title: Role of tissue factor in Mycobacterium tuberculosis-induced inflammation and disease pathogenesis.
abstract: Tuberculosis (TB) is a chronic lung infectious disease characterized by severe inflammation and lung granulomatous lesion formation. Clinical manifestations of TB include hypercoagulable states and thrombotic complications. We previously showed that Mycobacterium tuberculosis (M.tb) infection induces tissue factor (TF) expression in macrophages in vitro. TF plays a key role in coagulation and inflammation. In the present study, we investigated the role of TF in M.tb-induced inflammatory responses, mycobacterial growth in the lung and dissemination to other organs. Wild-type C57BL/6 and transgenic mice expressing human TF, either very low levels (low TF) or near to the level of wild-type (HTF), in place of murine TF were infected with M.tb via aerosol exposure. Levels of TF expression, proinflammatory cytokines and thrombin-antithrombin complexes were measured post M.tb infection and mycobacterial burden in the tissue homogenates were evaluated. Our results showed that M.tb infection did not increase the overall TF expression in lungs. However, macrophages in the granulomatous lung lesions in all M.tb-infected mice, including low TF mice, showed increased levels of TF expression. Conspicuous fibrin deposition in the granuloma was detected in wild-type and HTF mice but not in low TF mice. M.tb infection significantly increased expression levels of cytokines IFN-γ, TNF-α, IL-6 and IL-1ß in lung tissues. However, no significant differences were found in proinflammatory cytokines among the three experimental groups. Mycobacterial burden in lungs and dissemination into spleen and liver were essentially similar in all three genotypes. Our data indicate, in contrast to that observed in acute bacterial infections, that TF-mediated coagulation and/or signaling does not appear to contribute to the host-defense in experimental tuberculosis.
authors.affiliation: Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, TX 75708, United States of America.
authors.forename: Hema
authors.initials: H
authors.lastname: Kothari
authors.affiliation: Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, TX 75708, United States of America.
authors.forename: Shiva
authors.initials: S
authors.lastname: Keshava
authors.affiliation: Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, TX 75708, United States of America.
authors.forename: Rit
authors.initials: R
authors.lastname: Vatsyayan
authors.affiliation: Division of Hematology and Oncology, McAllister Heart Institute, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill NC 27599, United States of America.
authors.forename: Nigel
authors.initials: N
authors.lastname: Mackman
authors.affiliation: Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, TX 75708, United States of America.
authors.forename: L Vijaya Mohan
authors.initials: LV
authors.lastname: Rao
authors.affiliation: Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, TX 75708, United States of America.
authors.forename: Usha R
authors.initials: UR
authors.lastname: Pendurthi
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D007249:Inflammation / Q000209:etiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009169:Mycobacterium tuberculosis / Q000472:pathogenicity*; D013925:Thromboplastin / Q000502:physiology*; D014376:Tuberculosis / Q000150:complications / Q000503:physiopathology*
chemical_list: D013925:Thromboplastin