Stem cells have emerged as promising therapeutic options for several human diseases, including pulmonary fibrosis (PF). In this study, we investigated the therapeutic effects of adipose tissue-derived mesenchymal stem cells (ADMSCs) in the bleomycin-induced PF model rats and the underlying mechanisms. The PF model rats were generated by intratracheal injections of 5 mg/kg bleomycin sulfate. The ADMSC group rats were generated by injecting 2×10(6) ADMSCs via the tail vein at 0, 12, and 24 h after bleomycin injection. The control, PF, and ADMSC group rats were sacrificed on day 21 after bleomycin injections and the changes in lung histology and the levels of pro-inflammatory cytokines, collagen I, and caveolin-1 (Cav-1), and the activity of the NF-kappaB signaling pathway in the lung tissues was assessed by hematoxylin-eosin staining, ELISA, and western blotting assays. The lung tissues of the PF model rats showed significant infiltration of neutrophils, tissue destruction, and collagen deposition, but these effects were abrogated by the ADMSCs. The levels of pro-inflammatory cytokines such as IL-6, IL-1beta, and TGF-beta1 were elevated in the lung tissues and the bronchoalveolar lavage fluid (BALF) of the bleomycin-induced PF model rats, but these effects were reversed by the ADMSCs. The lung tissues of the PF model rats showed significant downregulation of Cav-1 and significantly higher activation of the pro-inflammatory NF-kappaB pathway. However, administration of the ADMSCs restored the expression levels of Cav-1 and suppressed the NF-kappaB signaling pathway in the lungs of the bleomycin-induced PF model rats. In conclusion, this study demonstrated that the ADMSCs protected against bleomycin-induced PF in the rat model by modulating the Cav-1/NF-kappaB axis.

Department of Respiratory The 1st People's Hospital of Wenling Wenling Zhejiang China

Zobrazit více v PubMed

Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 2000;342:1334–1349. doi: 10.1056/NEJM200005043421806. PubMed DOI

Perez A, Rogers RM, Dauber JH. The prognosis of idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol. 2003;29(3 Suppl):S19–S26. PubMed

Chlumský J, Stehlík L, Šterclová M, Smetanová J, Zindr O. Exercise tolerance in patients with idiopathic pulmonary fibrosis, effect of supplemental oxygen. Physiol Res. 2022;71:317–321. doi: 10.33549/physiolres.934764. PubMed DOI PMC

American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS) Am J Respir Crit Care Med. 2000;161:646–664. doi: 10.1164/ajrccm.161.2.ats3-00. PubMed DOI

Raghu G. Idiopathic pulmonary fibrosis: treatment options in pursuit of evidence-based approaches. Eur Respir J. 2006;28:463–465. doi: 10.1183/09031936.06.00086606. PubMed DOI

Sime PJ, Xing Z, Graham FL, Csaky KG, Gauldie J. Adenovector-mediated gene transfer of active transforming growth factor-beta1 induces prolonged severe fibrosis in rat lung. J Clin Invest. 1997;100:768–776. doi: 10.1172/JCI119590. PubMed DOI PMC

Scotton CJ, Chambers RC. Molecular targets in pulmonary fibrosis: the myofibroblast in focus. Chest. 2007;132:1311–1321. doi: 10.1378/chest.06-2568. PubMed DOI

Sueblinvong V, Weiss DJ. Stem cells and cell therapy approaches in lung biology and diseases. Transl Res. 2010;156:188–205. doi: 10.1016/j.trsl.2010.06.007. PubMed DOI PMC

Ortiz LA, Gambelli F, McBride C, Gaupp D, Baddoo M, Kaminski N, Phinney DG. Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. Proc Natl Acad Sci U S A. 2003;100:8407–8411. doi: 10.1073/pnas.1432929100. PubMed DOI PMC

Periera-Simon S, Xia X, Catanuto P, Coronado R, Kurtzberg J, Bellio M, Lee Y-S, et al. Anti-fibrotic effects of different sources of MSC in bleomycin-induced lung fibrosis in C57BL6 male mice. Respirology. 2021;26:161–170. doi: 10.1111/resp.13928. PubMed DOI

Leu S, Lin YC, Yuen CM, Yen CH, Kao YH, Sun CK, Yip H-K. Adipose-derived mesenchymal stem cells markedly attenuate brain infarct size and improve neurological function in rats. J Transl Med. 2010;8:63. doi: 10.1186/1479-5876-8-63. PubMed DOI PMC

Banas A, Teratani T, Yamamoto Y, Tokuhara M, Takeshita F, Osaki M, Kawamata M, et al. IFATS collection: in vivo therapeutic potential of human adipose tissue mesenchymal stem cells after transplantation into mice with liver injury. Stem Cells. 2008;26:2705–2712. doi: 10.1634/stemcells.2008-0034. PubMed DOI

Sanon VP, Sawaki D, Mjaatvedt CH, Jourdan-Le Saux C. Myocardial tissue caveolae. Compr Physiol. 2015;5:871–886. doi: 10.1002/cphy.c140050. PubMed DOI

Gvaramia D, Blaauboer ME, Hanemaaijer R, Everts V. Role of caveolin-1 in fibrotic diseases. Matrix Biol. 2013;32:307–315. doi: 10.1016/j.matbio.2013.03.005. PubMed DOI

Kulshrestha R, Singh H, Pandey A, Mehta A, Bhardwaj S, Jaggi AS. Caveolin-1 as a critical component in the pathogenesis of lung fibrosis of different etiology: Evidences and mechanisms. Exp Mol Pathol. 2019;111:104315. doi: 10.1016/j.yexmp.2019.104315. PubMed DOI

He R, Yuan X, Lv X, Liu Q, Tao L, Meng J. Caveolin-1 negatively regulates inflammation and fibrosis in silicosis. J Cell Mol Med. 2021 doi: 10.1111/jcmm.17045. PubMed DOI PMC

Yao Y, Xia Z, Cheng F, Jang Q, He J, Pan C, Zhang L, et al. Human placental mesenchymal stem cells ameliorate liver fibrosis in mice by upregulation of Caveolin1 in hepatic stellate cells. Stem Cell Res Ther. 2021;12:294. doi: 10.1186/s13287-021-02358-x. PubMed DOI PMC

Li F, Niyibizi C. Cells derived from murine induced pluripotent stem cells (iPSC) by treatment with members of TGF-beta family give rise to osteoblasts differentiation and form bone in vivo. BMC Cell Biol. 2012;13:35. doi: 10.1186/1471-2121-13-35. PubMed DOI PMC

Ashcroft T, Simpson JM, Timbrell V. Simple method of estimating severity of pulmonary fibrosis on a numerical scale. J Clin Pathol. 1988;41:467–470. doi: 10.1136/jcp.41.4.467. PubMed DOI PMC

Roshandel E, Mehravar M, Dehghani Ghorbi M, Tabarraee M, Salimi M, Hajifathali A. Potential and challenges of placenta-derived decidua stromal cell therapy in inflammation-associated disorders. Hum Immunol. 2022;83:580–588. doi: 10.1016/j.humimm.2022.04.011. PubMed DOI

Itro A, Trotta MC, Miranda R, Paoletta M, De Cicco A, Lepre CC, Tarantino U, et al. Why use adipose-derived mesenchymal stem cells in tendinopathic patients: A systematic review. Pharmaceutics. 2022;14:1151. doi: 10.3390/pharmaceutics14061151. PubMed DOI PMC

Ding N, Li E, Ouyang X, Guo J, Wei B. The therapeutic potential of bone marrow mesenchymal stem cells for articular cartilage regeneration in osteoarthritis. Curr Stem Cell Res Ther. 2021;16:840–847. doi: 10.2174/1574888X16666210127130044. PubMed DOI

Gu C, Zhang H, Zhao S, He D, Gao Y. Mesenchymal stem cell exosomal miR-146a mediates the regulation of the TLR4/MyD88/NF-κB signaling pathway in inflammation due to diabetic retinopathy. Comput Math Methods Med. 2022;2022:3864863. doi: 10.1155/2022/3864863. PubMed DOI PMC

Basir HRG, Karbasi A, Ravan AP, Abbasalipourkabir R, Bahmani M. Is human umbilical cord mesenchymal stem cell-derived conditioned medium effective against oxidative and inflammatory status in CCl(4)-induced acute liver injury? Life Sci. 2022:120730. doi: 10.1016/j.lfs.2022.120730. PubMed DOI

Liu H, Shi M, Li X, Lu W, Zhang M, Zhang T, Wu Y, et al. Adipose mesenchymal stromal cell-derived exosomes prevent testicular torsion injury via activating PI3K/AKT and MAPK/ERK1/2 pathways. Oxid Med Cell Longev. 2022;2022:8065771. doi: 10.1155/2022/8065771. PubMed DOI PMC

Xia Y, Xu X, Guo Y, Lin C, Xu X, Zhang F, Fan M, et al. Mesenchymal stromal cells overexpressing farnesoid X receptor exert cardioprotective effects against acute ischemic heart injury by binding endogenous bile acids. Adv Sci (Weinh) 2022;9:e2200431. doi: 10.1002/advs.202200431. PubMed DOI PMC

Abbaszadeh H, Ghorbani F, Abbaspour-Aghdam S, Kamrani A, Valizadeh H, Nadiri M, Sadeghi A, et al. Chronic obstructive pulmonary disease and asthma: mesenchymal stem cells and their extracellular vesicles as potential therapeutic tools. Stem Cell Res Ther. 2022;13:262. doi: 10.1186/s13287-022-02938-5. PubMed DOI PMC

Radwan SM, Ghoneim D, Salem M, Saeed M, Saleh Y, Elhamy M, Wael K, et al. Adipose tissue-derived mesenchymal stem cells protect against amiodarone-induced lung injury in rats. Appl Biochem Biotechnol. 2020;191:1027–1041. doi: 10.1007/s12010-020-03227-8. PubMed DOI

Shao L, Zhang Y, Shi W, Ma L, Xu T, Chang P, Dong L. Mesenchymal stromal cells can repair radiation-induced pulmonary fibrosis via a DKK-1-mediated Wnt/β-catenin pathway. Cell Tissue Res. 2021;384:87–97. doi: 10.1007/s00441-020-03325-3. PubMed DOI

Nie YJ, Wu SH, Xuan YH, Yan G. Role of IL-17 family cytokines in the progression of IPF from inflammation to fibrosis. Mil Med Res. 2022;9:21. doi: 10.1186/s40779-022-00382-3. PubMed DOI PMC

Cai L, Yi F, Dai Z, Huang X, Zhao YD, Mirza MK, Xu J, et al. Loss of caveolin-1 and adiponectin induces severe inflammatory lung injury following LPS challenge through excessive oxidative/nitrative stress. Am J Physiol Lung Cell Mol Physiol. 2014;306:L566–L573. doi: 10.1152/ajplung.00182.2013. PubMed DOI PMC

Liu J, Huang X, Hu S, He H, Meng Z. Dexmedetomidine attenuates lipopolysaccharide induced acute lung injury in rats by inhibition of caveolin-1 downstream signaling. Biomed Pharmacother. 2019;118:109314. doi: 10.1016/j.biopha.2019.109314. PubMed DOI

Gao W, Shao R, Zhang X, Liu D, Liu Y, Fa X. Up-regulation of caveolin-1 by DJ-1 attenuates rat pulmonary arterial hypertension by inhibiting TGFβ/Smad signaling pathway. Exp Cell Res. 2017;361:192–198. doi: 10.1016/j.yexcr.2017.10.019. PubMed DOI

Ohnuma K, Inoue H, Uchiyama M, Yamochi T, Hosono O, Dang NH, Morimoto C. T-cell activation via CD26 and caveolin-1 in rheumatoid synovium. Mod Rheumatol. 2006;16:3–13. doi: 10.1007/s10165-005-0452-4. PubMed DOI PMC

Xu L, Li T, Chen Q, Liu Z, Chen Y, Hu K, Zhang X. The α2AR/Caveolin-1/p38MAPK/NF-κB axis explains dexmedetomidine protection against lung injury following intestinal ischaemia-reperfusion. J Cell Mol Med. 2021;25:6361–6372. doi: 10.1111/jcmm.16614. PubMed DOI PMC

Li Q, Wang C, Dong W, Su Y, Ma Z. WTAP facilitates progression of endometrial cancer via CAV-1/NF-κB axis. Cell Biol Int. 2021;45:1269–1277. doi: 10.1002/cbin.11570. PubMed DOI

Kopincova J, Mikolka P, Kolomaznik M, Kosutova P, Calkovska A, Mokra D. Selective inhibition of NF-kappaB and surfactant therapy in experimental meconium-induced lung injury. Physiol Res. 2017;66(Suppl 2):S227–S236. doi: 10.33549/physiolres.933678. PubMed DOI

Liu L, Chen X, Jiang Y, Yuan Y, Yang L, Hu Q, Tang J, et al. Brevilin A ameliorates acute lung injury and inflammation through inhibition of NF-κB signaling via targeting IKKα/β. Front Pharmacol. 2022;13:911157. doi: 10.3389/fphar.2022.911157. PubMed DOI PMC

Guo H, Song Y, Li F, Fan Y, Li Y, Zhang C, Hou H, et al. ACT001 suppressing M1 polarization against inflammation via NF-κB and STAT1 signaling pathways alleviates acute lung injury in mice. Int Immunopharmacol. 2022;110:108944. doi: 10.1016/j.intimp.2022.108944. PubMed DOI

Jiang W, Wang J, Xue W, Xin J, Shi C, Wen J, Feng X, et al. Caveolin-1 attenuates acetaminophen aggravated lipid accumulation in alcoholic fatty liver by activating mitophagy via the Pink-1/Parkin pathway. Eur J Pharmacol. 2021;908:174324. doi: 10.1016/j.ejphar.2021.174324. PubMed DOI

Dou S-D, Zhang J-N, Xie X-L, Liu T, Hu J-L, Jiang X-Y, Wang M-M, Jiang H-D. MitoQ inhibits hepatic stellate cell activation and liver fibrosis by enhancing PINK1/parkin-mediated mitophagy. Open Med (Wars) 2021;16:1718–1727. doi: 10.1515/med-2021-0394. PubMed DOI PMC

Ma N, Wei Z, Hu J, Gu W, Ci X. Farrerol ameliorated cisplatin-induced chronic kidney disease through mitophagy induction via Nrf2/PINK1 pathway. Front Pharmacol. 2021;12:768700. doi: 10.3389/fphar.2021.768700. PubMed DOI PMC