Vascular endothelial growth factor as a marker of disease activity in neurotuberculosis

doi:10.1016/j.jinf.2007.11.004

Journal of Infection

Volume 56, Issue 2, February 2008, Pages 114-119

https://doi.org/10.1016/j.jinf.2007.11.004 Get rights and content

Summary

Vascular endothelial growth factor (VEGF) is a potent angiogenesis mediator. Scant reports are available defining the role of VEGF in active and inactive tubercular meningitis (TBM) with no studies on brain tuberculoma. We quantified VEGF levels by enzyme linked immunoassay (ELISA) in cerebrospinal fluid (CSF) and serum in 20 cases each with active and inactive TBM as well as 22 cases of intraparenchymal tuberculoma. VEGF expression and microvessel angiogenesis quantification was done in 7 cases where tuberculomas were excised. Significantly increased VEGF levels in CSF were found in active TBM cases (106.0 ± 50.0 pg/ml) compared to inactive TBM cases (14.7 ± 10.0 pg/ml) (p < 0.001). Mean serum VEGF levels in active TBM, inactive TBM and tuberculoma were 694.93 ± 820.66 pg/ml, 499.61 ± 238.33 pg/ml and 541.0 ± 389.0 pg/ml, respectively. Immunohistochemical staining of excised tuberculoma demonstrated high expression of VEGF in granulomatous areas with intense positivity in inflammatory mononuclear cells, Langhan's giant cells as well as reactive astrocytes and fibrocytes. A strong positive correlation was observed between microvessel density and VEGF expression. Serial decrease in serum VEGF levels was observed with increasing duration of therapy in tuberculoma. We conclude that increased CSF and serum VEGF levels are a measure of activity of the disease in neurotuberculosis and its gradual decrease over a period of time is probably an indicator of therapeutic response.

Introduction

Neurotuberculosis comprises 10–15% of extrapulmonary tuberculosis in the developing countries.¹ Broadly neurotuberculosis can be categorized into a meningeal form presenting as tubercular meningitis (TBM) and parenchymal tuberculosis including tuberculoma and infrequently tubercular abscess. Vascular endothelial growth factor (VEGF) is a potent stimulator of angiogenesis in various neoplastic and inflammatory conditions.2, 3 Significantly increased levels of serum VEGF in active compared to inactive cases of pulmonary tuberculosis have been observed.⁴ VEGF levels in serum and cerebrospinal fluid (CSF) have been reported as a marker of disease activity and effective chemotherapy in tubercular meningitis.⁵

To date no study on VEGF levels in tuberculomas is available in the literature. In this study we have estimated both serum and CSF VEGF levels in cases of active (n = 20) and inactive TBM (n = 20). In case of tuberculomas (n = 22) we have estimated serum VEGF levels over time and also compared the serum VEGF levels with immunohistochemical expression of VEGF in 7 cases where surgical resection of the tuberculoma was done. VEGF in sections was further correlated with the extent of neoangiogenesis as estimated by microvessel density and morphometric parameters.

Section snippets

Materials and methods

Cases of CNS tuberculosis included in the study were categorized into three study groups: study group 1, 20 cases with active untreated tubercular meningitis; study group 2, 20 cases with the inactive form of tubercular meningitis; study group 3, 22 cases with CNS tuberculoma; seven of these cases underwent surgical excision and tissue was used for histological studies. The diagnostic criteria to define a case of tubercular meningitis were demonstration of Mycobacterium tuberculosis in CSF by

Results

All the intraparenchymal tuberculoma (n = 22) showed a hyperintense rim on the MT T1 weighted image which enhanced on the immediate post contrast T1 weighted image. PMRS showed lipid alone in 16 cases; lipid along with choline was seen in the remaining 6 cases. The active TBM (n = 20) showed hyperintense meninges on the MT T1 weighted image which enhanced on the post contrast T1 weighted image. The inactive TBM showed no hyperintensity on the MT T1 weighted image as well as no enhancement on the

Discussion

VEGF121 and VEGF165 are vascular endothelial growth factor splice variants that promote the proliferation of endothelial cells and angiogenesis.¹⁰ The ELISA used in the study quantified these variants. We have also estimated VEGF expression and correlated it with the angiogenesis quantified by microvessel morphometry in tuberculomas.

We have observed a significantly lower level of VEGF in CSF of patients with inactive tuberculosis compared to cases with active tubercular meningitis. Matsuyama

Acknowledgements

This work is funded by Department of Science and Technology, New Delhi, India via grant no. SP/SO/HS-50/2002. Mohammad Haris received financial assistance from the University Grant Commission, New Delhi, India.

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Granuloma cells have finite lifespans and so dying cells must be continuously replaced to sustain Mtb-constraining inflammation (Schreiber et al., 2011a, 2011b). In humans high levels of vascular endothelial growth factor (VEGF-A) have been found in almost every granulomatous disease where it has been measured, including pulmonary tuberculosis (Abe et al., 2001; Alatas et al., 2004; Matsuyama et al., 2000), tuberculosis meningitis (Husain et al., 2008; van der Flier et al., 2004), schistosomiasis (Shariati et al., 2011), Crohn’s disease (Bousvaros et al., 1999; Griga et al., 1999, 2002; Kanazawa et al., 2001), and sarcoidosis (Sekiya et al., 2003; Tolnay et al., 1998), and is also present in human tubercle granulomas (Kang et al., 2014). In patients with active tuberculosis, serum VEGF-A levels decrease after antibiotic treatment (Alatas et al., 2004).
Many autoimmune and infectious diseases are characterized by the formation of granulomas which are inflammatory lesions that consist of spatially organized immune cells. These sites protect the host and control pathogens like Mycobacterium tuberculosis (Mtb), but are highly inflammatory and cause pathology. Using bacille Calmette-Guerin (BCG) and Mtb infection in mice that induce sarcoid or caseating granulomas, we show that a subpopulation of granuloma macrophages produces vascular endothelial growth factor (VEGF-A), which recruits immune cells to the granuloma by a non-angiogenic pathway. Selective blockade of VEGF-A in myeloid cells, combined with granuloma transplantation, shows that granuloma VEGF-A regulates granulomatous inflammation. The severity of granuloma-related inflammation can be ameliorated by pharmaceutical or genetic inhibition of VEGF-A, which improves survival of mice infected with virulent Mtb without altering host protection. These data show that VEGF-A inhibitors could be used as a host-directed therapy against granulomatous diseases like tuberculosis and sarcoidosis, thereby expanding the value of already existing and approved anti-VEGF-A drugs.
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In response to hypoxia, glioma cells increase the production of VEGF, which is secreted into the tumor microenvironment (Damert et al., 1997). Increased levels of VEGF in CSF can also occur in noncancerous disease such as neurotuberculosis or moyamoya disease (Husain et al., 2008; Weinberg et al., 2011). VEGF has raised considerable interest as a circulating biomarker for several types of cancer.
CNS malignancies include primary tumors that originate within the CNS as well as secondary tumors that develop as a result of metastatic cancer. The delicate nature of the nervous systems makes tumors located in the CNS notoriously difficult to reach, which poses several problems during diagnosis and treatment. CSF can be acquired relatively easy through lumbar puncture and offers an important compartment for analysis of cells and molecules that carry information about the malignant process. Such techniques have opened up a new field of research focused on the identification of specific biomarkers for several types of CNS malignancies, which may help in diagnosis and monitoring of tumor progression or treatment response. Biomarkers are sought in DNA, (micro)RNA, proteins, exosomes and circulating tumor cells in the CSF. Techniques are rapidly progressing to assess these markers with increasing sensitivity and specificity, and correlations with clinical parameters are being investigated. It is expected that these efforts will, in the near future, yield clinically relevant markers that aid in diagnosis, monitoring and (tailored) treatment of patients bearing CNS tumors. This chapter provides a summary of the current state of affairs of the field of biomarkers of different types of CNS tumors.
Over-expression of thymosin β4 in granulomatous lung tissue with active pulmonary tuberculosis
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We also examined the expression patterns of Tβ4 in another lung diseases, including lung tumors and pneumonia, and found some positive staining of Tβ4 in lung cancer and inflammatory lymphocyte accumulation (data not shown), but high expression of Tβ4 in the core region of granulomas is specific to TB tissues. VEGF has been reported to be higher in TB patients than in control patients and could therefore be considered a marker of TB infection [6,31]. We determined that Tβ4 mRNA levels in patient sputum were also significantly higher, especially at low levels of inflammation during TB infection.
Recent studies have shown that thymosin β4 (Tβ4) stimulates angiogenesis by inducing vascular endothelial growth factor (VEGF) expression and stabilizing hypoxia inducible factor-1α (HIF-1α) protein. Pulmonary tuberculosis (TB), a type of granulomatous disease, is accompanied by intense angiogenesis and VEGF levels have been reported to be elevated in serum or tissue inflamed by pulmonary tuberculosis.
We investigated the expression of Tβ4 in granulomatous lung tissues at various stages of active pulmonary tuberculosis, and we also examined the expression patterns of VEGF and HIF-1α to compare their Tβ4 expression patterns in patients' tissues and in the tissue microarray of TB patients.
Tβ4 was highly expressed in both granulomas and surrounding lymphocytes in nascent granulomatous lung tissue, but was expressed only surrounding tissues of necrotic or caseous necrotic regions. The expression pattern of HIF-1α was similar to that of Tβ4. VEGF was expressed in both granulomas and blood vessels surrounding granulomas. The expression pattern of VEGF co-localized with CD31 (platelet endothelial cell adhesion molecule, PECAM-1), a blood endothelial cell marker, and partially co-localized with Tβ4. However, the expression of Tβ4 did not co-localize with alveolar macrophages. Stained alveolar macrophages were present surrounding regions of granuloma highly expressing Tβ4.
We also analyzed mRNA expression in the sputum of 10 normal and 19 pulmonary TB patients. Expression of Tβ4 was significantly higher in patients with pulmonary tuberculosis than in normal controls.
These data suggest that Tβ4 is highly expressed in granulomatous lung tissue with active pulmonary TB and is associated with HIF-1α- and VEGF-mediated inflammation and angiogenesis. Furthermore, the expression of Tβ4 in the sputum of pulmonary tuberculosis patients can be used as a potential marker for diagnosis.
Modulation of angiogenic factor VEGF by DNA-hsp65 vaccination in a murine CNS tuberculosis model
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Therefore, the increase in vascular permeability and angiogenesis ascribed to VEGF production in TB may prove to have an essential role in the disease progression to TBM. Several studies showed that VEGF increases in inflammatory processes, and it is counterbalanced by anti-inflammatory therapy, such as anti-tuberculous corticosteroid terapy18,22,35,38 stroke associated with TBM therapy,39 and anti-angiogenic tumor therapy.11 van der Flier et al.18 demonstrated that inflammatory cells secrete VEGF during TBM, and CSF VEGF correlates with BBB disruption.
Tuberculosis (TB) is a serious public health problem. Development of experimental models and vaccines are essential to elucidate physiopathological mechanisms and to control the disease. Vascular endothelial growth factor (VEGF) is a potent activator of vascular permeability and angiogenesis. VEGF seems to participate in breakdown of the blood brain-barrier (BBB) in tuberculous meningitis (TBM), contributing to worsening of disease. Therefore, the objective here was to extent the characterization of our previously described murine model of central nervous system TB (CNS-TB) by describing the VEGF participation in the CNS disease, and suggesting a vaccination plan in mice. Plasmid encoding DNA protein antigen DNA-hsp65 has been described as a protector against TB infection and was used here to test its effectiveness in the prevention of VEGF production and TB disease. Vaccinated mice and its controls were injected with Mycobacterium bovis bacillus Calmette-Guerin (BCG) in cerebellum. Four weeks after BCG injection, mice were perfused and brains were paraffin-embedded for VEGF expression analysis. We observed VEGF immunohistochemical expression in TBM and granulomas in non-vaccinated mice. The DNA-hsp65 treatment blocked the expression of VEGF in mice TBM. Therefore, our murine model indicated the VEGF participation in the physiopathology of CNS-TB and the potential prevention of the DNA-hsp65 in the disease progression.
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It remains unclear whether serum concentrations reflect VEGF expression in the central nervous system. In this regard a study reported a parallel alteration of VEGF serum and CSF (Cerebrospinal Fluid) levels in subjects with neurotuberculosis (Husain et al., 2008), moreover consistent evidence indicated that peripheral effectors as VEGF and other growth factors (BDNF, IGF-1) can influence brain neurogenesis (Fabel et al., 2003). In contrast, a recent study did not find alteration in serum VEGF levels in an animal model of depression (Elfving et al., 2010).
Vascular endothelial growth factor (VEGF) is an angiogenic cytokine, which induces vasopermeability and facilitates neurogenesis and synaptic plasticity in the adult brain. Expression studies in animal models have reported that brain VEGF is regulated by electroconvulsive seizures (ECS), which are used in an experimental paradigm similar to clinical electroconvulsive therapy (ECT) a treatment for drug resistant depressed (TRD) patients. The aim of this study was to investigate putative modulations of ECT on VEGF serum levels in TRD patients.
Nineteen patients were enrolled in the study; illness severity and VEGF serum contents were assessed before the treatment (T0), the day after the end of ECT (T1) and one month later the end of ECT (T2).
ECT treatment improved depression symptomatology as measured by MADRS scores (p < 0.0001). No changes occurred in serum VEGF between T0 and T1, whereas a significant increase was observed between T0 and T2 (p = 0.042). Moreover a significant correlation was observed between the VEGF increase at T2 and the reduction in MADRS scores (p = 0.049).
This study is the first to evaluate putative modulations of serum VEGF induced by ECT in TRD patients.

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Vascular endothelial growth factor as a marker of disease activity in neurotuberculosis

Summary

Introduction

Section snippets

Materials and methods

Results

Discussion

Acknowledgements

Chest

J Neurol Sci

Magn Reson Imaging

J Biol Chem

Global epidemiology of tuberculosis. Morbidity and mortality of a worldwide epidemic

JAMA

Angiogenesis in cancer and other diseases

Nature

Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis

Am J Pathol

MR imaging of intracranial tuberculomas

J Comput Assist Tomogr