Share：
Share this content in WeChat
X
[Chinese] [PDF] 62 3
• Original Article •
Mechanism of intracranial tuberculous granuloma in rats based on MRI tracer technology
ZHU Yicong  MING Jie  LI Jin  NUERBIYEMU·Abulikemu   HE Qingyuan  TAN Hanbo  JIANG Tao  WANG Gang  GULIMIRE·Yilihamu   JIANG Yuda  JIANG Chunhui  LIU Wenya  WANG Yunling  WANG Jian 

DOI:10.12015/issn.1674-8034.2026.07.013.


[Abstract] Objective To establish a brain tuberculous granuloma model in Sprague-Dawley (SD) rats through BCG vaccination, and investigate the changes in the extracellular space (ECS) of brain tuberculous granulomas and the tracer distribution and clearance.Materials and Methods Forty SD rats were used. Thirty rats were randomly selected to establish a brain tuberculosis granuloma model by stereotactic injection of BCG suspension into the caudate nucleus of the rats, while the remaining ten received saline injections at the same site to serve as the control group. Four weeks after modeling, MRI scans were performed to observe granuloma formation. Rats in the tuberculosis granuloma model group and the saline group underwent tracer-based MRI scans with gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA) as the contrast agent. Ten rats in the tuberculosis granuloma group meeting the inclusion criteria (intracranial tuberculosis granulomas confirmed by pathology) and eight rats in the saline group were used for parameter measurement on tracer-based imaging (effective diffusion coefficient D*, volume fraction α, clearance rate constant K, and half-life T1/2). The ECS parameters of the two groups were compared to analyze changes in the ECS and its mechanism.Results A brain tuberculosis granuloma model was established using 1×106 CFU/mL BCG suspension, and four weeks after modeling, the formation rate of tuberculosis granulomas in rats was 56.7% (17/30). Experimental results showed that compared with the saline group, the brain tuberculosis granuloma model group exhibited significant changes in multiple ECS parameters: the clearance rate (K) in the granuloma model group was lower than that in the saline group (K: P = 0.006), while the diffusion coefficient (D*), half-life (T1/2), and volume fraction (α) were all higher than those in the saline group (D*: P = 0.024;T1/2:P = 0.011;α: P = 0.029).Conclusions A brain tuberculosis granuloma model in SD rats can be established using a BCG bacterial suspension at a dose of 1×106 CFU/mL. Due to cell necrosis and matrix remodeling, the ECS structure in the granuloma area is altered, allowing tracers to diffuse faster and over a wider range. However, the structural barrier of the granuloma wall obstructs local drainage, leading to prolonged tracer retention. MRI tracer techniques can effectively monitor the morphological and functional changes of the ECS under pathological conditions, providing a theoretical basis for drug delivery via the ECS.
[Keywords] rat；granuloma of brain tuberculosis；extracellular space；magnetic resonance imaging tracer；central nervous system

ZHU Yicong1   MING Jie2   LI Jin3   NUERBIYEMU·Abulikemu 1   HE Qingyuan4   TAN Hanbo4   JIANG Tao1   WANG Gang1   GULIMIRE·Yilihamu 1   JIANG Yuda1   JIANG Chunhui1   LIU Wenya1   WANG Yunling1   WANG Jian1*  

1 Imaging Center, the First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, China

2 Imaging Center, Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi 830011, China

3 Department of Ultrasound, People's Hospital of Changji Hui Autonomous Prefecture, Changji 831100, China

4 Institute of Medical Technology, School of Medicine, Peking University, Beijing Key Laboratory of Intelligent Neuromodulation and Brain Disorder Treatment, Beijing 100191, China

Corresponding author: WANG J, E-mail: jeanw1265@163.com

Conflicts of interest   None.

Received  2025-12-22
Accepted  2026-06-08
DOI: 10.12015/issn.1674-8034.2026.07.013
DOI:10.12015/issn.1674-8034.2026.07.013.

[1]
CHEN Z, WANG T, DU J L, et al. Decoding the WHO global tuberculosis report 2024: a critical analysis of global and Chinese key data[J/OL]. Zoonoses, 2025, 5(1) [2025-12-21]. https://www.scienceopen.com/hosted-documentdoi=10.15212/ZOONOSES-2024-0061. DOI: 10.15212/zoonoses-2024-0061.
[2]
DAHAL P, PARAJULI S. Magnetic resonance imaging findings in central nervous system tuberculosis: a pictorial review[J/OL]. Heliyon, 2024, 10(8): e29779[2025-12-21]. https://pubmed.ncbi.nlm.nih.gov/38699716/. DOI: 10.1016/j.heliyon.2024.e29779.
[3]
BELLETTATO C M, SCARPA M. Possible strategies to cross the blood-brain barrier[J/OL]. Ital J Pediatr, 2018, 44(S2): 131 [2025-12-21]. https://pubmed.ncbi.nlm.nih.gov/30442184/. DOI: 10.1186/s13052-018-0563-0.
[4]
PIANTINO M, KANG D H, FURIHATA T, et al. Development of a three-dimensional blood-brain barrier network with opening capillary structures for drug transport screening assays[J/OL]. Mater Today Bio, 2022, 15: 100324 [2025-12-21]. https://pubmed.ncbi.nlm.nih.gov/35757028/. DOI: 10.1016/j.mtbio.2022.100324.
[5]
SUN Y, SUN X P. Exploring the interstitial system in the brain: the last mile of drug delivery[J]. Rev Neurosci, 2021, 32(4): 363-377. DOI: 10.1515/revneuro-2020-0057.
[6]
ESTAÚN-PANZANO J, LOVISOTTO A, MAZZOCCO C, et al. Alzheimer's Tau seeds-induced pathology enhances hippocampal extracellular diffusion[J/OL]. Commun Biol, 2025, 8(1): 1660 [2025-12-21]. https://pubmed.ncbi.nlm.nih.gov/41286491/. DOI: 10.1038/s42003-025-09054-z.
[7]
GAO Y, SU J W, MA Y X, et al. Efficacy and safety of intrathecal dexamethasone combined with isoniazid in the treatment of tuberculous meningitis: a meta-analysis[J/OL]. BMC Neurol, 2024, 24(1): 194 [2025-12-21]. https://pubmed.ncbi.nlm.nih.gov/38858618/. DOI: 10.1186/s12883-024-03701-4.
[8]
ASHIZAWA N, KUBO R, TAGAWA R, et al. Efficacy of intrathecal isoniazid and steroid therapy in refractory tuberculous meningitis[J]. Intern Med, 2024, 63(4): 583-586. DOI: 10.2169/internalmedicine.1917-23.
[9]
Medical Association Tuberculosis Branch Tuberculous Meningitis Professional Committee. 2019 Chinese guidelines for the diagnosis and treatment of central nervous system tuberculosis[J]. Chin J Infect Dis, 2020, 38(7): 400-408. DOI: 10.3760/cma.j.cn311365-20200606-00645.
[10]
ZOU J, GAO T, WANG Y, et al. Dynamic distribution and clearance of 99mTc-DTPA in brain extracellular space[J]. Beijing Da Xue Xue Bao. Yi Xue Ban, 2025, 57(3): 562-568. DOI: 10.19723/j.issn.1671-167X.2025.03.021.
[11]
WANG H, ZHOU J, CHENG Y M, et al. Design and application of brain tissue channel tracer-based magnetic resonance imaging analyzer[J]. Chin J Magn Reson Imaging, 2023, 14(2): 109-115, 124. DOI: 10.12015/issn.1674-8034.2023.02.019.
[12]
YAO W W, ZHANG H W, MA Y P, et al. Comparative analysis of the performance of hepatobiliary agents in depicting MRI features of microvascular infiltration in hepatocellular carcinoma[J]. Abdom Radiol, 2024, 49(7): 2242-2249. DOI: 10.1007/s00261-024-04311-x.
[13]
REISI ZARGARI N, EBRAHIMI F, AKHLAGHI M, et al. Novel Gd-DTPA-peptide for targeted breast tumor magnetic resonance imaging[J/OL]. Biomed Pharmacother, 2024, 178: 117189 [2025-12-21]. https://pubmed.ncbi.nlm.nih.gov/39059353/. DOI: 10.1016/j.biopha.2024.117189.
[14]
LI K, ZHANG Y J, HE D Q, et al. Homogeneous orthogonal diffusion of drugs in the rat brain[J]. Clin Exp Pharmacol Physiol, 2019, 46(4): 398-403. DOI: 10.1111/1440-1681.13057.
[15]
ZHAO G M, CHEN H, YAN J H, et al. Efficacy of citicoline delivered via brain extracellular space against experimental acute ischemic stroke in rats[J]. Int J Med Sci, 2024, 21(7): 1274-1279. DOI: 10.7150/ijms.93482.
[16]
GUAN X P, WANG W, WANG A B, et al. Brain interstitial fluid drainage alterations in glioma-bearing rats[J/OL]. Aging Dis, 2018, 9(2): 228 [2025-12-21]. https://www.aginganddisease.org/EN/10.14336/AD.2017.0415. DOI: 10.14336/ad.2017.0415.
[17]
WANG G, NUERBIYEMU ·A, ZHAO J J, et al. MRI tracer imaging explore the diffusion changes of brain extracellular space in a rat model of intracranial cryptococcal infection[J]. Chin J Magn Reson Imaging, 2023, 14(2): 103-108. DOI: 10.12015/issn.1674-8034.2023.02.018.
[18]
ABULIKEMU N, GAO X, WANG W, et al. Mechanism of extracellular space changes in cryptococcal brain granuloma revealed by MRI tracer[J/OL]. Front Neurosci, 2022, 16: 1034091 [2025-12-21]. https://pubmed.ncbi.nlm.nih.gov/36605557/. DOI: 10.3389/fnins.2022.1034091.
[19]
WANG W, HE Q Y, HOU J, et al. Stimulation modeling on three-dimensional anisotropic diffusion of MRI tracer in the brain interstitial space[J/OL]. Front Neuroinform, 2019, 13: 6 [2025-12-21]. https://pubmed.ncbi.nlm.nih.gov/30837860/. DOI: 10.3389/fninf.2019.00006.
[20]
HAN H B, LI K, YAN J H, et al. An in vivo study with an MRI tracer method reveals the biophysical properties of interstitial fluid in the rat brain[J]. Sci China Life Sci, 2012, 55(9): 782-787. DOI: 10.1007/s11427-012-4361-4.
[21]
SÁNCHEZ-GARIBAY C, SALINAS-LARA C, GÓMEZ-LÓPEZ M A, et al. Mycobacterium tuberculosis infection induces BCSFB disruption but No BBB disruption in vivo: implications in the pathophysiology of tuberculous meningitis[J/OL]. Int J Mol Sci, 2022, 23(12): 6436 [2025-12-21]. https://pubmed.ncbi.nlm.nih.gov/35742886/. DOI: 10.3390/ijms23126436.
[22]
KRAUSGRUBER T, REDL A, BARRECA D, et al. Single-cell and spatial transcriptomics reveal aberrant lymphoid developmental programs driving granuloma formation[J/OL]. Immunity, 2023, 56(2): 289-306.e7 [2025-12-21]. https://pubmed.ncbi.nlm.nih.gov/36750099/. DOI: 10.1016/j.immuni.2023.01.014.
[23]
POH X Y, LOH F K, FRIEDLAND J S, et al. Neutrophil-mediated immunopathology and matrix metalloproteinases in central nervous system-tuberculosis[J/OL]. Front Immunol, 2021, 12: 788976 [2025-12-21]. https://pubmed.ncbi.nlm.nih.gov/35095865/. DOI: 10.3389/fimmu.2021.788976.
[24]
SONG L, ZHANG D, WANG H K, et al. Automated quantitative assay of fibrosis characteristics in tuberculosis granulomas[J/OL]. Front Microbiol, 2023, 14: 1301141 [2025-12-21]. https://pubmed.ncbi.nlm.nih.gov/38235425/. DOI: 10.3389/fmicb.2023.1301141.
[25]
JHILTA A, JADHAV K, SINGH R, et al. Breaking the cycle: matrix metalloproteinase inhibitors as an alternative approach in managing tuberculosis pathogenesis and progression[J]. ACS Infect Dis, 2024, 10(8): 2567-2583.
[26]
MCMAHON M, YE S Y, PEDRINA J, et al. Extracellular matrix enzymes and immune cell biology[J/OL]. Front Mol Biosci, 2021, 8: 703868 [2025-12-21]. https://pubmed.ncbi.nlm.nih.gov/34527702/. DOI: 10.3389/fmolb.2021.703868.
[27]
SINCLAIR B, YASUDA C L, NICOLO J P, et al. Enlarged perivascular spaces in the basal ganglia across epilepsy subtypes[J]. Epilepsia, 2026, 67(2): 815-829. DOI: 10.1111/epi.18694.
[28]
DING J W, ZHAO C B, HAO X Y, et al. Glymphatic and meningeal lymphatic dysfunction in Alzheimer's disease: Mechanisms and therapeutic perspectives[J/OL]. Alzheimers Dement, 2025, 21(10): e70709[2025-12-21]. https://pubmed.ncbi.nlm.nih.gov/41152198/. DOI: 10.1002/alz.70709.
[29]
YAO X Y, GAO M C, BAI S W, et al. Enlarged perivascular spaces, neuroinflammation and neurological dysfunction in NMOSD patients[J/OL]. Front Immunol, 2022, 13: 966781 [2025-12-21]. https://pubmed.ncbi.nlm.nih.gov/36248814/. DOI: 10.3389/fimmu.2022.966781.
[30]
JIA L Y, CHEN Y, LI H Z, et al. The glymphatic system in neurodegenerative diseases and brain tumors: mechanistic insights, biomarker advances, and therapeutic opportunities[J/OL]. Acta Neuropathol Commun, 2025, 14(1): 19 [2025-12-21]. https://pubmed.ncbi.nlm.nih.gov/41390476/. DOI: 10.1186/s40478-025-02203-9.
[31]
DATTA M, KENNEDY M, SIRI S, et al. Mathematical model of oxygen, nutrient, and drug transport in tuberculosis granulomas[J/OL]. PLoS Comput Biol, 2024, 20(2): e1011847[2025-12-21]. https://pubmed.ncbi.nlm.nih.gov/38335224/. DOI: 10.1371/journal.pcbi.1011847.
[32]
SALAVATI H, DEBBAUT C, PULLENS P, et al. Interstitial fluid pressure as an emerging biomarker in solid tumors[J/OL]. Biochim Biophys Acta BBA Rev Cancer, 2022, 1877(5): 188792 [2025-12-21]. https://pubmed.ncbi.nlm.nih.gov/36084861/. DOI: 10.1016/j.bbcan.2022.188792.
[33]
TØNNESEN J, HRABĔTOVÁ S, SORIA F N. Local diffusion in the extracellular space of the brain[J/OL]. Neurobiol Dis, 2023, 177: 105981 [2025-12-21]. https://pubmed.ncbi.nlm.nih.gov/36581229/. DOI: 10.1016/j.nbd.2022.105981.
[34]
TURECKOVA J, KAMENICKA M, KOLENICOVA D, et al. Compromised astrocyte swelling/volume regulation in the hippocampus of the triple transgenic mouse model of Alzheimer's disease[J/OL]. Front Aging Neurosci, 2021, 13: 783120 [2025-12-21]. https://pubmed.ncbi.nlm.nih.gov/35153718/. DOI: 10.3389/fnagi.2021.783120.
[35]
ESTAUN-PANZANO J, NANDI S, GRESIL Q, et al. Intracellular α-synuclein assemblies are sufficient to alter nanoscale diffusion in the striatal extracellular space[J/OL]. NPJ Parkinsons Dis, 2024, 10(1): 236 [2025-12-21]. https://pubmed.ncbi.nlm.nih.gov/39738158/. DOI: 10.1038/s41531-024-00850-8.
[36]
HIGASHIHARA M, ISHIBASHI K, TOKUMARU A M, et al. Brain PET imaging of 11C-methionine, 18F-FDG, and 18F-THK5351 in a case of lymphomatoid granulomatosis[J/OL]. Clin Nucl Med, 2022, 47(12): e749-e751 [2025-12-21]. https://pubmed.ncbi.nlm.nih.gov/36342805/. DOI: 10.1097/RLU.0000000000004388.
[37]
KANIPE C, BOGGIATTO P M, PUTZ E J, et al. Histopathologic differences in granulomas of Mycobacterium bovis bacille Calmette Guérin (BCG) vaccinated and non-vaccinated cattle with bovine tuberculosis[J/OL]. Front Microbiol, 2025, 16: 1571061 [2025-12-21]. https://pubmed.ncbi.nlm.nih.gov/36425039/. DOI: 10.3389/fmicb.2022.1048648.
[38]
BINI E I, MATA ESPINOSA D, MARQUINA CASTILLO B, et al. The influence of sex steroid hormones in the immunopathology of experimental pulmonary tuberculosis[J/OL]. PLoS One, 2014, 9(4): e93831[2025-12-21]. https://pubmed.ncbi.nlm.nih.gov/24722144/. DOI: 10.1371/journal.pone.0093831.
[39]
ZUCCHI F C, PELEGRINI-DA-SILVA A, NEDER L, et al. The contribution of a murine CNS-TB model for the understanding of the host-pathogen interactions in the formation of granulomas[J]. J Neurosci Methods, 2012, 206(1): 88-93. DOI: 10.1016/j.jneumeth.2012.02.015.

PREV Value of multiparametric MR black-blood thrombus imaging in staging diagnosis of lower extremity deep vein thrombosis
NEXT Advances in MRI research on cognitive impairment in type 1 diabetes
  


LINK


Tel & Fax: +8610-67113815    E-mail: editor@cjmri.cn