title: Trehalose 6,6-Dimycolate from Mycobacterium tuberculosis Induces Hypercoagulation.
abstract: 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.
authors.affiliation: Gulf States Hemophilia and Thrombophilia Center, Department of Pediatrics, University of Texas Medical School at Houston, Houston, Texas.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Donnachie
authors.affiliation: Department of Anatomic Pathology, St. Petersburg State Pediatric Medical University, St. Petersburg, Russia.
authors.forename: Elena P
authors.initials: EP
authors.lastname: Fedotova
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Texas Medical School at Houston, Houston, Texas. Electronic address: shen-an.hwang@uth.tmc.edu.
authors.forename: Shen-An
authors.initials: SA
authors.lastname: Hwang
mesh_terms: D000276:Adjuvants, Immunologic / Q000633:toxicity*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D003311:Cord Factors / Q000633:toxicity*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D007113:Immunity, Innate / Q000187:drug effects; D008168:Lung / Q000098:blood supply / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis; D009504:Neutrophils / Q000276:immunology; D011014:Pneumonia / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D011668:Pulmonary Veno-Occlusive Disease / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D013916:Thrombelastography / Q000379:methods; D019851:Thrombophilia / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology
chemical_list: D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D003311:Cord Factors; D016207:Cytokines; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003094:Collagen