Cell and Organ Transplantology. 2024; 12(1):60-71
DOI: 10.22494/cot.v12i1.166
Morphofunctional changes in the kidneys of rats during acute respiratory distress syndrome and its treatment with human umbilical cord-derived mesenchymal stem cells
Palii I.
, Dovgalyuk A.
, Redko O.
, Dovbush A.
, Kramar S.
, Nebesna Z.
, Korda M.![]()
- I. Horbachevsky Ternopil National Medical University, Ternopil, Ukraine
Abstract
Acute respiratory distress syndrome (ARDS) is a severe pathological condition often accompanied by kidney injury. It is known that mesenchymal stem cells (MSCs) have high potential for treating various diseases due to their ability to paracrinely stimulate the regeneration of damaged cells and tissues and restore impaired organ functions.
Purpose: To investigate the nephroprotective effect of human umbilical cord MSCs in a model of ARDS induced in rats by intranasal administration of lipopolysaccharide (LPS).
Materials and methods: Seventy-two sexually mature male Wistar rats were randomly divided into nine groups: intact animals, 3 days, 7 days, and 28 days of ARDS development, MSC control, and four treatment groups: 24 hours LPS + 2 days MSCs, 4 days LPS + 3 days MSCs, 14 days LPS + 14 days MSCs, 21 days LPS + 7 days MSCs. MSCs were administered intraperitoneally at a dose of 106 cells/kg body weight. Levels of structural kidney damage were assessed using histological analysis of sections stained with hematoxylin and eosin. The expression of the fibrosis marker TGF-β1 in kidney tissues was evaluated by immunohistochemistry technique. Creatinine, urea, and uric acid levels in blood serum were measured using a kinetic method.
Results: The conducted studies revealed the presence of significant damage to the kidney parenchyma, signs of fibrosis, and impaired nephron function in rats with modeled ARDS. The severity of pathological changes increased with the duration of the experiment. The use of human umbilical MSCs as a treatment factor significantly reduced the severity of coagulopathy, tubular necrosis, and destruction of renal corpuscles, inhibited the development of interstitial fibrosis, and improved the levels of renal blood markers. The best nephroprotective effect of MSCs was observed on the 28th day of the experiment in the group 14 daysLPS + 14 daysMSCs. This is likely due to the earlier use and longer duration of action of the stem cells compared to the group 21 daysLPS + 7 daysMSCs.
Conclusion: Human umbilical MSCs have regenerative, antifibrotic, and nephroprotective effects in an animal model of kidney injury caused by ARDS. This may indicate the therapeutic potential of umbilical MSCs for the treatment of nephropathies of various origins.
Keywords:kidney injury; human umbilical cord mesenchymal stem cells; histological analysis; immunohistochemical analysis; renal blood markers
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| 1. Ramji HF, Hafiz M, Altaq HH, Hussain ST, Chaudry F. Acute Respiratory Distress Syndrome; A Review of Recent Updates and a Glance into the Future. Diagnostics (Basel). 2023 Apr 24;13(9):1528. https://doi.org/10.3390/diagnostics13091528 PMid:37174920 PMCid:PMC10177247 |
||||
| 2. Diamond M, Peniston HL, Sanghavi DK, Mahapatra S. Acute Respiratory Distress Syndrome. 2023 Apr 6. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan. Bookshelf ID: NBK436002 PMID: 28613773. | ||||
| 3. Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults. Lancet. 1967 Aug 12;2(7511):319-23. https://doi.org/10.1016/S0140-6736(67)90168-7 PMid:4143721 |
||||
| 4. Bellani G, Laffey JG, Pham T, Fan E, Brochard L, Esteban A, Gattinoni L, van Haren F, Larsson A, McAuley DF, Ranieri M, Rubenfeld G, Thompson BT, Wrigge H, Slutsky AS, Pesenti A; LUNG SAFE Investigators; ESICM Trials Group. Epidemiology, Patterns of Care, and Mortality for Patients With Acute Respiratory Distress Syndrome in Intensive Care Units in 50 Countries. JAMA. 2016 Feb 23;315(8):788-800. https://doi.org/10.1001/jama.2016.0291 PMid:26903337 |
||||
| 5. Bos LDJ, Ware LB. Acute respiratory distress syndrome: causes, pathophysiology, and phenotypes. Lancet. 2022 Oct 1;400(10358):1145-1156. https://doi.org/10.1016/S0140-6736(22)01485-4 PMid:36070787 |
||||
| 6. Huppert LA, Matthay MA, Ware LB. Pathogenesis of Acute Respiratory Distress Syndrome. Semin Respir Crit Care Med. 2019 Feb;40(1):31-39. https://doi.org/10.1055/s-0039-1683996 PMID: 31060086 |
||||
| 7. Kaku S, Nguyen CD, Htet NN, Tutera D, Barr J, Paintal HS, Kuschner WG. Acute Respiratory Distress Syndrome: Etiology, Pathogenesis, and Summary on Management. J Intensive Care Med. 2020 Aug;35(8):723-737. https://doi.org/10.1177/0885066619855021 PMid:31208266 |
||||
| 8. Saguil A, Fargo MV. Acute Respiratory Distress Syndrome: Diagnosis and Management. Am Fam Physician. 2020 Jun 15;101(12):730-738. PMID: 32538594. | ||||
| 9. Krynytska I, Marushchak M, Birchenko I, Dovgalyuk A, Tokarskyy O. COVID-19-associated acute respiratory distress syndrome versus classical acute respiratory distress syndrome (a narrative review). Iran J Microbiol. 2021; 13(6):728-738. https://doi.org/10.18502/ijm.v13i6.8072 PMid:35222850 PMCid:PMC8816697 |
||||
| 10. Zhang YY, Li BR, Ning BT. The Comparative Immunological Characteristics of SARS-CoV, MERS-CoV, and SARS-CoV-2 Coronavirus Infections. Front Immunol. 2020 Aug 14;11:2033. https://doi.org/10.3389/fimmu.2020.02033 PMid:32922406 PMCid:PMC7457039 |
||||
| 11. Keith P, Day M, Choe C, et al. The successful use of therapeutic plasma exchange for severe COVID-19 acute respiratory distress syndrome with multiple organ failure. SAGE Open Medical Case Reports. 2020;8. https://doi.org/10.1177/2050313X20933473 PMid:32595974 PMCid:PMC7303771 |
||||
| 12. Cortesi С. Acute Respiratory Distress Syndrome from a Kidney Perspective. ASN Kidney News. Vol. 12: Issue 8, Aug 2020. P: 22-23 | ||||
| 13. Palii, I., & Dovgalyuk, A. (2023). Morphofunctional state of the kidneys of laboratory rats during acute respiratory distress syndrome. Bulletin of Medical and Biological Research, 5(4), 42-52. https://doi.org/10.61751/bmbr/4.2023.42 |
||||
| 14. Pilarczyk K, Huenges K, Bewig B, Balke L, Cremer J, Haneya A, Panholzer B. Acute Kidney Injury in Patients with Severe ARDS Requiring Extracorporeal Membrane Oxygenation: Incidence, Prognostic Impact and Risk Factors. J Clin Med. 2022 Feb 18;11(4):1079. https://doi.org/10.3390/jcm11041079 PMid:35207357 PMCid:PMC8874829 |
||||
| 15. Lee KH, Tseng WC, Yang CY, Tarng DC. The Anti-Inflammatory, Anti-Oxidative, and Anti-Apoptotic Benefits of Stem Cells in Acute Ischemic Kidney Injury. Int J Mol Sci. 2019 Jul 19;20(14):3529. https://doi.org/10.3390/ijms20143529 PMid:31330934 PMCid:PMC6678402 |
||||
| 16. Rabb H, Griffin MD, McKay DB, Swaminathan S, Pickkers P, Rosner MH, Kellum JA, Ronco C; Acute Dialysis Quality Initiative Consensus XIII Work Group. Inflammation in AKI: Current Understanding, Key Questions, and Knowledge Gaps. J Am Soc Nephrol. 2016 Feb;27(2):371-9. https://doi.org/10.1681/ASN.2015030261 PMid:26561643 PMCid:PMC4731128 |
||||
| 17. Malek M, Nematbakhsh M. Renal ischemia/reperfusion injury; from pathophysiology to treatment. J Renal Inj Prev. 2015 Jun 1;4(2):20-7. https://doi.org/10.12861/jrip.2015.06 |
||||
| 18. Mulay SR, Holderied A, Kumar SV, Anders HJ. Targeting Inflammation in So-Called Acute Kidney Injury. Semin Nephrol. 2016 Jan;36(1):17-30. https://doi.org/10.1016/j.semnephrol.2016.01.006 PMid:27085732 |
||||
| 19. Yang Y, Gao J, Wang S, Wang W, Zhu FL, Wang X, Liang S, Feng Z, Lin S, Zhang L, Chen X, Cai G. Efficacy of umbilical cord mesenchymal stem cell transfusion for the treatment of severe AKI: a protocol for a randomised controlled trial. BMJ Open. 2022 Feb 21;12(2):e047622. https://doi.org/10.1136/bmjopen-2020-047622 PMid:35190406 PMCid:PMC8862499 |
||||
| 20. Tammaro A, Kers J, Scantlebery AML, Florquin S. Metabolic Flexibility and Innate Immunity in Renal Ischemia Reperfusion Injury: The Fine Balance Between Adaptive Repair and Tissue Degeneration. Front Immunol. 2020 Jul 7;11:1346. https://doi.org/10.3389/fimmu.2020.01346 PMid:32733450 PMCid:PMC7358591 |
||||
| 21. Gharaie Fathabad S, Kurzhagen JT, Sadasivam M, Noel S, Bush E, Hamad ARA, Rabb H. T Lymphocytes in Acute Kidney Injury and Repair. Semin Nephrol. 2020 Mar;40(2):114-125. https://doi.org/10.1016/j.semnephrol.2020.01.003 PMid:32303275 |
||||
| 22. Chen W, Li D. Reactive Oxygen Species (ROS)-Responsive Nanomedicine for Solving Ischemia-Reperfusion Injury. Front Chem. 2020 Aug 21;8:732. https://doi.org/10.3389/fchem.2020.00732 PMid:32974285 PMCid:PMC7472733 |
||||
| 23. Pavyde E, Usas A, Maciulaitis R. Regenerative pharmacology for the treatment of acute kidney injury: Skeletal muscle stem/progenitor cells for renal regeneration? Pharmacol Res. 2016 Nov;113(Pt B):802-807. https://doi.org/10.1016/j.phrs.2016.03.014 PMid:27001227 |
||||
| 24. Zhao H, Alam A, Soo AP, George AJT, Ma D. Ischemia-Reperfusion Injury Reduces Long Term Renal Graft Survival: Mechanism and Beyond. EBioMedicine. 2018 Feb;28:31-42. https://doi.org/10.1016/j.ebiom.2018.01.025 PMid:29398595 PMCid:PMC5835570 |
||||
| 25. Aghajani Nargesi A, Lerman LO, Eirin A. Mesenchymal stem cell-derived extracellular vesicles for kidney repair: current status and looming challenges. Stem Cell Res Ther. 2017 Dec 4;8(1):273. https://doi.org/10.1186/s13287-017-0727-7 PMid:29202871 PMCid:PMC5713024 |
||||
| 26. Hu H, Zou C. Mesenchymal Stem Cells in Renal Ischemia-Reperfusion Injury: Biological and Therapeutic Perspectives. Curr Stem Cell Res Ther. 2017;12(3):183-187. https://doi.org/10.2174/1574888X11666161024143640 PMid:27781940 |
||||
| 27. Özmert E, Arslan U. Management of retinitis pigmentosa by Wharton’s jelly derived mesenchymal stem cells: preliminary clinical results. Stem Cell Res Ther. 2020 Jan 13;11(1):25. https://doi.org/10.1186/s13287-020-1549-6 PMid:31931872 PMCid:PMC6958670 |
||||
| 28. Redko O, Dovgalyuk A, Nebesna Z, Kramar S, Sverstyuk A, Korda M. Human umbilical cord-derived мesenchymal stromal cells mitigate lipopolysaccharide-induced liver injury in rats. Cell Organ Transpl. 2023; 11(1):34-45. https://doi.org/10.22494/cot.v11i1.148 |
||||
| 29. Fan X, Li L, Ye Z, Zhou Y, Tan WS, Yang J. Advances in umbilical cord mesenchymal stem cells: A review of their potential in regenerative medicine. Expert Opin Biol Ther. 2021; 21(10):1355-1366. https://doi.org/10.1080/14712598.2021.1921837 |
||||
| 30. Redko O, Dovgalyuk A, Dovbush A, Nebesna Z, Yakubyshyna L, Krynytska I. Liver injury associated with acute respiratory distress syndrome and the prospects of mesenchymal stem cells therapy for liver failure. Cell Organ Transpl. 2021; 9(2):136-142. https://doi.org/10.22494/cot.v9i2.130 |
||||
| 31. Panitchote, A., Mehkri, O., Hastings, A. et al. Factors associated with acute kidney injury in acute respiratory distress syndrome. Ann. Intensive Care 9, 74 (2019). https://doi.org/10.1186/s13613-019-0552-5 PMid:31264042 PMCid:PMC6603088 |
||||
| 32. Shebl, Emana, Zake, Lamiaa G.a; Mowafy, Sherif M.b; Abd El-Hameed, Ayman R.c. Risk of acute kidney injury in patients with acute respiratory distress syndrome and its effect on the outcome. The Egyptian Journal of Chest Diseases and Tuberculosis 69(4):p 671-675, Oct-Dec 2020. https://doi.org/10.4103/ejcdt.ejcdt_213_19 |
||||
| 33. Huen SC, Cantley LG. Macrophages in Renal Injury and Repair. Annu Rev Physiol. 2017 Feb 10;79:449-469. https://doi.org/10.1146/annurev-physiol-022516-034219 PMid:28192060 |
||||
| 34. Packialakshmi, B., Stewart, I. J., Burmeister, D. M., Chung, K. K., & Zhou, X. (2020). Large animal models for translational research in acute kidney injury. Renal Failure, 42(1), 1042-1058. https://doi.org/10.1080/0886022X.2020.1830108 PMid:33043785 PMCid:PMC7586719 |
||||
| 35. Kim DJ, Moon JY, Kim SM, Seo JW, Lee YH, Jung SW, Kim K, Kim YG, Lim SJ, Lee S, Son Y, Lee SH. Substance P Improves Renal Ischemia Reperfusion Injury Through Modulating Immune Response. Front Immunol. 2020 Apr 23;11:600. https://doi.org/10.3389/fimmu.2020.00600 PMid:32391002 PMCid:PMC7190869 |
||||
| 36. Allinson, Charles Stuart; Pollock, Carol A.; Chen, Xinming. Mesenchymal Stem Cells in the Treatment of Acute Kidney Injury (AKI), Chronic Kidney Disease (CKD) and the AKI-to-CKD Transition. Integrative Medicine in Nephrology and Andrology 10(1):e00014, March 2023. https://doi.org/10.1097/IMNA-D-22-00014 |
||||
| 37. Changizi-Ashtiyani S, Hafazeh L, Ghasemi F, Najafi H, Babaei S, JalallyMashayekhi F, Hoseini SJ, Bastani B. The effect of adipose-derived mesenchymal stem cells on renal function and histopathology in a rat model of ischemia-reperfusion induced acute kidney injury. Iran J Basic Med Sci. 2020 Aug;23(8):999-1006. https://10.22038/ijbms.2020.40334.9601 |
||||
| 38. Cóndor JM, Rodrigues CE, Sousa Moreira Rd, Canale D, Volpini RA, Shimizu MH, Camara NO, Noronha Ide L, Andrade L. Treatment With Human Wharton’s Jelly-Derived Mesenchymal Stem Cells Attenuates Sepsis-Induced Kidney Injury, Liver Injury, and Endothelial Dysfunction. Stem Cells Transl Med. 2016 Aug;5(8):1048-57. https://doi.org/10.5966/sctm.2015-0138 PMid:27280799 PMCid:PMC4954445 |
||||
| 39. Xu, Q., Yan, P., Duan, X., Wu, X., Chen, X., Luo, M., Peng, J., Feng, L., Liu, J., Zhong, H., Cheng, W., Zou, Q., Duan, S.”Human umbilical cord derived mesenchymal stem cells and human cord blood mononuclear cells protect against cisplatin induced acute kidney injury in rat models”. Experimental and Therapeutic Medicine 20, no. 6 (2020): 145. https://doi.org/10.3892/etm.2020.9274 PMid:33093883 PMCid:PMC7571324 |
||||
| 40. Tseng, WC., Lee, PY., Tsai, MT. et al. Hypoxic mesenchymal stem cells ameliorate acute kidney ischemia-reperfusion injury via enhancing renal tubular autophagy. Stem Cell Res Ther 12, 367 (2021). https://doi.org/10.1186/s13287-021-02374-x PMid:34183058 PMCid:PMC8240301 |
||||
| 41. Missoum A. Recent Updates on Mesenchymal Stem Cell Based Therapy for Acute Renal Failure. Curr Urol. 2020 Jan;13(4):189-199. https://doi.org/10.1159/000499272 PMid:31998051 PMCid:PMC6976998 |
||||
| 42. Zhou T, Liao C, Lin S, Lin W, Zhong H, Huang S. The Efficacy of Mesenchymal Stem Cells in Therapy of Acute Kidney Injury Induced by Ischemia-Reperfusion in Animal Models. Stem Cells Int. 2020 Aug 3;2020:1873921. https://doi.org/10.1155/2020/1873921 PMid:32831852 PMCid:PMC7422493 |
||||
| 43. Fawzy MA, Beshay ON, Bekhit AA, Abdel-Hafez SMN, Batiha GE, Bin Jardan YA, Fathy M. Nephroprotective effect of AT-MSCs against cisplatin-induced EMT is improved by azilsartan via attenuating oxidative stress and TGF-β/Smad signaling. Biomed Pharmacother. 2023 Feb;158:114097. https://doi.org/10.1016/j.biopha.2022.114097 PMid:36502757 |
||||
| 44. Lee M, Kim SH, Jhee JH, Kim TY, Choi HY, Kim HJ, Park HC. Microparticles derived from human erythropoietin mRNA-transfected mesenchymal stem cells inhibit epithelial-to-mesenchymal transition and ameliorate renal interstitial fibrosis. Stem Cell Res Ther. 2020 Sep 29;11(1):422. https://doi.org/10.1186/s13287-020-01932-z PMid:32993806 PMCid:PMC7523343 |
||||
| 45. Isaka Y. Targeting TGF-β Signaling in Kidney Fibrosis. Int J Mol Sci. 2018 Aug 27;19(9):2532. https://doi.org/10.3390/ijms19092532 PMid:30150520 PMCid:PMC6165001 |
||||
| 46. Ma TT, Meng XM. TGF-β/Smad and Renal Fibrosis. Adv Exp Med Biol. 2019;1165:347-364. https://doi.org/10.1007/978-981-13-8871-2_16 PMid:31399973 |
||||
| 47. Hu HH, Chen DQ, Wang YN, Feng YL, Cao G, Vaziri ND, Zhao YY. New insights into TGF-β/Smad signaling in tissue fibrosis. Chem Biol Interact. 2018 Aug 25;292:76-83. https://doi.org/10.1016/j.cbi.2018.07.008 PMid:30017632 |
||||
| 48. Tang PC, Chan AS, Zhang CB, García Córdoba CA, Zhang YY, To KF, Leung KT, Lan HY, Tang PM. TGF-β1 Signaling: Immune Dynamics of Chronic Kidney Diseases. Front Med (Lausanne). 2021 Feb 25;8:628519. https://doi.org/10.3389/fmed.2021.628519 PMid:33718407 PMCid:PMC7948440 |
||||
| 49. Sureshbabu A, Muhsin SA, Choi ME. TGF-β signaling in the kidney: profibrotic and protective effects. Am J Physiol Renal Physiol. 2016 Apr 1;310(7):F596-F606. doi: 10.1152/ajprenal.00365.2015. Epub 2016 Jan 6. https://doi.org/10.1152/ajprenal.00365.2015 PMid:26739888 PMCid:PMC4824143 |
||||
| 50. Huang C, Meng M, Li S, Liu S, Li L, Su Y, Gao H, He S, Zhao Y, Zhang M, Hou Z, Wang W, Wang X. Umbilical Cord Mesenchymal Stem Cells Ameliorate Kidney Injury in MRL/Ipr Mice Through the TGF-β1 Pathway. Front Cell Dev Biol. 2022 Apr 5;10:876054. https://doi.org/10.3389/fcell.2022.876054 PMid:35478960 PMCid:PMC9037034 |
||||
| 51. Ullah M, Liu DD, Rai S, Dadhania A, Jonnakuti S, Concepcion W, Thakor AS. Reversing Acute Kidney Injury Using Pulsed Focused Ultrasound and MSC Therapy: A Role for HSP-Mediated PI3K/AKT Signaling. Mol Ther Methods Clin Dev. 2020 Mar 30;17:683-694. https://doi.org/10.1016/j.omtm.2020.03.023 PMid:32346546 PMCid:PMC7177168 |
||||
| 52. Torres Crigna A, Daniele C, Gamez C, Medina Balbuena S, Pastene DO, Nardozi D, Brenna C, Yard B, Gretz N, Bieback K. Stem/Stromal Cells for Treatment of Kidney Injuries With Focus on Preclinical Models. Front Med (Lausanne). 2018 Jun 15;5:179. https://doi.org/10.3389/fmed.2018.00179 PMid:29963554 PMCid:PMC6013716 |
||||
| 53. Usunier B, Benderitter M, Tamarat R, Chapel A. Management of fibrosis: the mesenchymal stromal cells breakthrough. Stem Cells Int. 2014;2014:340257. DOI: 10.1155/2014/340257. Epub 2014 Jul 14. https://doi.org/10.1155/2014/340257 PMid:25132856 PMCid:PMC4123563 |
||||
| 54. de Almeida DC, Donizetti-Oliveira C, Barbosa-Costa P, Origassa CS, Câmara NO. In search of mechanisms associated with mesenchymal stem cell-based therapies for acute kidney injury. Clin Biochem Rev. 2013 Nov;34(3):131-44. PMID: 24353358; PMCID: PMC3866950. | ||||
Palii I, Dovgalyuk A, Redko O, Dovbush A, Kramar S, Nebesna Z, Korda M. Morphofunctional changes in the kidneys of rats during acute respiratory distress syndrome and its treatment with human umbilical cord-derived mesenchymal stem cells. Cell Organ Transpl. 2024; 12(1):60-71. Available from: https://doi.org/10.22494/cot.v12i1.166

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