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1.
J Infect Dis ; 227(8): 993-1001, 2023 04 18.
Artículo en Inglés | MEDLINE | ID: mdl-36200236

RESUMEN

Herpes zoster (HZ; shingles) caused by varicella zoster virus reactivation increases stroke risk for up to 1 year after HZ. The underlying mechanisms are unclear, however, the development of stroke distant from the site of zoster (eg, thoracic, lumbar, sacral) that can occur months after resolution of rash points to a long-lasting, virus-induced soluble factor (or factors) that can trigger thrombosis and/or vasculitis. Herein, we investigated the content and contributions of circulating plasma exosomes from HZ and non-HZ patient samples. Compared with non-HZ exosomes, HZ exosomes (1) contained proteins conferring a prothrombotic state to recipient cells and (2) activated platelets leading to the formation of platelet-leukocyte aggregates. Exosomes 3 months after HZ yielded similar results and also triggered cerebrovascular cells to secrete the proinflammatory cytokines, interleukin 6 and 8. These results can potentially change clinical practice through addition of antiplatelet agents for HZ and initiatives to increase HZ vaccine uptake to decrease stroke risk.


Asunto(s)
Herpes Zóster , Accidente Cerebrovascular , Humanos , Exosomas , Herpes Zóster/epidemiología , Herpesvirus Humano 3/fisiología , Accidente Cerebrovascular/epidemiología , Medición de Riesgo , Masculino , Femenino , Plasma/citología , Trombosis/virología
2.
Am J Physiol Lung Cell Mol Physiol ; 320(3): L413-L421, 2021 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-33264579

RESUMEN

Inflammation is central to the pathogenesis of pulmonary vascular remodeling and pulmonary hypertension (PH). Inflammation precedes remodeling in preclinical models, thus supporting the concept that changes in immunity drive remodeling in PH. Platelets are recognized as mediators of inflammation, but whether platelets contribute to hypoxia-driven inflammation has not been studied. We utilized a murine hypoxia model to test the hypothesis that platelets drive hypoxia-induced inflammation. We evaluated male and female 9-wk-old normoxic and hypoxic mice and in selected experiments included hypoxic thrombocytopenic mice. Thrombocytopenic mice were generated with an anti-GP1bα rat IgG antibody. We also performed immunostaining of lung sections from failed donor controls and patients with idiopathic pulmonary arterial hypertension. We found that platelets are increased in the lungs of hypoxic mice and hypoxia induces platelet activation. Platelet depletion prevents hypoxia-driven increases in the proinflammatory chemokines CXCL4 and CCL5 and attenuates hypoxia-induced increase in plasma CSF-2. Pulmonary interstitial macrophages are increased in the lungs of hypoxic mice; this increase is prevented in thrombocytopenic mice. To determine the potential relevance to human disease, lung sections from donors and patients with advanced idiopathic pulmonary arterial hypertension (iPAH) were immunostained for the platelet-specific protein CD41. We observed iPAH lungs had a two-fold increase in CD41, compared with controls. Our data provide evidence that the platelet count is increased in the lungs and activated in mice with hypoxia-induced inflammation and provides rationale for the further study of the potential contribution of platelets to inflammatory mediated vascular remodeling and PH.


Asunto(s)
Plaquetas/inmunología , Hipoxia/inmunología , Pulmón/inmunología , Activación Plaquetaria/inmunología , Neumonía/inmunología , Animales , Plaquetas/patología , Quimiocina CCL5/inmunología , Modelos Animales de Enfermedad , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Hipoxia/patología , Inflamación/inmunología , Inflamación/patología , Pulmón/patología , Masculino , Ratones , Factor Plaquetario 4/inmunología , Neumonía/patología , Trombocitopenia/inducido químicamente , Trombocitopenia/inmunología , Trombocitopenia/patología
3.
Am J Respir Cell Mol Biol ; 46(4): 479-87, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22052877

RESUMEN

Influenza A virus (IAV) is a worldwide public health problem causing 500,000 deaths each year. Palmitoyl-oleoyl-phosphatidylglycerol (POPG) is a minor component of pulmonary surfactant, which has recently been reported to exert potent regulatory functions upon the innate immune system. In this article, we demonstrate that POPG acts as a strong antiviral agent against IAV. POPG markedly attenuated IL-8 production and cell death induced by IAV in cultured human bronchial epithelial cells. The lipid also suppressed viral attachment to the plasma membrane and subsequent replication in Madin-Darby canine kidney cells. Two virus strains, H1N1-PR8-IAV and H3N2-IAV, bind to POPG with high affinity, but exhibit only low-affinity interactions with the structurally related lipid, palmitoyl-oleoyl-phosphatidylcholine. Intranasal inoculation of H1N1-PR8-IAV in mice, in the presence of POPG, markedly suppressed the development of inflammatory cell infiltrates, the induction of IFN-γ recovered in bronchoalveolar lavage, and viral titers recovered from the lungs after 5 days of infection. These findings identify supplementary POPG as a potentially important new approach for treatment of IAV infections.


Asunto(s)
Antivirales/farmacología , Virus de la Influenza A/efectos de los fármacos , Virus de la Influenza A/patogenicidad , Gripe Humana/tratamiento farmacológico , Fosfatidilgliceroles/farmacología , Administración Intranasal , Animales , Bronquios/citología , Bronquios/efectos de los fármacos , Bronquios/virología , Muerte Celular/efectos de los fármacos , Células Cultivadas , Citocinas/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/virología , Femenino , Humanos , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Subtipo H1N1 del Virus de la Influenza A/patogenicidad , Subtipo H3N2 del Virus de la Influenza A/efectos de los fármacos , Subtipo H3N2 del Virus de la Influenza A/patogenicidad , Virus de la Influenza A/metabolismo , Gripe Humana/virología , Interleucina-8/metabolismo , Ratones , Ratones Endogámicos BALB C , Infecciones por Orthomyxoviridae/tratamiento farmacológico , Infecciones por Orthomyxoviridae/virología , Fosfolípidos/metabolismo , Proteínas Virales/metabolismo , Replicación Viral/efectos de los fármacos
4.
Physiol Rep ; 10(19): e15482, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-36200294

RESUMEN

Serotonin (5-hydroxytryptamine, 5-HT) is a potent pulmonary vasoconstrictor and contributes to high pulmonary vascular resistance in the developing ovine lung. In experimental pulmonary hypertension (PH), pulmonary expression of tryptophan hydroxylase-1 (TPH1), the rate limiting enzyme in 5-HT synthesis, and plasma 5-HT are increased. 5-HT blockade increases pulmonary blood flow and prevents pulmonary vascular remodeling and PH in neonatal models of PH with bronchopulmonary dysplasia (BPD). We hypothesized that neonatal tph1 knock-out (KO) mice would be protected from hypoxia-induced alveolar simplification, decreased vessel density, and PH. Newborn wild-type (WT) and tph1 KO mice were exposed to normoxia or hypoxia for 2 weeks. Normoxic WT and KO mice exhibited similar alveolar development, pulmonary vascular density, right ventricular systolic pressures (RVSPs), and right heart size. Circulating (plasma and platelet) 5-HT decreased in both hypoxia-exposed WT and KO mice. Tph1 KO mice were not protected from hypoxia-induced alveolar simplification, decreased pulmonary vascular density, or right ventricular hypertrophy, but displayed attenuation to hypoxia-induced RVSP elevation compared with WT mice. Tph1 KO neonatal mice are not protected against hypoxia-induced alveolar simplification, reduction in pulmonary vessel density, or RVH. While genetic and pharmacologic inhibition of tph1 has protective effects in adult models of PH, our results suggest that tph1 inhibition would not be beneficial in neonates with PH associated with BPD.


Asunto(s)
Displasia Broncopulmonar , Hipertensión Pulmonar , Animales , Ratones , Animales Recién Nacidos , Displasia Broncopulmonar/genética , Displasia Broncopulmonar/prevención & control , Hipertensión Pulmonar/genética , Hipertensión Pulmonar/prevención & control , Hipertrofia Ventricular Derecha/genética , Hipertrofia Ventricular Derecha/prevención & control , Hipoxia/complicaciones , Hipoxia/genética , Ratones Noqueados , Serotonina/metabolismo , Ovinos , Triptófano Hidroxilasa/genética , Vasoconstrictores/efectos adversos
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