. 10.1016/j.prrv.2019.08.002
8. Zhang J, Zhou Y, Gu H, Zhang J, Tang H, Rong Q, et al. LncRNA-AK149641 associated with airway inflammation in an OVA-induced asthma mouse model. J Bioenerg Biomembr. 2020;52(5):355–65. 10.1007/s10863-020-09844-6
9. Jones TL, Neville DM, Chauhan AJ. Diagnosis and treatment of severe asthma: A phenotype-based approach. Clin Med (Lond). 2018;18(Suppl 2):s36–40. 10.7861/clinmedicine.18-2-s36
10. Niessen NM, Gibson PG, Simpson JL, Scott HA, Baines KJ, Fricker M. Airway monocyte modulation relates to tumour necrosis factor dysregulation in neutrophilic asthma. ERJ Open Res. 2021;7(3):131-2021. 10.1183/23120541.00131-2021
11. Li Y, Wright GL, Peterson JM. C1q/TNF-related protein 3 (CTRP3) function and regulation. Compr Physiol. 2017;7(3):863–78. 10.1002/cphy.c160044
12. Wei WY, Ma ZG, Zhang N, Xu SC, Yuan YP, Zeng XF, et al. Overexpression of CTRP3 protects against sepsis-induced myocardial dysfunction in mice. Mol Cell Endocrinol. 2018;476:27–36. 10.1016/j.mce.2018.04.006
13. Lv C, He Y, Wei M, Xu G, Chen C, Xu Z, et al. CTRP3 ameliorates cerulein-induced severe acute pancreatitis in mice via SIRT1/NF-kappaB/p53 axis. Biosci Rep. 2020;40(10):BSR20200092. 10.1042/BSR20200092.
14. Wu D, Lei H, Wang JY, Zhang CL, Feng H, Fu FY, et al. CTRP3 attenuates post-infarct cardiac fibrosis by targeting Smad3 activation and inhibiting myofibroblast differentiation. J Mol Med (Berl). 2015;93(12):1311–25. 10.1007/s00109-015-1309-8
15. National Research Council (US) Committee for the Update of the Guide for the Care and Use of Laboratory Animals. Guide for the Care and Use of Laboratory Animals, 8th ed. Washington, DC: National Academies Press; 2011. Reports funded by National Institutes of Health. PMid: 21595115.
16. Strobel B, Duechs MJ, Schmid R, Stierstorfer BE, Bucher H, Quast K, et al. Modeling pulmonary disease pathways using recombinant adeno-associated virus 6.2. Am J Respir Cell Mol Biol. 2015;53(3):291–302. 10.1165/rcmb.2014-0338MA
17. Liang S, Zhou Z, Zhou Z, Liang J, Lin W, Zhang C, et al. Blockade of CBX4-mediated beta-catenin SUMOylation attenuates airway epithelial barrier dysfunction in asthma. Int Immunopharmacol. 2022;113(Pt A):109333. 10.1016/j.intimp.2022.109333
18. Rahmati M, Shariatzadeh Joneydi M, Koyanagi A, Yang G, Ji B, Won Lee S, et al. Resistance training restores skeletal muscle atrophy and satellite cell content in an animal model of Alzheimer’s disease. Sci Rep. 2023;13(1):2535. 10.1038/s41598-023-29406-1
19. Rahmati M, Taherabadi SJ. The effects of exercise training on Kinesin and GAP-43 expression in skeletal muscle fibers of STZ-induced diabetic rats. Sci Rep. 2021;11(1):9535. 10.1038/s41598-021-89106-6
20. Bostani M, Rahmati M, Mard SA. The effect of endurance training on levels of LINC complex proteins in skeletal muscle fibers of STZ-induced diabetic rats. Sci Rep. 2020;10(1):8738. 10.1038/s41598-020-65793-5
21. Rahmati M, Rashno A. Automated image segmentation method to analyse skeletal muscle cross section in exercise-induced regenerating myofibers. Sci Rep. 2021;11(1):21327. 10.1038/s41598-021-00886-3
22. Rehman A, Amin F, Sadeeqa S. Prevalence of asthma and its management: A review. J Pak Med Assoc. 2018;68(12):1823–7.
23. Miller RL, Grayson MH, Strothman K. Advances in asthma: New understandings of asthma’s natural history, risk factors, underlying mechanisms, and clinical management. J Allergy Clin Immunol. 2021;148(6):1430–41. 10.1016/j.jaci.2021.10.001
24. Wu HK, Chang ES, Cheng CW, Chien WC, Chou HH. Impact of COVID-19 pandemic waves on pediatric emergency department patients presenting with asthma attacks in Taiwan. Signa Vitae. 2022; 18(6):27-32. https://www.signavitae.com/articles/10.22514/sv.2022.045
25. Tanaka K, Arakawa M, Miyake Y. Perinatal smoking exposure and risk of asthma in the first three years of life: A prospective prebirth cohort study. Allergol Immunopathol (Madr). 2020;48(6):530–6. 10.1016/j.aller.2020.03.008
26. Bimstein E, Wilson J, Guelmann M, Primosch RE. The relationship between oral and demographic characteristics of children with asthma. J Clin Pediatr Dent. 2006;31(2):86–9. 10.17796/jcpd.31.2.977776084511l005
27. Cazzola M, Rogliani P, Ora J, Calzetta L, Matera MG. Asthma and comorbidities: Recent advances. Pol Arch Intern Med. 2022;132(4):16250. 10.20452/pamw.16250.
28. Funston W, Higgins B. Improving the management of asthma in adults in primary care. Practitioner. 2014;258(1776):15–9, 2.
29. Hu TY, Li LM, Pan YZ. CTRP3 inhibits high glucose-induced human glomerular mesangial cell dysfunction. J Cell Biochem. 2019;120(4):5729–36. 10.1002/jcb.27859
30. Petersen PS, Wolf RM, Lei X, Peterson JM, Wong GW. Immunomodulatory roles of CTRP3 in endotoxemia and metabolic stress. Physiol Rep. 2016;4(5):e12735. 10.14814/phy2.12735
31. Yu H, Zhang Z, Li G, Feng Y, Xian L, Bakhsh F, et al. Adipokine C1q/tumor necrosis factor-related protein 3 (CTRP3) attenuates intestinal inflammation via Sirtuin 1/NF-kappaB signaling. Cell Mol Gastroenterol Hepatol. 2023;15(4):1000–1015. 10.1101/2022.05.08.491034
32. Zhang J, Lin X, Xu J, Tang F, Tan L. CTRP3 protects against uric acid-induced endothelial injury by inhibiting inflammation and oxidase stress in rats. Exp Biol Med (Maywood). 2022;247(2):174–83. 10.1177/15353702211047183
33. Meng J, Wang DM, Luo LL. CTRP3 acts as a novel regulator in depressive-like behavior associated inflammation and apoptosis by meditating p38 and JNK MAPK signaling. Biomed Pharmacother. 2019;120:109489. 10.1016/j.biopha.2019.109489
34. Guo B, Zhuang T, Xu F, Lin X, Li F, Shan SK, et al. New insights into implications of CTRP3 in obesity, metabolic dysfunction, and cardiovascular diseases: Potential of therapeutic interventions. Front Physiol. 2020;11:570270. 10.3389/fphys.2020.570270
35. Yaribeygi H, Rashidfarrokhi F, Atkin SL, Sahebkar A. C1q/TNF-related protein-3 and glucose homeostasis. Diabetes Metab Syndr. 2019;13(3):1923–7. 10.1016/j.dsx.2019.04.047
36. Turkeli A, Yilmaz O, Karaman M, Kanik ET, Firinci F, Inan S, et al. Anti-VEGF treatment suppresses remodeling factors and restores epithelial barrier function through the E-cadherin/beta-catenin signaling axis in experimental asthma models. Exp Ther Med. 2021;22(1):689. 10.3892/etm.2021.10121
37. Pu Y, Liu Y, Liao S, Miao S, Zhou L, Wan L. Azithromycin ameliorates OVA-induced airway remodeling in Balb/c mice via suppression of epithelial-to-mesenchymal transition. Int Immunopharmacol. 2018;58:87–93. 10.1016/j.intimp.2018.03.016
38. Gai YL, Hao YF, Guo K. PIM2 promotes lung adenocarcinoma cell migration by regulating XIAP/NF-κB pathway. J Men Health. 2021; 17(3):153-159. https://www.jomh.org/articles/10.31083/jomh.2021.052
39. Sheng XJ, Zhou DM, Liu Q, Lou SY, Song QY, Zhou YQ. BRMS1 inhibits expression of NF-kappa B subunit p65, uPA and OPN in ovarian cancer cells. Eur J Gynaecol Oncol. 2014;35(3):236–42.
40. Wang Q, Cui Y, Wu X, Wang J. Evodiamine protects against airway remodelling and inflammation in asthmatic rats by modulating the HMGB1/NF-kappaB/TLR-4 signalling pathway. Pharm Biol. 2021;59(1):192–9. 10.1080/13880209.2020.1871374
41. Huo R, Tian X, Chang Q, Liu D, Wang C, Bai J, et al. Targeted inhibition of beta-catenin alleviates airway inflammation and remodeling in asthma via modulating the profibrotic and anti-inflammatory actions of transforming growth factor-beta(1). Ther Adv Respir Dis. 2021;15:1753466620981858. 10.1177/1753466620981858
42. Poddighe D, Mathias CB, Freyschmidt EJ, Kombe D, Caplan B, Marseglia GL, et al. Basophils are rapidly mobilized following initial aeroallergen encounter in naive mice and provide a priming source of IL-4 in adaptive immune responses. J Biol Regul Homeost Agents. 2014;28(1):91–103.
