Datta Meenal, Via Laura E, Kamoun Walid S, Liu Chong, Chen Wei, Seano Giorgio, Weiner Danielle M, Schimel Daniel, England Kathleen, Martin John D, Gao Xing, Xu Lei, Barry Clifton E, Jain Rakesh K
Edwin L. Steele Laboratory for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; Department of Chemical and Biological Engineering, Tufts University, Medford, MA 02155;
Tuberculosis Research Section, Laboratory of Clinical Infectious Disease, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD 20892;
Proc Natl Acad Sci U S A. 2015 Feb 10;112(6):1827-32. doi: 10.1073/pnas.1424563112. Epub 2015 Jan 26.
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.
结核病每年导致近200万人死亡，而且越来越多的患者对现有疗法产生耐药性。患有结核病的患者需要进行长期化疗，这可能是因为抗生素难以渗透到杆菌所在的肉芽肿中。肉芽肿在形态上与实体癌性肿瘤相似，因为它们含有缺氧微环境，并且可能高度纤维化。在这里，我们表明，由于血管功能异常，感染结核病的兔子体内小分子向这些病灶部位的分布受损，一种低分子量示踪剂仅积聚在肉芽肿病变的周边区域。与肉芽肿相关的血管在形态和空间上具有异质性，在人类和实验性兔结核肉芽肿中，血管周细胞覆盖率都很低。此外，我们发现这两个物种中的血管内皮生长因子（VEGF）表达均增强。在肿瘤中，抗血管生成治疗，特别是抗VEGF治疗，可以使血管“正常化”，减少缺氧，并为同步化疗创造机会窗口；因此，我们研究了兔结核肉芽肿中的血管正常化情况。用抗VEGF抗体贝伐单抗治疗感染结核病的兔子，可显著减少血管总数，同时使剩余血管正常化。结果，这些肉芽肿的缺氧部分减少，小分子示踪剂的递送增加。这些发现表明，贝伐单抗治疗可促进血管正常化，改善小分子递送，并降低结核肉芽肿中的缺氧程度，从而为改善当前治疗方案的递送和疗效提供了一条潜在途径。
