Manipulation of Host Angiogenesis as a Therapeutic Strategy against Invasive Pulm

操纵宿主血管生成作为针对侵袭性肺结核的治疗策略

• 批准号: 7905095
• 负责人: DIMITRIOS P KONTOYIANNIS
• 金额: $ 7.7万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7905095
• 关键词: Acute; Adjuvant; Amphotericin B; Angiogenesis Inhibitors; Angiopoietin-1; Antifungal Agents; Aspergillosis; Aspergillus; Autopsy; Biological Assay; Blood Vessels; Cessation of life; Cyclophosphamide; Disease Progression; Down-Regulation; Failure; Fibroblast Growth Factor 2; Gene Expression; Growth Factor; Hematopoietic stem cells; High Pressure Liquid Chromatography; Immune system; Immunocompromised Host; In Vitro; Infarction; Infection; Intervention; Invaded; Ischemia; Lesion; Link; Lung; Malignant Neoplasms; Measures; Mediator of activation protein; Modeling; Mus; Mycoses; Neutropenia; Outcome; Patients; Penetration; Pharmaceutical Preparations; Polymerase Chain Reaction; Reproduction spores; Resistance; Role; Site; Stem cell transplant; Subcutaneous Injections; Supportive care; Survival Rate; Suspension substance; Suspensions; Testing; Therapeutic; Thrombosis; Tissue Survival; Tissues; Vascular Diseases; Vascular Endothelial Growth Factors; angiogenesis; blood vessel occlusion; density; improved; in vivo; matrigel; mortality; neovascularization; novel; public health relevance; respiratory; response; synergism; treatment effect

DESCRIPTION (provided by applicant): Invasive aspergillosis (IA) is an important cause of respiratory and disseminated infection in immunocompromised patients, and the most common cause of infectious pneumonic mortality in recipients of hematopoietic stem cell transplants. Mortality from IA remains unacceptably high despite the availability of novel antifungal agents. The poor efficacy of antifungal drugs against IA may be linked to the propensity of Aspergillus species to invade pulmonary blood vessels, causing intravascular thrombosis, tissue ischemia and infarction. This vasculopathy sequesters infected tissue, thereby limiting the delivery of antifungal agents to the site of infection. Furthermore, IA is associated with down-regulation of the expression of genes encoding for important mediators of angiogenesis, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), suggesting that the vascular response to IA is suppressed. We hypothesize that therapeutic administration of pro-angiogenic growth factors together with antifungal drugs will increase the survival rate in experimental IA by increasing the tissue concentrations of the antifungal drugs. In aim 1, we propose to assess the feasibility of treating IA with pro-angiogenic growth factors, alone or in combination with the antifungal drug amphotericin B (AMB). To that end, we will use two murine models of IA following induction of neutropenia with cyclophosphamide: (1) An acute pulmonary model, in which infection is established by intranasal instillation of a concentrated spore suspension; (2) A subacute model, in which myocutaneous infection is induced by subcutaneous injection of spore suspension. In each model, the following treatment groups will be assessed: VEGF, bFGF, VEGF plus bFGF, AMB, AMB plus VEGF, AMB plus bFGF, and AMB plus VEGF and bFGF. Two additional groups of mice will receive treatment with sunitinib, an inhibitor of angiogenesis, alone or in combination with AMB. Three types of endpoints will be assessed and compared among treatment groups: (1) Survival over a period of 7 days (pulmonary model only); (2) Tissue fungal burden, measured by quantitative polymerase chain reaction (qPCR); and (3) Angiogenesis at the site of infection, assessed in vivo in the myocutaneous model using the previously described matrigel assay, and in pulmonary tissue sections using microvessel density. In aim 2, we will determine the effect of treatment with VEGF and bFGF on the tissue concentration of AMB. AMB concentrations will be measured in pulmonary tissue and in matrigel plugs using high performance liquid chromatography, and compared between groups of mice receiving AMB alone and groups receiving AMB plus VEGF and/or bFGF. PUBLIC HEALTH RELEVANCE: Invasive aspergillosis is a major cause of sickness and death in patients with cancer and a weakened immune system. Despite the availability of new antifungal drugs and improved supportive care, mortality from these infections remains unacceptably high. We hypothesize that the occlusion of blood vessels in the course of invasive aspergillosis limits the penetration of antifungal drugs into infected tissue, and that treatment with growth factors that enhance the formation of new vessels might improve the outcome of this severe fungal infection.

描述（由申请人提供）：侵入性曲霉菌病（IA）是免疫功能低下患者呼吸和传播感染的重要原因，也是造血干细胞移植剂接受者感染性肺炎死亡率的最常见原因。尽管新型抗真菌剂的可用性可用，但IA的死亡率仍然令人难以置信。抗真菌药物对IA的功效不佳可能与曲霉物种侵入肺血管的倾向有关，导致血管内血栓形成，组织缺血和梗塞。这种血管病隔离感染了组织，从而限制了抗真菌剂的递送到感染部位。此外，IA与为血管生成的重要介质（例如血管内皮生长因子（VEGF））和基本成纤维细胞生长因子（BFGF）的基因表达下调有关，表明血管对IA的血管反应受到抑制。我们假设促血管生长因子与抗真菌药物的治疗施用将通过增加抗真菌药物的组织浓度来提高实验IA的存活率。在AIM 1中，我们建议单独或与抗真菌药物两性霉素B（ABS）相结合，以评估使用促血管生长生长因子治疗IA的可行性。为此，我们将在诱导中性粒细胞减少症中使用环磷酰胺的两个鼠模型IA模型：（1）急性肺模型，其中通过对浓缩孢子悬浮液的鼻内滴注建立感染； （2）一个亚急性模型，其中孢子悬浮液的皮下注射会诱导心肌感染。在每种模型中，将评估以下治疗组：VEGF，BFGF，VEGF加BFGF，AMB，AMB，AMB PURES VEGF，AMB PLUS BFGF以及AMB PLUS PLUS VEGF和VEGF和BFGF。另外两组小鼠将接受单独或与AMB联合使用的血管生成抑制剂舒尼尼治疗。将评估三种类型的终点，并在治疗组之间进行比较：（1）在7天的时间内生存（仅肺模型）； （2）通过定量聚合酶链反应（QPCR）测量组织真菌负担； （3）感染部位的血管生成，使用先前描述的矩阵测定法和使用微血管密度在肺组织切片中进行体内评估。在AIM 2中，我们将确定使用VEGF和BFGF治疗对AMB组织浓度的影响。 AMB浓度将在肺组织和矩阵塞中使用高性能液相色谱法测量，并比较单独接收AMB的小鼠组与接收AMB加VEGF和/或BFGF的组之间进行比较。公共卫生相关性：侵入性曲霉病是癌症患者疾病和死亡的主要原因，免疫系统弱。尽管有新的抗真菌药物的可用性和改善的支持性护理，但这些感染的死亡率仍然令人难以置信。我们假设在侵入性曲霉菌病过程中，血管阻塞限制了抗真菌药物在感染组织中的渗透，并且使用增强新血管形成的生长因子的治疗可能会改善这种严重的真菌感染的结果。

项目成果

Candiduria in haematologic malignancy patients without a urinary catheter: nothing more than a frailty marker?

• DOI: 10.1111/myc.12024
• 发表时间: 2013-05-01
• 期刊: MYCOSES
• 影响因子: 4.9
• 作者: Georgiadou, Sarah P.;Tarrand, Jeffrey;Kontoyiannis, Dimitrios P.
• 通讯作者: Kontoyiannis, Dimitrios P.

Concurrent lung infections in patients with hematological malignancies and invasive pulmonary aspergillosis: how firm is the Aspergillus diagnosis?

血液系统恶性肿瘤和侵袭性肺曲霉菌病患者并发肺部感染：曲霉菌诊断有多可靠？

• DOI: 10.1016/j.jinf.2012.05.001
• 发表时间: 2012
• 期刊: The Journal of infection
• 作者: Georgiadou,SarahP;Kontoyiannis,DimitriosP
• 通讯作者: Kontoyiannis,DimitriosP

Rare opportunistic (non-Candida, non-Cryptococcus) yeast bloodstream infections in patients with cancer.

• DOI: 10.1016/j.jinf.2011.11.002
• 发表时间: 2012-01
• 期刊: JOURNAL OF INFECTION
• 影响因子: 28.2
• 作者: Chitasombat, Maria N.;Kofteridis, Diamantis P.;Jiang, Ying;Tarrand, Jeffrey;Lewis, Russell E.;Kontoyiannis, Dimitrios P.
• 通讯作者: Kontoyiannis, Dimitrios P.

Risk factors for early mortality in haematological malignancy patients with pulmonary mucormycosis.

• DOI: 10.1111/myc.12101
• 发表时间: 2014-01
• 期刊: Mycoses
• 影响因子: 4.9
• 作者: Lewis RE;Georgiadou SP;Sampsonas F;Chamilos G;Kontoyiannis DP
• 通讯作者: Kontoyiannis DP

Open-lung biopsy in patients with undiagnosed lung lesions referred at a tertiary cancer center is safe and reveals noncancerous, noninfectious entities as the most common diagnoses.

• DOI: 10.1007/s10096-012-1720-9
• 发表时间: 2013-01
• 期刊: EUROPEAN JOURNAL OF CLINICAL MICROBIOLOGY & INFECTIOUS DISEASES
• 影响因子: 4.5
• 作者: Georgiadou, S. P.;Sampsonas, F. L.;Rice, D.;Granger, J. M.;Swisher, S.;Kontoyiannis, D. P.
• 通讯作者: Kontoyiannis, D. P.