RESUMEN
BACKGROUND: The predominant mode of HIV-1 transmission is by heterosexual contact. The cervical/vaginal mucosa is the main port of HIV entry in women. A safe and effective topical microbicide against HIV is urgently needed to prevent sexual transmission. Hence, we evaluated griffithsin (GRFT), a 12.7 kDa carbohydrate-binding protein, both native and recombinant GRFT, potently inhibited both CXCR4-and CCR5-tropic HIV infection and transmission in vitro. METHODS: The antiviral efficacy of native and recombinant GRFT against CXCR4-and CCR5-tropic HIV and SHIV strains and SIVmac251 was evaluated by in vitro assays. We also evaluated the time course of antiviral activity and stability of GRFT in cervical/vaginal lavage as a function of pH 4-8. RESULTS: Griffithsin blocked CXCR4-and CCR5-tropic viruses at less than 1 nm concentrations and exhibited a high potency. GRFT was stable in cervical/vaginal lavage fluid and maintained a similar potency of anti-HIV activity. GRFT is not only a highly potent HIV entry inhibitor, but also prevents cell fusion and cell-to-cell transmission of HIV. CONCLUSIONS: The in vitro efficacy of GRFT revealed low cytotoxicity, high potency, rapid onset of antiviral activity and long-term stability in cervical/vaginal lavage. GRFT is an excellent candidate for anti-HIV microbicide development.
Asunto(s)
Proteínas Algáceas/farmacología , Fármacos Anti-VIH/farmacología , Infecciones por VIH/prevención & control , Lectinas/farmacología , Macaca nemestrina , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Virus de la Inmunodeficiencia de los Simios/fisiología , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Humanos , Concentración de Iones de Hidrógeno , Cinética , Lectinas de Plantas , Receptores CCR5/metabolismo , Receptores CXCR4/metabolismo , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/metabolismo , Ducha VaginalRESUMEN
We report that simian immunodeficiency virus (SIV) infection in macaques is a valuable animal model for studying post-exposure chemoprophylaxis (PECP). PECP with the acyclic nucleoside reverse transcriptase inhibitors 9-(2-phosphonylmetho-xyethyl)adenine (PMEA) and (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA) at early viral infection can provide long-term protection against subsequent heterologous SIV challenge. Eight macaques previously treated with PECP (called PECP macaques) and four naive controls were challenged intravenously with the most virulent form of SIV, SIV(PBj14). All controls showed signs of SIV(PBj14)-induced acute disease syndrome on days 6 and 7 post-inoculation (PI). One had a fatal viral infection and two surviving controls had persistent infection and decreased CD4+ cell count. Virologic studies of the three surviving controls revealed SIV in multiple lymphoid tissues and peripheral blood mononuclear cells (PBMCs) at necropsy. In contrast, the PECP macaques showed none to mild signs of acute disease syndrome at day 9 PI and exhibited only transient SIV infection in PBMCs between weeks 1 and 8 PI. In virologic studies of five PECP macaques necropsied, two macaques were SIV-negative and the other three were SIV-positive only in either lymph node or bone marrow. Three SIV(PBj14)-challenged PECP macaques, that were randomly reserved for a follow-up study for > 4.0 years PI showed extremely low to undetectable levels of PBMC-associated viremia and normal to increased levels of CD4 + and CD8 + cell counts throughout the study. Our results indicate that early PECP could activate immune responses to protect against subsequent infection with heterologous challenge virus.
Asunto(s)
Adenina/análogos & derivados , Organofosfonatos , Compuestos Organofosforados/uso terapéutico , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Virus de la Inmunodeficiencia de los Simios/aislamiento & purificación , Adenina/uso terapéutico , Animales , ADN Viral/análisis , Modelos Animales de Enfermedad , Infecciones por VIH/prevención & control , Infecciones por VIH/transmisión , Humanos , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Macaca fascicularis , Reacción en Cadena de la Polimerasa , Síndrome de Inmunodeficiencia Adquirida del Simio/transmisión , TenofovirRESUMEN
(R)-9-(2-Phosphonylmethoxypropyl)adenine (PMPA), an acyclic nucleoside phosphonate analog, is one of a new class of potent antiretroviral agents. Previously, we showed that PMPA treatment for 28 days prevented establishment of persistent simian immunodeficiency virus (SIV) infection in macaques even when therapy was initiated 24 h after intravenous virus inoculation. In the present study, we tested regimens involving different intervals between intravenous inoculation with SIV and initiation of PMPA treatment, as well as different durations of treatment, for the ability to prevent establishment of persistent infection. Twenty-four cynomolgus macaques (Macaca fascicularis) were studied for 46 weeks after inoculation with SIV. All mock-treated control macaques showed evidence of productive infection within 2 weeks postinoculation (p.i.). All macaques that were treated with PMPA for 28 days beginning 24 h p.i. showed no evidence of viral replication following discontinuation of PMPA treatment. However, extending the time to initiation of treatment from 24 to 48 or 72 h p.i. or decreasing the duration of treatment reduced effectiveness in preventing establishment of persistent infection. Only half of the macaques treated for 10 days, and none of those treated for 3 days, were completely protected when treatment was initiated at 24 h. Despite the reduced efficacy of delayed and shortened treatment, all PMPA-treated macaques that were not protected showed delays in the onset of cell-associated and plasma viremia and antibody responses compared with mock controls. These results clearly show that both the time between virus exposure and initiation of PMPA treatment as well as the duration of treatment are crucial factors for prevention of acute SIV infection in the macaque model.
Asunto(s)
Adenina/análogos & derivados , Antivirales/administración & dosificación , Organofosfonatos , Compuestos Organofosforados/administración & dosificación , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Adenina/administración & dosificación , Adenina/efectos adversos , Animales , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD8-positivos/efectos de los fármacos , Esquema de Medicación , Evaluación de Medicamentos , Femenino , Humanos , Macaca fascicularis , Masculino , Compuestos Organofosforados/efectos adversos , Síndrome de Inmunodeficiencia Adquirida del Simio/sangre , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Tenofovir , Células Tumorales Cultivadas , Latencia del VirusRESUMEN
Monkeys infected rectally with low dose simian immunodeficiency virus (SIV) were resistant to high dose challenge with SIV. Peripheral blood mononuclear cells (PBMC) from two of four challenged monkeys were unable to support SIV replication in vitro unless cultures were depleted of CD8+ lymphocytes. Monkeys that had survived high dose rectal infection with SIV also suppressed virus replication in cultured PBMC. PBMC from uninfected monkeys supported virus replication in both unfractionated and CD8-depleted cultures. Virus-suppressive activity of PBMC may be an important correlate of protective immunity in AIDS.
Asunto(s)
Activación de Linfocitos , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/fisiología , Linfocitos T/inmunología , Replicación Viral , Animales , Linfocitos T CD8-positivos/inmunología , Células Cultivadas , Inmunidad Celular , Depleción Linfocítica , Macaca mulatta , Recto , Síndrome de Inmunodeficiencia Adquirida del Simio/transmisión , Virus de la Inmunodeficiencia de los Simios/patogenicidad , Linfocitos T/virologíaRESUMEN
Asymptomatic infection with simian immunodeficiency virus (SIV) has been demonstrated in African Sykes' monkeys (Cercopithecus mitis albogularis), and virus isolation confirmed infection with a novel SIV from Sykes' monkeys (SIVsyk). Macaques inoculated with SIVsyk became persistently infected but remained clinically healthy. We utilized polymerase chain reaction amplification to generate a full-length, infectious molecular clone of SIVsyk. The genome organization of SIVsyk is similar to that of the other primate lentiviruses, consisting of gag, pol, vif, vpr, tat, rev, env, and nef. A unique feature is the absence of the highly conserved NF-kappa B binding site in the long terminal repeat. SIVsyk is genetically equidistant from other primate lentiviruses. Thus, SIVsyk represents a new group that is distinct from the four previously recognized primate lentivirus groups: human immunodeficiency virus type 1 (HIV-1), SIV from sooty mangabeys (SIVsmm) and HIV-2, SIV from African green monkeys (SIVagm), and SIV from mandrills (SIVmnd). The genetic differences between SIVsyk and SIVagm, isolates derived from monkeys of the same genus, underscore the potential for other distinct SIVs which have yet to be isolated and characterized.
Asunto(s)
Cercopithecus/microbiología , Lentivirus/clasificación , Enfermedades de los Monos/microbiología , Virus de la Inmunodeficiencia de los Simios/genética , África , Secuencia de Aminoácidos , Animales , Animales Salvajes/microbiología , Secuencia de Bases , Línea Celular , Clonación Molecular , Productos del Gen gag/genética , Productos del Gen pol/clasificación , Productos del Gen pol/genética , Genes Reguladores/genética , VIH-1/genética , Lentivirus/genética , Lentivirus/aislamiento & purificación , Lentivirus/patogenicidad , Macaca/microbiología , Datos de Secuencia Molecular , Filogenia , Reacción en Cadena de la Polimerasa , Secuencias Repetitivas de Ácidos Nucleicos/genética , Homología de Secuencia de Aminoácido , Virus de la Inmunodeficiencia de los Simios/aislamiento & purificación , Virus de la Inmunodeficiencia de los Simios/patogenicidad , Especificidad de la Especie , Transfección , VirulenciaRESUMEN
Intrarectal inoculation of rhesus monkeys with low doses of SIVmac led to a prolonged clinical and virological latency that was not observed for high intrarectal doses or for intravenous inoculation. Animals infected intrarectally with low virus doses remained negative for serum antibody responses to SIV for at least one year even though they readily transferred SIV to naive recipients via transfusion of whole blood.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida del Simio/etiología , Animales , Anticuerpos Antivirales/sangre , Secuencia de Bases , ADN Viral/genética , ADN Viral/aislamiento & purificación , Modelos Animales de Enfermedad , Infecciones por VIH/transmisión , VIH-1 , Mucosa Intestinal/microbiología , Leucocitos Mononucleares/microbiología , Macaca mulatta , Masculino , Datos de Secuencia Molecular , Recto/microbiología , Síndrome de Inmunodeficiencia Adquirida del Simio/transmisión , Virus de la Inmunodeficiencia de los Simios/genética , Virus de la Inmunodeficiencia de los Simios/inmunología , Virus de la Inmunodeficiencia de los Simios/aislamiento & purificación , Factores de TiempoRESUMEN
We studied the effects of vitamin D3 compounds on the replication of human immunodeficiency virus type 1 (HIV-1) in the monoblastoid cell line U937 and in primary monocyte-derived macrophage cultures to understand how modulators of monocyte/macrophage effector function might affect the pathogenesis of HIV-1 infection. U937 cell cultures exposed to 1, alpha 25-dihydroxyvitamin D3 prior to HIV-1 infection showed enhanced virus replication that was apparently due to increased cellular resistance to viral cytopathic effects; a marked inhibition of virus replication was noted in cells exposed to 1 alpha,25-dihydroxyvitamin D3 subsequent to infection. Exposure of blood-derived monocyte/macrophages to vitamin D3 compounds prior to infection also affected virus growth; in most cases, substantial inhibition of HIV-1 replication was noted in vitamin D3-treated macrophage cultures. Our results demonstrate that vitamin D3 compounds with recognized abilities to induce cellular differentiation can modulate HIV-1 infection of human macrophages.
Asunto(s)
Colecalciferol/farmacología , VIH-1/fisiología , Macrófagos/fisiología , Monocitos/fisiología , Replicación Viral/efectos de los fármacos , Calcifediol/farmacología , Calcitriol/farmacología , Células Cultivadas , Seropositividad para VIH , VIH-1/efectos de los fármacos , Humanos , Cinética , Macrófagos/efectos de los fármacos , Monocitos/efectos de los fármacos , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Analysis of serum samples from 100 wild-caught or colony-born Sykes' monkeys (Cercopithecus mitis) in Kenya revealed that 59 animals had antibodies cross-reactive to human immunodeficiency virus type 2 (HIV-2) and to simian immunodeficiency viruses (SIVs). A lentivirus, designated SIVsyk, was isolated from five of six seropositive asymptomatic Sykes' monkeys, but in four cases isolation was possible only after depletion of CD8+ lymphocytes and cocultivation of the CD4(+)-enriched cell population with peripheral blood mononuclear cells from seronegative Sykes' monkeys. SIVsyk resembled other SIVs and HIVs morphologically, had an Mg2(+)-dependent reverse transcriptase enzyme, and replicated in and was cytopathic for CEMx174 and Sup-T1 cells. SIVsyk differred substantially from other SIVs, however, in that it failed to replicate in normal human, mangabey, and macaque peripheral blood mononuclear cells and serum from seropositive Sykes' monkeys immunoprecipitated env antigens from HIV-1 as well as from HIV-2, SIVsmm, and SIVagm. These data demonstrate a high prevalence of natural infection in Sykes' monkeys in Kenya with a lentivirus that appears to be unique with respect to its host range and antigenic cross-reactivity.
Asunto(s)
VIH-2/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/epidemiología , Virus de la Inmunodeficiencia de los Simios/inmunología , Animales , Cercopithecus , Reacciones Cruzadas , Efecto Citopatogénico Viral , Anticuerpos Anti-VIH/inmunología , Antígenos VIH/inmunología , Seroprevalencia de VIH , VIH-1/crecimiento & desarrollo , VIH-1/inmunología , VIH-2/crecimiento & desarrollo , Humanos , Kenia/epidemiología , Filogenia , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/crecimiento & desarrollo , Virus de la Inmunodeficiencia de los Simios/aislamiento & purificación , Linfocitos T Reguladores/microbiología , Replicación ViralRESUMEN
The effects of Escherichia coli endotoxin infusions (1.0 or 2.5 micrograms kg-1 over 6 h) on pregnancy were investigated in cows in the first, second and third trimester of gestation. Endotoxin increased the plasma levels of prostaglandins (PGs), thromboxane B2 and cortisol, and decreased progesterone. The severity of the clinical signs and the magnitude of the increases in plasma PGs, thromboxane B2 and cortisol tended to depend on the dose of endotoxin, but were independent of the gestation period. There was hyperglycemia followed by hypoglycemia and lactic acidemia. Hyperglycemia and lactic acidemia were significant only at the high dose of endotoxin. Endotoxin infusion at both doses caused a preferential mobilization of oleic acid from adipose tissue, and also had some effects on the mobilization of palmitic and stearic acids during the post-infusion period. The cows in the first trimester of gestation were more sensitive to the abortifacient effect of endotoxin than cows in the second and third trimester of gestation. The results of this study indicate that the mechanism of endotoxin-induced abortion in cows initially involves a prolonged release of PGF2 alpha and its subsequent stimulant effect on uterine smooth muscle contraction and luteolytic effect leading to a gradual decline in the plasma levels of progesterone. It was concluded that pregnancy terminates in the absence of an adequate level of progesterone, especially during the first trimester of gestation, when progesterone of extraluteal origin is not yet available, coupled with the PGF2 alpha-induced propulsive contraction of the uterus. In addition, the metabolic and circulatory failures in severe cases of endotoxemia, especially at the high dose of endotoxin, resulting either directly or indirectly via the release of various autacoids, catecholamines and cortisol, may also contribute to the termination of pregnancy at any stage of gestation.
Asunto(s)
Aborto Veterinario/etiología , Enfermedades de los Bovinos/etiología , Endotoxinas/toxicidad , Escherichia coli , Preñez/sangre , Animales , Glucemia/análisis , Temperatura Corporal , Bovinos , Dinoprost/sangre , Ácidos Grasos/sangre , Femenino , Hidrocortisona/sangre , Lactatos/sangre , Ácido Láctico , Embarazo , Progesterona/sangre , Prostaglandinas/sangre , Tromboxano B2/sangre , Contracción Uterina/efectos de los fármacosRESUMEN
Xanthine (X) and xanthine oxidase (XO) were injected intratracheally (IT) in hamsters at Day 0 (38 mg X, 100 micrograms XO) and Day 5 (38 mg X, 250 micrograms XO). Control hamsters received saline or X (38 mg) plus boiled XO (100, 250 micrograms). Cytoplasmic superoxide dismutase (SOD) activity increased from control of 286 to 337 and 335 units/lung at Days 12 and 19, respectively, but decreased to 228 units/lung at Day 33; mitochondrial SOD activity increased at Day 12 from control of 57 to 71 units/lung and then decreased at Days 26 and 33 to 42 and 33 units/lung, respectively. Glutathione peroxidase (GP) and glutathione reductase (GR) activities rose from their control values of 1161 and 1151 to 1561 and 2287 units/lung at Day 12, respectively; thereafter, GR activity decreased to 512 and 462 units/lung at Days 19 and 26, respectively. Glutathione transferase declined at Day 12 but increased at Day 26 after initial treatment. Glucose-6-phosphate dehydrogenase activity declined from control of 1071 to 693 units/lung at Day 2 and returned to control thereafter. Catalase activity remained unaffected. Hydroxyproline was increased from 903 micrograms/lung in control to 1080, 1301, 1195, and 1148 micrograms/lung at Days 12, 19, 26, and 33, respectively. Malonaldehyde increased from 40 nmole/lung in control to 70 and 113 nmole/lung at Days 12 and 33, respectively. The ratio of right ventricle to left ventricle and septum increased significantly from control of 0.277 to 0.318 at Day 33. Histopathology at Days 2 and 4 revealed peribronchiolar and arteriolar inflammation, and diffuse alveolitis. By Day 12 there were thickened alveolar septa and foci of fibrotic consolidation.
Asunto(s)
Colágeno/metabolismo , Peróxidos Lipídicos/metabolismo , Enfermedades Pulmonares/inducido químicamente , Pulmón/enzimología , Xantina Oxidasa/administración & dosificación , Xantinas/administración & dosificación , Animales , Catalasa/metabolismo , Cricetinae , Radicales Libres , Glucosafosfato Deshidrogenasa/metabolismo , Glutatión Peroxidasa/metabolismo , Glutatión Reductasa/metabolismo , Corazón/efectos de los fármacos , Intubación Intratraqueal , Pulmón/metabolismo , Enfermedades Pulmonares/patología , Superóxido Dismutasa/metabolismo , Factores de Tiempo , XantinaRESUMEN
The present study examined the potency of smooth or rough Pasteurella haemolytica lipopolysaccharide infusion (LPS, 24 ng kg-1 min-1 for 500 min) on plasma cyclic-nucleotides and several free fatty acids (FFA) in calves. Both smooth or rough LPS increased plasma cAMP immediately to its maximum at 1 h of infusion, whereas plasma cGMP levels rose slowly and peaked 12 h later. The increases in cAMP levels were more prolonged for smooth LPS than rough LPS. The maximum plasma cAMP rise coincided with increases of several plasma FFA. Rough LPS increased plasma oleic greater than palmitic greater than stearic greater than linoleic acids in the second hour and reached their steady state levels between 2 h of infusion and 5 h post-infusion. Thereafter, oleic acid remained maximally elevated, while stearic acid decreased and other FFA returned to baseline. Smooth LPS had no effects on palmitic and stearic acids, but elevated oleic acid in an essentially similar manner to rough LPS and increased linoleic acid initially at 5 h, followed by decreases throughout post-infusion. These results demonstrate that endotoxemia produces early marked elevations in plasma cAMP, a gradual rise in plasma cGMP and disproportionate increases in several plasma FFA. The data also demonstrate that smooth and rough LPS differ in their abilities to increase plasma cAMP and FFA and these may be attributed to differences in their in vivo mechanisms of action. The study suggests that cAMP and cGMP may mediate actions of endotoxin at the cellular level and that differences exist in release and/or utilization of each FFA at different stages of endotoxemia.
Asunto(s)
Bovinos/sangre , Ácidos Grasos no Esterificados/sangre , Lipopolisacáridos/toxicidad , Nucleótidos Cíclicos/sangre , Pasteurella , Animales , AMP Cíclico/sangre , GMP Cíclico/sangre , Endotoxinas/administración & dosificación , Endotoxinas/toxicidad , Infusiones Intravenosas , Lipopolisacáridos/administración & dosificación , MasculinoRESUMEN
By inoculating Klebsiella pneumoniae into the teat canals of mammary glands, coliform mastitis was induced experimentally in 6 lactating cows. Release of eicosanoids, histamine, and serotonin in plasma and milk was studied in response to 2 doses of K pneumoniae. A low dose (mean, 5,000 organisms/ml) was inoculated into cows 1 through 4, and a high dose (mean, 200,000 organisms/ml) was inoculated into cows 5 and 6. Milk and blood samples were collected before inoculation (0 hours), and hourly, from 3 to 24 hours after inoculation. Concentrations of prostaglandin F2 alpha (PGF2 alpha), prostaglandin E (PGE), thromboxane B2 (TxB2), histamine, and serotonin were measured in plasma and milk obtained from control (NaCl solution-inoculated) and infected quarters. Fluorometric analysis of milk from infected quarters revealed significantly increased histamine and serotonin concentrations regardless of the dose of K pneumoniae. The mean (+/- SEM) peak concentrations of histamine were significantly (P less than 0.01) increased from the preinoculation value of 44 (+/- 12) ng/ml to 312 (+/- 104) ng/ml in milk from infected quarters and 72 (+/- 24) ng/ml in milk from control quarters. The mean peak concentration of serotonin increased significantly from the preinoculation concentration of 436 (+/- 37) ng/ml to 1,754 (+/- 662) ng/ml and 4,867 (+/- 1,248) ng/ml in milk from control (P less than 0.02) and infected (P less than 0.001) quarters, respectively. However, serotonin concentration in milk from infected quarters was approximately 2.8 times greater than that in milk from control quarters. Concentrations of PGF2 alpha, PGE, and TxB2 in milk and plasma were evaluated by radioimmunoassay.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Liberación de Histamina , Infecciones por Klebsiella/veterinaria , Mastitis Bovina/microbiología , Prostaglandinas E/fisiología , Prostaglandinas F/fisiología , Serotonina/fisiología , Tromboxano B2/fisiología , Animales , Bovinos , Dinoprost , Femenino , Histamina/análisis , Infecciones por Klebsiella/etiología , Infecciones por Klebsiella/fisiopatología , Klebsiella pneumoniae , Mastitis Bovina/etiología , Mastitis Bovina/fisiopatología , Leche/análisis , Leche/citología , Prostaglandinas E/análisis , Prostaglandinas F/análisis , Serotonina/análisis , Tromboxano B2/análisisRESUMEN
In the pathogenesis of bovine pneumonic pasteurellosis, immunodepression induced by stress or respiratory viral infection permits superinfection of the lungs with Pasteurella hemolytica, which results in exudative fibrinous pneumonia. Therefore, bovine pneumonic pasteurellosis was induced by sequential inoculations of calves with bovine herpes virus-1 (BHV-1, 3 X 10(7) tissue culture infectious dose 50 (TCID50)/nostril), followed 3 days later by challenge with P. hemolytica (15 X 10(9) colony-forming units (cfu) intratracheally). To study the pathogenic mechanisms of the disease, we examined the alterations in plasma prostaglandins (PG), thromboxane B2 (TxB2), histamine, serotonin and long-chain fatty acids (LCFA) during BHV-1 infection alone and after challenge exposure to P. hemolytica (i.e. during BHV-1-pneumonic pasteurellosis). BHV-1 infection alone markedly increased plasma PGE but modestly elevated PGF2 alpha, TxB2 and arachidonic, oleic and palmitic acids. After challenge with P. hemolytica, the levels of plasma arachidonic, oleic, and palmitic acids, together with PGE and 6-keto-PGF1 alpha, were elevated markedly, in association with clinical signs of bovine pneumonic pasteurellosis. However, PGF2 alpha and stearic acid increased only transiently whereas TxB2 was unchanged from the control. On the other hand, plasma linoleic acid, histamine and serotonin remained unaltered. These results indicate enhanced eicosanoid biosynthesis and disproportionate rises in LCFA during BHV-1 pneumonic pasteurellosis. While LCFA are needed for energy metabolism, eicosanoids may mediate the immunologic, inflammatory and pulmonary vascular reactions leading to the clinico-pathologic features of BHV-1 pneumonic pasteurellosis.
Asunto(s)
Enfermedades de los Bovinos/sangre , Ácidos Eicosanoicos/sangre , Ácidos Grasos/sangre , Neumonía/sangre , Animales , Temperatura Corporal , Bovinos , Dinoprost , Herpesvirus Bovino 1 , Consumo de Oxígeno , Pasteurella , Neumonía/microbiología , Prostaglandinas E/sangre , Prostaglandinas F/sangre , Tromboxano B2/sangreRESUMEN
Effect of IV infusions of smooth and rough Pasteurella hemolytica lipopolysaccharides (LPS; 24 ng/kg/min for 500 min) on circulating levels of arachidonic acid, prostaglandins (PG), thromboxane B2 (TxB2), histamine, and serotonin in calves was evaluated. Both smooth and rough LPS had no effects on plasma PGE but caused maximal increases in arachidonic acid, TxB2, and PGF2 alpha at 1 hr and 6-keto-PGF1 alpha at 3 hr of infusion, respectively. The increases in arachidonic acid and its metabolites were greater and more prolonged for smooth LPS than for rough LPS. Although both rough and smooth LPS increased plasma serotonin transiently at 25 min of infusion, only rough LPS decreased serotonin in the later period of endotoxemia. In contrast, smooth, but not rough, LPS decreased plasma histamine during endotoxemia. These results indicate that during endotoxemia there is increased PG and TxA2 synthesis secondary to marked arachidonic acid release into circulation. The data also demonstrate that smooth and rough LPS differ in their abilities to release histamine, serotonin, and eicosanoids. These effects might be due to differences in the in vivo mechanisms of action of smooth and rough LPS and may partly explain the differential potency of smooth and rough LPS in producing pathophysiological changes.
Asunto(s)
Autacoides/sangre , Ácidos Grasos/sangre , Lipopolisacáridos/farmacología , Pasteurella , Animales , Ácido Araquidónico , Ácidos Araquidónicos/sangre , Bovinos , Histamina/sangre , Masculino , Prostaglandinas/sangre , Serotonina/sangre , Choque Séptico/sangre , Tromboxano B2/sangreRESUMEN
Intravenous infusion of Pasteurella hemolytica endotoxin caused marked increases in the plasma levels of thromboxane B2 (TxB2), prostaglandins (PG) and serotonin in sheep. The control values for TxB2, 6-keto-PGF1 alpha, PGF2 alpha, and serotonin before endotoxin infusion averaged 283 +/- 53 (standard error of mean), 281 +/- 14 and 199 +/- 27 pg/ml and 57 +/- 3 ng/ml, respectively. At 50 min during endotoxin infusion, these values were increased to their maximum of 376, 339, 325 and 202% of control, respectively. Body temperature increased from the control value of 39.5 +/- 0.1 degrees C to a maximum of 41.5 +/- 0.1 degrees C at 200-300 min of infusion. In the second part of this study, we have examined the effects of ibuprofen on endotoxin-induced increases in plasma PG, TxB2, and serotonin levels and body temperature. The control values for TxB2, 6-keto-PGF1 alpha, PGF2 alpha, and temperature prior to ibuprofen and endotoxin infusion averaged 238 +/- 35, 335 +/- 44 and 248 +/- 28 pg/ml, 65 +/- 3 ng/ml and 40.1 +/- 0.2 degrees C, respectively. A loading dose (15 mg/kg) of ibuprofen was followed by infusion of endotoxin (12 micrograms/kg) and ibuprofen (43.3 mg/kg) over 500 min. Plasma levels of 6-keto-PGF1 alpha and serotonin increased only to 131 and 149% of control at 50 min of infusion, and levels of PGF2 alpha and TxB2 decreased to 50 and 80% of control at 100 and 150 min of infusion, respectively. Temperature remained unchanged. Ibuprofen effectively suppressed endotoxin-induced increases in the plasma levels of TxB2, 6-keto-PGF1 alpha, PGF2 alpha, and serotonin and body temperature. It was concluded from the present study that nonsteroidal anti-inflammatory drugs as an adjunct to antibiotic therapy might have a rational basis in treatment of endotoxin toxicity.
Asunto(s)
Endotoxinas/toxicidad , Fiebre/veterinaria , Ibuprofeno/farmacología , Infecciones por Pasteurella/veterinaria , Pasteurella/metabolismo , Prostaglandinas/sangre , Serotonina/sangre , Tromboxanos/sangre , 6-Cetoprostaglandina F1 alfa/sangre , Animales , Dinoprost , Femenino , Fiebre/inducido químicamente , Prostaglandinas F/sangre , Ovinos , Enfermedades de las Ovejas/sangre , Enfermedades de las Ovejas/etiología , Tromboxano B2/sangreRESUMEN
Calves given 2 subcutaneous inoculations (4 ml, 4.5 weeks apart) of an inactivated bluetongue virus serotype 17 (BTV-17), aluminum hydroxide adjuvant, and cimetidine (600 mg) or levamisole (819 mg, 6 ml) combination were challenge exposed with virulent BTV-17 (2.5 x 10(5) embryo lethal dose) 9 weeks after the 1st inoculation and were monitored for 35 days. Plasma prostaglandins (PG) and thromboxane (Tx) B2 were measured by radioimmunoassay. Histamine was assayed spectrofluorometrically. During the inoculation period (9 weeks from the 1st inoculation to challenge exposure) PGE and histamine increased from base-line concentrations of 34 +/- 3 pg/ml and 1.2 +/- 0.1 ng/ml to 83 +/- 8 pg/ml and 2.0 +/- 0.1 ng/ml, respectively, whereas PGF2 alpha decreased from base-line values of 356 +/- 41 pg/ml to 226 +/- 16 pg/ml. Significant (P less than or equal to 0.05) changes from base-line TxB2 values (110 +/- 7 pg/ml) were not observed during the inoculation period. After challenge exposure, maximum increases were observed in TxB2 (157 +/- 10 pg/ml), PGF2 alpha (713 +/- 93 pg/ml), PGE (140 +/- 30 pg/ml), and histamine (3.6 +/- 0.2 ng/ml) concentrations at 4, 7, 7, and 14 days after challenge exposure, respectively. Concentrations of PGF2 alpha and TxB2 decreased from base-line values to 211 +/- 42 pg/ml and 75 +/- 11 pg/ml, respectively, 21 days after challenge exposure and then returned to base-line values. Significant changes were not observed in plasma concentrations of 6-keto-PGF1 alpha. Results indicate that PG, TxA2, and histamine may be involved in the hypersensitivity reaction to BTV in cattle.
Asunto(s)
Lengua Azul/inmunología , Enfermedades de los Bovinos/inmunología , Histamina/fisiología , Hipersensibilidad/veterinaria , Prostaglandinas/fisiología , Tromboxano A2/fisiología , Tromboxanos/fisiología , Animales , Virus de la Lengua Azul/inmunología , Bovinos , Cimetidina/farmacología , Histamina/sangre , Levamisol/farmacología , Prostaglandinas/sangre , Ovinos , Tromboxano B2/sangreRESUMEN
Pasteurella hemolytica endotoxin (12 micrograms/kg) was infused intravenously into ewes over 500 min. Blood was sampled for 60 min before the infusion and at intervals during the infusion and for 1500 min postinfusion. The control values for plasma TxB2, 6-keto-PGF1 alpha, PGF2 alpha, and serotonin were 283 +/- 53 pg/ml (mean +/- standard error of mean), 281 +/- 14 pg/ml, 199 +/- 27 pg/ml, and 56.8 +/- 2.0 ng/ml, respectively. The plasma concentrations of TxB2, 6-keto-PGF1 alpha, PGF2 alpha, and serotonin significantly increased to a maximum at 50 min of infusion to 359%, 344%, 313%, and 201% of the control, respectively. PGF2 alpha and TxB2 returned to control levels at 300 min during infusion and 6-keto-PGF1 alpha at 60 min postinfusion and serotonin at 100 min of infusion. Serotonin concentration decreased significantly at 450 min of infusion to 73% of control and returned to control level at 1500 min postinfusion. No significant changes were found in the plasma levels of PGE, histamine, and ACE activity. We conclude that release of TxA2, PGI2, PGF2 alpha, and serotonin may contribute to pathophysiology induced by P. hemolytica endotoxin in sheep.