Anti-vascular endothelial growth factor treatment normalizes tuberculosis granuloma vasculature and improves small molecule delivery
| Autor: | John D. Martin, Meenal Datta, Lei Xu, Clifton E. Barry, Rakesh K. Jain, Walid S. Kamoun, Wei Chen, Kathleen England, Laura E. Via, Daniel Schimel, Chong Liu, Danielle M. Weiner, Giorgio Seano, Xing Gao |
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| Rok vydání: | 2015 |
| Předmět: |
Vascular Endothelial Growth Factor A
Pathology medicine.medical_specialty Tuberculosis Granuloma Respiratory Tract Bevacizumab medicine.drug_class medicine.medical_treatment Antibiotics Antibodies Monoclonal Humanized hemic and lymphatic diseases medicine Animals Humans Coloring Agents Chemotherapy Multidisciplinary biology business.industry Biological Sciences medicine.disease Small molecule Peripheral Positron-Emission Tomography Granuloma biology.protein Blood Vessels Rabbits Antibody Pericytes Tomography X-Ray Computed business medicine.drug |
| Zdroj: | Proceedings of the National Academy of Sciences. 112:1827-1832 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1424563112 |
| Popis: | Tuberculosis (TB) causes almost 2 million deaths annually, and an increasing number of patients are resistant to existing therapies. Patients who have TB require lengthy chemotherapy, possibly because of poor penetration of antibiotics into granulomas where the bacilli reside. Granulomas are morphologically similar to solid cancerous tumors in that they contain hypoxic microenvironments and can be highly fibrotic. Here, we show that TB-infected rabbits have impaired small molecule distribution into these disease sites due to a functionally abnormal vasculature, with a low-molecular-weight tracer accumulating only in peripheral regions of granulomatous lesions. Granuloma-associated vessels are morphologically and spatially heterogeneous, with poor vessel pericyte coverage in both human and experimental rabbit TB granulomas. Moreover, we found enhanced VEGF expression in both species. In tumors, antiangiogenic, specifically anti-VEGF, treatments can "normalize" their vasculature, reducing hypoxia and creating a window of opportunity for concurrent chemotherapy; thus, we investigated vessel normalization in rabbit TB granulomas. Treatment of TB-infected rabbits with the anti-VEGF antibody bevacizumab significantly decreased the total number of vessels while normalizing those vessels that remained. As a result, hypoxic fractions of these granulomas were reduced and small molecule tracer delivery was increased. These findings demonstrate that bevacizumab treatment promotes vascular normalization, improves small molecule delivery, and decreases hypoxia in TB granulomas, thereby providing a potential avenue to improve delivery and efficacy of current treatment regimens. |
| Databáze: | OpenAIRE |
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