食道および気管・気管支との位置関係に基づいた気管支動脈の解剖学的分類

博士(医学)琉球大

Increased permeability of human endothelial cell line EA.hy926 induced by hantavirus-specific cytotoxic T lymphocytes

Hantavirus infection causes two human diseases, hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. The typical feature of these diseases is increased permeability in microvascular beds in the kidneys and the lungs, respectively. The mechanism of capillary leakage, however, is not understood. Some evidence suggests that hantavirus disease pathogenesis is immunologically mediated by cytotoxic T lymphocytes and other immune cells in target organs producing inflammatory cytokines. In this study we examined the roles of virus-specific cytotoxic T lymphocytes in increased permeability of human endothelial cells infected with hantavirus. We used a human CD8(+) hantavirus-specific cytotoxic T lymphocyte line, 1A-E2, specific for the HLA-A24-restricted epitope in Sin Nombre and Puumala virus G2 protein, and the human endothelial cell line, EA.hy926 that expresses HLA-A24 molecule. The cytotoxic T lymphocyte line recognized and lysed target cells infected with Sin Nombre virus, and in transwell permeability assays increased permeability of EA.hy926 cell monolayer infected with Sin Nombre virus or recombinant adenovirus expressing the Sin Nombre virus G2 protein. These results suggest that cytotoxic T lymphocyte activity contribute to capillary leakage observed in patients with hantavirus pulmonary syndrome or hemorrhagic fever with renal syndrome

Immunopathogenesis of hantavirus pulmonary syndrome and hemorrhagic fever with renal syndrome: Do CD8+ T cells trigger capillary leakage in viral hemorrhagic fevers

There are many viruses known to cause viral hemorrhagic fevers in humans. The mechanisms causing hemorrhage are likely to vary among viruses. Some viruses, such as Marburg virus, are directly cytopathic to infected endothelial cells, suggesting infection of endothelial cells alone can cause hemorrhage. On the other hand, there are viruses which infect endothelial cells without causing any cytopathic effects, suggesting the involvement of host immune responses in developing hemorrhage. Typical examples of these include viruses of the hantavirus species. We hypothesize that impairment of endothelial cell\u27s defense mechanisms against cytotoxic CD8+ T cells is the mechanism of capillary leakage in hantavirus pulmonary syndrome and hemorrhagic fever with renal syndrome, which may be common to other viral hemorrhagic fevers. CD8+ T cells may be a potential target for therapy of some viral hemorrhagic fevers

Recombinant adenovirus vector vaccine induces stronger cytotoxic T-cell responses than recombinant vaccinia virus vector, plasmid DNA, or a combination of these

The efficiency of prime-boost vaccinations on the induction of T-cell responses to Sin Nombre virus nucleocapsid protein expressed by recombinant vaccinia virus, replication-deficient adenovirus, and plasmid DNA in mice was quantitated by the number of epitope-specific interferon-gamma-producing T cells and cytotoxic T-lymphocyte activity induced. In prime-boost immunizations, all combinations that included the recombinant adenovirus induced a much higher number of epitope-specific interferon-gamma-producing T cells than did other combinations. A single immunization of the recombinant adenovirus was able to induce similarly high levels of epitope-specific interferon-gamma-producing cells, despite the fact that the recombinant adenovirus produces less amount of the Sin Nombre virus nucleocapsid protein

Stress-induced stenotic vascular remodeling via reduction of plasma omega-3 fatty acid metabolite 4-oxoDHA by noradrenaline

Abstract Stress has garnered significant attention as a prominent risk factor for inflammation-related diseases, particularly cardiovascular diseases (CVDs). However, the precise mechanisms underlying stress-driven CVDs remain elusive, thereby impeding the development of preventive and therapeutic strategies. To explore the correlation between plasma lipid metabolites and human depressive states, liquid chromatography–mass spectrometry (LC/MS) based analysis of plasma and the self-rating depression (SDS) scale questionnaire were employed. We also used a mouse model with restraint stress to study its effects on plasma lipid metabolites and stenotic vascular remodeling following carotid ligation. In vitro functional and mechanistic studies were performed using macrophages, endothelial cells, and neutrophil cells. We revealed a significant association between depressive state and reduced plasma levels of 4-oxoDHA, a specific omega-3 fatty acid metabolite biosynthesized by 5-lipoxygenase (LO), mainly in neutrophils. In mice, restraint stress decreased plasma 4-oxoDHA levels and exacerbated stenotic vascular remodeling, ameliorated by 4-oxoDHA supplementation. 4-oxoDHA enhanced Nrf2-HO-1 pathways, exerting anti-inflammatory effects on endothelial cells and macrophages. One of the stress hormones, noradrenaline, reduced 4-oxoDHA and the degraded 5-LO in neutrophils through the proteasome system, facilitated by dopamine D2-like receptor activation. Our study proposed circulating 4-oxoDHA levels as a stress biomarker and supplementation of 4-oxoDHA as a novel therapeutic approach for controlling stress-related vascular inflammation