脊髓损伤后神经源性膀胱纤维化机制研究进展*

doi:10.3870/j.issn.1672-0741.25.03.008

摘要/Abstract

摘要： 神经源性膀胱(neurogenic bladder,NB)是脊髓损伤后最常见的并发症,常引起膀胱储尿和排尿功能障碍,严重影响患者日常生活。膀胱纤维化是脊髓损伤病理过程导致膀胱结构发生不可逆性改变的关键,因此寻找减轻膀胱纤维化的方法对于治疗NB至关重要。尽管目前针对NB的治疗如清洁间歇导尿、肉毒杆菌毒素注射和手术干预可部分缓解NB纤维化进展,但治疗作用有限。脊髓损伤后膀胱无法耐受神经营养因子、炎症因子介导的炎症反应和细胞焦亡以及膀胱机械应力导致的机械敏感性离子通道的激活等都可能与NB纤维化有关。了解脊髓损伤后NB纤维化的分子机制和潜在的激活路径有望为治疗NB纤维化提供新方向。本文就脊髓损伤后NB纤维化的潜在机制以及存在的信号通路研究进行综述,以期为临床治疗和药物研发提供新的思路。

关键词: 脊髓损伤, 神经源性膀胱, 纤维化

Abstract: Neurogenic bladder(NB)is the most common complication after spinal cord injury,often causing bladder storage and urination dysfunction,seriously affecting patients’daily life.Although current treatments for NB such as antimuscarinic drugs,botox injections,and surgery relieve NB symptoms,they are not effective in reducing cystic fibrosis progression.Cystic fibrosis is the key to cause irreversible changes in the structure of the bladder in the pathological process,so finding ways to alleviate cystic fibrosis is crucial for the treatment of NB.The inability of the bladder to accept neurotrophic factors,inflammatory response mediated by inflammatory factors and cell pyrodeath,and the activation of mechanically sensitive ion channels caused by mechanical stress of the bladder may be related to NB fibrosis after spinal cord injury.Understanding the molecular mechanism and potential activation pathway of NB fibrosis after spinal cord injury is expected to provide a new direction for the treatment of NB fibrosis.In this paper,the potential mechanism of NB fibrosis after spinal cord injury and the possible signaling pathway were reviewed in order to provide new ideas for clinical treatment and drug development.

Key words: spinal cord injury, neurogenic bladder, fibrosis

中图分类号:

R556.5

江晶晶, 李彦杰, 杨新宇. 脊髓损伤后神经源性膀胱纤维化机制研究进展^*[J]. 华中科技大学学报（医学版）, 2026, 55(3): 431-437.

Jiang Jingjing, Li Yanjie, Yang Xinyu. Research Advances in the Mechanisms of Fibrosis in Neurogenic Bladder Following Spinal Cord Injury[J]. Acta Medicinae Universitatis Scientiae et Technologiae Huazhong, 2026, 55(3): 431-437.

参考文献

[1] Liao L.Evaluation and management of neurogenic bladder:What is new in China?[J].Int J Mol Sci,2015,16(8):18580-18600.
[2] Tashiro S,Nakamura M,Okano H.Regenerative rehabilitati-on and stem cell therapy targeting chronic spinal cord injury:A review of preclinical studies[J].Cells,2022,11(4):685.
[3] Bushnell J Y,Cates L N,Hyde J E,et al.Early detrusor application of botulinum toxin a results in reduced bladder hypertrophy and fibrosis after spinal cord injury in a rodent model[J].Toxins,2022,14(11):777.
[4] Stein R,Bogaert G,Dogan H S,et al.EAU/ESPU guidelines on the management of neurogenic bladder in children and adolescent partⅠ diagnostics and conservative treatment[J].Neurourol Urodyn,2020,39(1):45-57.
[5] 刘益豪,尚振华,李广萍,等.MicroRNA在膀胱纤维化发生发展中的作用机制研究进展[J].山东医药,2021,61(3):100-103.
Liu Y H,Shang Z H,Li G P,et al.Research progress on the mechanism of microRNA in the development of bladder fibrosis[J].Shandong Medical Journal,2021,61(3):100-103.
[6] Zhu D,Zhang Q,Li Q,et al.Inhibition of AHNAK nucleoprotein 2 alleviates pulmonary fibrosis by downregulating the TGF-β1/Smad3 signaling pathway[J].J Gene Med,2022,24(9):e3442.
[7] Peng D,Fu M,Wang M,et al.Targeting TGF-β signal transduction for fibrosis and cancer therapy[J].Mol Cancer,2022,21(1):104.
[8] Chia Z J,Cao Y N,Little P J,et al.Transforming growth factor-β receptors:versatile mechanisms of ligand activation[J].Acta Pharmacol Sin,2024,45(7):1337-1348.
[9] Yang Z,Mu Z,Dabovic B,et al.Absence of integrin-mediated TGFβ1 activation in vivo recapitulates the phenotype of TGFβ1-null mice[J].J Cell Biol,2007,176(6):787-793.
[10] Afroz R,Kumarapperuma H,Nguyen Q V N,et al.Lipopolysaccharide acting via toll-like receptor 4 transactivates the TGF-β receptor in vascular smooth muscle cells[J].Cell Mol Life Sci,2022,79(2):121.
[11] Hanna A,Frangogiannis N G.The role of the TGF-β superfamily in myocardial infarction[J].Front Cardiovasc Med,2019,6:140.
[12] Derynck R,Budi E H.Specificity,versatility,and control of TGF-β family signaling[J].Sci Signal,2019,12(570):eaav5183.
[13] Chen Y,Zhang Q,Zhou Y,et al.Inhibition of miR-182-5 p attenuates pulmonary fibrosis via TGF-β/Smad pathway[J].Hum Exp Toxicol,2020,39(5):683-695.
[14] Miyazawa K,Miyazono K.Regulation of TGF-β family signaling by inhibitory smads[J].Cold Spring Harb Perspect Biol,2017,9(3):a022095.
[15] Welniarz A,Levy J,Even A,et al.Ice water test to predict long-term detrusor activity in persistent neurogenic acontractile detrusor[J].Fr J Urol,2025,35(5):102865.
[16] Yu W,MacIver B,Zhang L,et al.Deletion of mechanosensory β1-integrin from bladder smooth muscle results in voiding dysfunction and tissue remodeling[J].Function,2022,3(5):zqac042.
[17] 陈燕,马源,何育霖,等.神经源性膀胱幼鼠膀胱形态结构功能变化及转化生长因子β1通路相关蛋白表达[J].中华实用儿科临床杂志,2020,35(17):1336-1340.
Chen Y,Ma Y,He Y L,et al.Changes in the bladder morphological structure and function and the expression significance of transforming growth factor-beta1 pathway-related proteins in neurogenic bladder rats[J].Chinese Journal of Applied Clinical Pediatrics,2020,35(17):1336-1340.
[18] 贾春松,赵彦坡,尚振华,等.RNA干扰降低膀胱TGF-β1表达能够改善脊髓损伤大鼠的膀胱功能和纤维化[J].基础医学与临床,2021,41(7):1007-1012.
Jia C S,Zhao Y P,Shang Z H,et al.RNAi-reduced bladder TGF-β1 expression improves bladder function and fibrosis in rats with spinal cord injury[J].Basic & Clinical Medicine,2021,41(7):1007-1012.
[19] Border W A,Noble N A.Interactions of transforming growth factor-beta and angiotensinⅡin renal fibrosis[J].Hypertension,1998,31(1 Pt 2):181-188.
[20] Zhao M,Ding N,Wang H,et al.Activation of TRPA1 in bladder suburothelial myofibroblasts counteracts TGF-β1-induced fibrotic changes[J].Int J Mol Sci,2023,24(11):9501.
[21] Jiang X,Zhang Y,Li F,et al.Allicin as a possible adjunctive therapeutic drug for stageⅡoral submucous fibrosis:A preliminary clinical trial in a Chinese cohort[J].Int J Oral Maxillofac Surg,2015,44(12):1540-1546.
[22] Kurahara L H,Hiraishi K,Hu Y,et al.Activation of myofibroblast TRPA1 by steroids and pirfenidone ameliorates fibrosis in experimental Crohn’s disease[J].Cell Mol Gastroenterol Hepatol,2018,5(3):299-318.
[23] Yap J M G,Ueda T,Kanemitsu Y,et al.AITC inhibits fibroblast-myofibroblast transition via TRPA1-independent MAPK and NRF2/HO-1 pathways and reverses corticosteroids insensitivity in human lung fibroblasts[J].Respir Res,2021,22(1):51.
[24] Zhao M,Chen Z,Liu L,et al.Functional expression of transient receptor potential and Piezo1 channels in cultured interstitial cells of human-bladder lamina propria[J].Front Physiol,2022,12:762847.
[25] Steiner C,Gevaert T,Ganzer R,et al.Comparative immunohistochemical characterization of interstitial cells in the urinary bladder of human,guinea pig and pig[J].Histochem Cell Biol,2018,149(5):491-501.
[26] Wójcik-Pszczoła K,Chłoń-Rzepa G,Jankowska A,et al.A novel,pan-PDE inhibitor exerts anti-fibrotic effects in human lung fibroblasts via inhibition of TGF-β signaling and activation of cAMP/PKA signaling[J].Int J Mol Sci,2020,21(11):4008.
[27] Chen W,Lam S S,Srinath H,et al.Competition between Ski and CREB-binding protein for binding to Smad proteins in transforming growth factor-beta signaling[J].J Biol Chem,2007,282(15):11365-11376.
[28] Aikawa K,Ishibashi K,Sakai T,et al.Effect of the renin-angiotensin system on the obstructed bladder[J].Low Urin Tract Symptoms,2012,4(Suppl 1):81-86.
[29] 郑岩,马源,任雪景,等.基于AngⅡ/TGF-β1/Smads信号通路关于神经源性膀胱诱导肾脏纤维化的研究[J].中华肾脏病杂志,2021,37(12):1001-1007.
Zheng Y,Ma Y,Ren X J,et al.Study on neurogenic bladder-induced renal fibrosis based on AngⅡ/TGF-β1/Smads signaling pathway[J].Chinese Journal of Nephrology,2021,37(12):1001-1007.
[30] Yang F,Chung A C K,Huang X R,et al.AngiotensinⅡ induces connective tissue growth factor and collagenⅠ expression via transforming growth factor-beta-dependent and-independent Smad pathways:the role of Smad3[J].Hypertension,2009,54(4):877-884.
[31] Chen Y,Ma Y,He Y,et al.The TGF-β1 pathway is early involved in neurogenic bladder fibrosis of juvenile rats[J].Pediatr Res,2021,90(4):759-767.
[32] Li H G,You P T,Xia Y,et al.Yu Gan long ameliorates hepatic fibrosis by inhibiting PI3K/Akt,ras/ERK and JAK1/STAT3 signaling pathways in CCl(4)-induced liver fibrosis rats[J].Curr Med Sci,2020,40(3):539-547.
[33] Xu J,Zheng J,Fu X,et al.Inhibition of N822K T>A mutation-induced constitutive c-KIT activation in AML cells triggers apoptotic and autophagic pathways leading to death[J].Int J Med Sci,2019,16(5):757-765.
[34] Sureshbabu A,Muhsin S A,Choi M E.TGF-β signaling in the kidney:profibrotic and protective effects[J].Am J Physiol Renal Physiol,2016,310(7):F596-F606.
[35] Chen J,Li Q,Hong Y,et al.Inhibition of the NF-κB signaling pathway alleviates pyroptosis in bladder epithelial cells and neurogenic bladder fibrosis[J].Int J Mol Sci,2023,24(13):11160.
[36] Song Z,Gong Q,Guo J.Pyroptosis:mechanisms and links wi-th fibrosis[J].Cells,2021,10(12):3509.
[37] Hughes F M Jr,Sexton S J,Jin H,et al.Bladder fibrosis during outlet obstruction is triggered through the NLRP3 inflammasome and the production of IL-1β[J].Am J Physiol Renal Physiol,2017,313(3):F603-F610.
[38] Knorr J,Kaufmann B,Inzaugarat M E,et al.Interleukin-18 signaling promotes activation of hepatic stellate cells in mouse liver fibrosis[J].Hepatology,2023,77(6):1968-1982.
[39] Xu H,He Y,Hong T,et al.Piezo1 in vascular remodeling of atherosclerosis and pulmonary arterial hypertension:A potential therapeutic target[J].Front Cardiovasc Med,2022,9:1021540.
[40] Braidotti N,Chen S N,Long C S,et al.Piezo1 channel as a potential target for hindering cardiac fibrotic remodeling[J].Int J Mol Sci,2022,23(15):8065.
[41] Zhao X,Kong Y,Liang B,et al.Mechanosensitive Piezo1 ch-annels mediate renal fibrosis[J].JCI Insight,2022,7(7):e152330.
[42] Feng S,Yu Z,Yang Y,et al.Mechanosensitive Piezo1 channels promote neurogenic bladder fibrosis via regulating TGF-β1/smad and Hippo/YAP1 pathways[J].Exp Cell Res,2024,442(1):114218.
[43] 吕磊,张艳平,李琦,等.机械敏感通道Piezo1和Piezo2促进幼鼠神经源性膀胱纤维化的初步研究[J].现代泌尿外科杂志,2025,30(4):343-349,363.
Lv L,Zhang Y P,Li Q,et al.A preliminary study of mechanosensitive channels Piezo1 and Piezo2 promoting neurogenic bladder fibrosis in young rats[J].Journal of Modern Urology,2025,30(4):343-349,363.
[44] Zhang Q,Wang L,Wang S,et al.Signaling pathways and targeted therapy for myocardial infarction[J].Signal Transduct Target Ther,2022,7(1):78.
[45] Koh S D,Lee H,Ward S M,et al.The mystery of the interstitial cells in the urinary bladder[J].Annu Rev Pharmacol Toxicol,2018,58:603-623.
[46] Schödel J,Ratcliffe P J.Mechanisms of hypoxia signalling:new implications for nephrology[J].Nat Rev Nephrol,2019,15(10):641-659.
[47] Li Q,Hong Y,Chen J,et al.Hypoxia-induced HIF-1α expression promotes neurogenic bladder fibrosis via EMT and pyroptosis[J].Cells,2022,11(23):3836.
[48] Chen Y,Fan Y,Guo D Y,et al.Study on the relationship between hepatic fibrosis and epithelial-mesenchymal transition in intrahepatic cells[J].Biomed Pharmacother,2020,129:110413.
[49] Xu Z,Davies E R,Yao L,et al.LKB1 depletion-mediated epithelial-mesenchymal transition induces fibroblast activation in lung fibrosis[J].Genes Dis,2024,11(3):101065.
[50] Wiafe B,Adesida A,Churchill T,et al.Hypoxia-increased expression of genes involved in inflammation,dedifferentiation,pro-fibrosis,and extracellular matrix remodeling of human bladder smooth muscle cells[J].In Vitro Cell Dev Biol Anim,2017,53(1):58-66.
[51] Liu Q,Wang R,Wang C,et al.The protective role of Schwann cells in bladder smooth muscle cell fibrosis[J].Int J Clin Exp Pathol,2019,12(10):3799-3806.
[52] Yang J,Kim K,Liu Y,et al.3D bioprinted dynamic bioactive living construct enhances mechanotransduction-assisted rapid neural network self-organization for spinal cord injury repair[J].Bioact Mater,2025,46:531-554.
[53] Sun C Y,Hu Y,Wang H F,et al.Brain-derived neurotrophic factor inducing angiogenesis through modulation of matrix-degrading proteases[J].Chin Med J,2006,119(7):589-595.
[54] 刘倩.施万细胞对膀胱平滑肌细胞纤维化的保护作用研究[D].济南:山东大学,2020.
Liu Q.Protective effect of Schwann cells on bladder smooth muscle cell fibrosis[D].Jinan:Shandong University,2020.

脊髓损伤后神经源性膀胱纤维化机制研究进展^*

Research Advances in the Mechanisms of Fibrosis in Neurogenic Bladder Following Spinal Cord Injury

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