Interplay of Heat Shock Proteins and Oxidative Stress in Modulating Neutrophil Activation in Cystic Fibrosis Inflammation
DOI:
https://doi.org/10.36283/ziun-pjmd14-2/018Keywords:
Heat Shock Proteins , Malondialdehyde (MDA) , Myeloperoxidase , Matrix Metalloproteinase-9Abstract
Background: Cystic fibrosis, is an autosomal recessive disorder characterized by persistent inflammation, unregulated immune responses, and pneumonic complications. The central role of CF-associated inflammation is neutrophil activation triggered by oxidative stress and Heat Shock Proteins (HSPs). The present study seeks to explore the interaction of oxidative stress, HSPs, and neutrophil activation in CF patients.
Methods: A case-control study was conducted from January-2023 to June-2024 at the School of Pain Regenerative Medicine, The University of Lahore, including 100 CF patients and 100 age and gender-matched controls. A purposive sampling method was employed to recruit participants for this retrospective case-control study. Serum MDA, 4-HNE, 8-OHdG, and isoprostanes were quantified. The HSP27, HSP70, and HSP90, neutrophil activation was measured using neutrophil elastase, myeloperoxidase, and matrix metalloproteinase-9. Values are expressed as mean±SD with a significance threshold of p < 0.05.
Results: The MDA values were (5.89±1.38 nmol/mg), 4-HNE (18.3±4.63 mol/L). HSP27 levels were significantly increased (72.53±12.27 ng/mL), HSP70 (110.23±15.67 ng/mL), and HSP90 (88.6±14.21 ng/mL). Neutrophil activation markers, (250.88±35.16 g/L) and MPO (340.01 42.22 ng/mL) were significantly increased. Neutrophil elastase (200 g/L) has a high sensitivity (83%) (95 % CI: 4.36-14.25), which is a significant predictor of neutrophil-driven inflammation.
Conclusion: The findings suggest that neutrophil activation and sustained inflammation in CF are caused by HSPs and oxidative stress. Elevated HSPs and oxidative stress markers are associated with increased pneumonic inflammation. Novel curative measures to reduce CF-associated inflammation are likely to be developed through target HSPs and oxidative stress variables.
References
Laucirica DR, Garratt LW, Kicic A. Progress in model systems of cystic fibrosis mucosal inflammation to understand aberrant neutrophil activity. Frontiers in immunology. 2020 Apr 7;11:595. https://doi.org/10.3389/fimmu.2020.00595.
Wang G, Nauseef WM. Neutrophil dysfunction in the pathogenesis of cystic fibrosis. Blood, The Journal of the American Society of Hematology. 2022 Apr 28;139(17):2622-31. https://doi.org/10.1182/blood.2021014699.
Keown K, Brown R, Doherty DF, Houston C, McKelvey MC, Creane S, Linden D, McAuley DF, Kidney JC, Weldon S, Downey DG. Airway inflammation and host responses in the era of CFTR modulators. International journal of molecular sciences. 2020 Sep 2;21(17):6379. https://doi.org/10.3390/ijms21176379.
Yonker LM, Marand A, Muldur S, Hopke A, Leung HM, De La Flor D, Park G, Pinsky H, Guthrie LB, Tearney GJ, Irimia D. Neutrophil dysfunction in cystic fibrosis. Journal of Cystic Fibrosis. 2021 Nov 1;20(6):1062-71. https://doi.org/10.1016/j.jcf.2021.01.012.
Abd El-Fattah EE, Zakaria AY. Targeting HSP47 and HSP70: promising therapeutic approaches in liver fibrosis management. Journal of Translational Medicine. 2022 Nov 26;20(1):544. https://doi.org/10.1186/s12967-022-03759-z.
Moliteo E, Sciacca M, Palmeri A, Papale M, Manti S, Parisi GF, Leonardi S. Cystic fibrosis and oxidative stress: the role of CFTR. Molecules. 2022 Aug 21;27(16):5324. https://doi.org/10.3390/molecules27165324.
Simon S, Aissat A, Degrugillier F, Simonneau B, Fanen P, Arrigo AP. Small Hsps as Therapeutic Targets of Cystic Fibrosis Transmembrane Conductance Regulator Protein. International Journal of Molecular Sciences. 2021 Apr 20;22(8):4252. https://doi.org/10.3390/ijms22084252.
Soares VE, do Carmo TI, Dos Anjos F, Wruck J, de Oliveira Maciel SF, Bagatini MD, de Resende E Silva DT. Role of inflammation and oxidative stress in tissue damage associated with cystic fibrosis: CAPE as a future therapeutic strategy. Molecular and Cellular Biochemistry. 2022 Jan;477(1):39-51. https://doi.org/10.1007/s11010-021-04263-6.
McKelvey MC, Weldon S, McAuley DF, Mall MA, Taggart CC. Targeting proteases in cystic fibrosis lung disease. Paradigms, progress, and potential. American Journal of Respiratory and Critical Care Medicine. 2020 Jan 15;201(2):141-7. https://doi.org/10.1164/rccm.201906-1190PP.
Voynow JA, Shinbashi M. Neutrophil elastase and chronic lung disease. Biomolecules. 2021 Jul 21;11(8):1065. https://doi.org/10.3390/biom11081065.
Causer AJ, Shute JK, Cummings MH, Shepherd AI, Gruet M, Costello JT, Bailey S, Lindley M, Pearson C, Connett G, Allenby MI. Circulating biomarkers of antioxidant status and oxidative stress in people with cystic fibrosis: A systematic review and meta-analysis. Redox biology. 2020 May 1;32:101436. https://doi.org/10.1016/j.redox.2020.101436.
Patergnani S, Vitto VA, Pinton P, Rimessi A. Mitochondrial stress responses and “Mito-Inflammation” in cystic fibrosis. Frontiers in pharmacology. 2020 Sep 30;11:581114. https://doi.org/10.3389/fphar.2020.581114.
Charan J, Biswas T. How to calculate sample size for different study designs in medical research? Indian J Psychol Med. 2013 Apr;35(2):121-6. doi: 10.4103/0253-7176.116232.
Frey DL, Boutin S, Dittrich SA, Graeber SY, Stahl M, Wege S, Herth FJ, Sommerburg O, Schultz C, Mall MA, Dalpke AH. Relationship between airway dysbiosis, inflammation and lung function in adults with cystic fibrosis. Journal of Cystic Fibrosis. 2021 Sep 1;20(5):754-60. https://doi.org/10.1016/j.jcf.2020.12.022.
Zhu J, Liu L, Ma X, Cao X, Chen Y, Qu X, Ji M, Liu H, Liu C, Qin X, Xiang Y. The role of DNA damage and repair in idiopathic pulmonary fibrosis. Antioxidants. 2022 Nov 19;11(11):2292. https://doi.org/10.3390/antiox11112292.
Tucker SL, Sarr D, Rada B. Neutrophil extracellular traps are present in the airways of ENaC-overexpressing mice with cystic fibrosis-like lung disease. BMC immunology. 2021 Dec;22:1-1. https://doi.org/10.1186/s12865-021-00397-w.
Almughem FA, Aldossary AM, Tawfik EA, Alomary MN, Alharbi WS, Alshahrani MY, Alshehri AA. Cystic fibrosis: overview of the current development trends and innovative therapeutic strategies. Pharmaceutics. 2020 Jul 2;12(7):616. https://doi.org/10.3390/pharmaceutics12070616.
Galiniak S, Mołoń M, Rachel M. Links between disease severity, bacterial infections and oxidative stress in cystic fibrosis. Antioxidants. 2022 Apr 29;11(5):887. https://doi.org/10.3390/antiox11050887.
Kapnadak SG, Dimango E, Hadjiliadis D, Hempstead SE, Tallarico E, Pilewski JM, Faro A, Albright J, Benden C, Blair S, Dellon EP. Cystic Fibrosis Foundation consensus guidelines for the care of individuals with advanced cystic fibrosis lung disease. Journal of Cystic Fibrosis. 2020 May 1;19(3):344-54. https://doi.org/10.1016/j.jcf.2020.02.015.
Esposito R, Mirra D, Spaziano G, Panico F, Gallelli L, D’Agostino B. The Role of MMPs in the Era of CFTR Modulators: An Additional Target for Cystic Fibrosis Patients?. Biomolecules. 2023 Feb 10;13(2):350. https://doi.org/10.3390/biom13020350.
Cameli P, Carleo A, Bergantini L, Landi C, Prasse A, Bargagli E. Oxidant/antioxidant disequilibrium in idiopathic pulmonary fibrosis pathogenesis. Inflammation. 2020 Feb;43:1-7. https://doi.org/10.1007/s10753-019-01059-1.
Regard L., Martin C., Chassagnon G., Burgel P.-R. Acute and Chronic Non-Pulmonary Complications in Adults with Cystic Fibrosis. Expert Rev. Respir. Med. 2019;13:23–38. doi: 10.1080/17476348.2019.1552832.
Yamada A., Komaki Y., Komaki F., Micic D., Zullow S., Sakuraba A. Risk of Gastrointestinal Cancers in Patients with Cystic Fibrosis: A Systematic Review and Meta-Analysis. Lancet Oncol. 2018;19:758–767. doi: 10.1016/S1470-2045(18)30188-8.
Bell S.C., Mall M.A., Gutierrez H., Macek M., Madge S., Davies J.C., Burgel P.-R., Tullis E., Castaños C., Castellani C., et al. The Future of Cystic Fibrosis Care: A Global Perspective. Lancet Respir. Med. 2020;8:65–124. doi: 10.1016/S2213-2600(19)30337-6.
Zhang X, Zhang X, Huang W, Ge X. The role of heat shock proteins in the regulation of fibrotic diseases. Biomedicine & Pharmacotherapy. 2021 Mar 1;135:111067. https://doi.org/10.1016/j.biopha.2020.111067.
Cabrini G, Rimessi A, Borgatti M, Lampronti I, Finotti A, Pinton P, Gambari R. Role of cystic fibrosis bronchial epithelium in neutrophil chemotaxis. Frontiers in immunology. 2020 Aug 4;11:1438. https://doi.org/10.3389/fimmu.2020.01438.
Ong T, Ramsey BW. Cystic fibrosis: a review. Jama. 2023 Jun 6;329(21):1859-71. https://doi.org/10.1001/jama.2023.8120.
Kumar V, Roy S, Behera BK, Das BK. Heat shock proteins (Hsps) in cellular homeostasis: a promising tool for health management in crustacean aquaculture. Life. 2022 Nov 3;12(11):1777. https://doi.org/10.3390/life12111777
Downloads
Published
Issue
Section
License
Copyright (c) 2025 Pakistan Journal of Medicine and Dentistry
This work is licensed under a Creative Commons Attribution 4.0 International License.
This is an open-access article distributed under the terms of the CreativeCommons Attribution License (CC BY) 4.0 https://creativecommons.org/licenses/by/4.0/
