Donnachie Elizabeth, Fedotova Elena P, Hwang Shen-An
Gulf States Hemophilia and Thrombophilia Center, Department of Pediatrics, University of Texas Medical School at Houston, Houston, Texas.
Department of Anatomic Pathology, St. Petersburg State Pediatric Medical University, St. Petersburg, Russia.
Am J Pathol. 2016 May;186(5):1221-33. doi: 10.1016/j.ajpath.2015.12.019. Epub 2016 Mar 8.
Tuberculosis (TB) remains a global health concern. Trehalose 6'6-dimycolate (TDM) activates innate inflammation and likely also stimulates chronic inflammation observed during disease progression. Noninfectious models using purified TDM oil/water emulsions elicit pathologic findings observed in patients with TB. We introduce a new TDM model that promotes inflammatory lung pathologic findings and vascular occlusion and hemorrhage. C57BL/6 and BALB/c mice were injected with 10 μg of i.p. TDM in light mineral oil (TDM-IP). At day 7, another injection of 10 μg of i.v. TDM in oil/water emulsion was given (TDM-IV). The i.p./i.v. TDM (TDM-IVIP) group was compared with mice injected once with i.v. or i.p. TDM. The responses to TDM-IP, TDM-IV, or TDM-IPIV were consistent between mouse strains. Mice that received TDM-IV and TDM-IPIV had inflammatory pathologic findings with increases in inflammatory and T-cell cytokines, and the TDM-IPIV group had further enhancement of IL-10 and granulocyte-macrophage colony-stimulating factor. The TDM-IPIV group had increased CD4(+) T cells in lung tissue, significantly increased coagulation, decreased clot formation time, and increased maximum clot firmness. Masson's trichrome staining revealed increased deposition of collagen in the occluded vasculature. TDM-IPIV promotes a hypercoagulopathy state, independent of inflammation. This new model argues that TDM is sufficient to generate the hypercoagulopathy observed in patients with TB.
结核病（TB）仍然是一个全球关注的健康问题。海藻糖6′,6″-二分枝菌酸（TDM）可激活先天性炎症，并且很可能还会刺激疾病进展过程中观察到的慢性炎症。使用纯化的TDM油/水乳液的非感染性模型可引发结核病患者中观察到的病理表现。我们引入了一种新的TDM模型，该模型可促进炎症性肺部病理表现以及血管闭塞和出血。将C57BL/6和BALB/c小鼠腹腔注射10μg溶解于轻质矿物油中的TDM（TDM-IP）。在第7天，再静脉注射10μg油/水乳液中的TDM（TDM-IV）。将腹腔/静脉注射TDM（TDM-IVIP）组与单次静脉注射或腹腔注射TDM的小鼠进行比较。小鼠品系对TDM-IP、TDM-IV或TDM-IPIV的反应是一致的。接受TDM-IV和TDM-IPIV的小鼠有炎症性病理表现，炎症和T细胞细胞因子增加，并且TDM-IPIV组中白细胞介素-10和粒细胞-巨噬细胞集落刺激因子进一步增强。TDM-IPIV组肺组织中CD4(+) T细胞增加，凝血显著增加，凝血形成时间缩短，最大凝块硬度增加。Masson三色染色显示闭塞血管中胶原蛋白沉积增加。TDM-IPIV促进高凝状态，与炎症无关。这个新模型表明TDM足以产生在结核病患者中观察到的高凝状态。
