RESUMO
A previous proteomic study examining the plasma acute-phase response of rainbow trout to sterile inflammation highlighted an unidentified 9.5-kDa spot using 2D-PAGE, which was dramatically increased. The 15 amino acid sequence obtained from this protein spot allowed rapid amplification of cDNA ends PCR to generate a 443-bp nucleotide sequence that was 98.6% similar to type-4 ice-structuring protein LS-12 from Atlantic salmon Salmo salar Linnaeus. Quantitative reverse translation PCR and an ELISA were used to measure gene expression and plasma concentrations of LS-12 following experimental intraperitoneal injection of rainbow trout with either 106 or 108 colony-forming units (CFU) of Flavobacterium psychrophilum. There was no significant change in the plasma concentration of LS-12 up to 15 days post-infection in any group. Hepatic LS-12 gene expression was significantly reduced at 3 and 6 days (p < 0.001) post-infection in fish injected with 108 CFU of F. psychrophilum relative to control fish, while branchial or head kidney expression was unchanged. Infected fish had significantly increased hepatic gene expression of serum amyloid A, confirming an acute-phase response. Under the conditions used, LS-12 is not a positive acute-phase protein in rainbow trout.
Assuntos
Reação de Fase Aguda/veterinária , Doenças dos Peixes/microbiologia , Proteínas de Peixes/genética , Infecções por Flavobacteriaceae/veterinária , Oncorhynchus mykiss/microbiologia , Reação de Fase Aguda/microbiologia , Animais , Proteínas de Peixes/sangue , Infecções por Flavobacteriaceae/microbiologia , Flavobacterium/patogenicidade , Reação em Cadeia da Polimerase , ProteômicaRESUMO
Acute-phase reactants indicate inflammation and are increasingly used in veterinary medicine to indicate and to monitor progression of disease. Hemostasis and inflammation have interconnected pathophysiologic pathways and influence each other on different levels. This study established observed normal ranges for acute-phase reactants and for coagulation and thromboelastographic (TEG) parameters in 49 dromedary camels ( Camelus dromedarius) and assessed the response to chronic and acute inflammation. Chronically infected animals suffering from lymph abscessation due to Corynebacterium spp. had significantly higher concentrations of the acute-phase reactants haptoglobin ( P < 0.005) and fibrinogen ( P < 0.013) and an increased clot strength characterized by an increase of the TEG parameters MA ( P < 0.039), representing the maximum amplitude of the clot strengths, and G, the global clot strength ( P < 0.022), compared to healthy animals. When the acute-phase and hemostatic responses of 10 males receiving a gonadotropin-releasing hormone vaccine and of 9 males that were surgically castrated over 7 days were studied, haptoglobin proved to be a minor positive acute-phase protein, with moderate levels in healthy animals. It increased significantly after both vaccination and castration and remained elevated 7 days postinsult. The negative reactant iron significantly decreased over the 7-day period after castration, whereas a similar decrease following vaccination lasted less than 3 days. Fibrinogen reacted as a positive, minor reactant, with a significant increase and a peak on days 3-5, with higher values seen after castration. Prothrombin time showed a slight shortening at days 5-7, and the TEG parameters MA and G showed significantly increased values, similar to fibrinogen. The acute-phase protein serum amyloid A showed poor repeatability, suggesting that the assay was not reliable.
Assuntos
Proteínas de Fase Aguda/metabolismo , Reação de Fase Aguda/veterinária , Camelus , Infecções por Corynebacterium/veterinária , Hemostasia/imunologia , Reação de Fase Aguda/imunologia , Reação de Fase Aguda/microbiologia , Animais , Corynebacterium/fisiologia , Infecções por Corynebacterium/imunologia , Infecções por Corynebacterium/microbiologia , Estudos Transversais , Feminino , Masculino , EspanhaRESUMO
Systemic inflammation, induced by disease or experimental intervention, is well established to result in elevated levels of circulating triglycerides, and reduced levels of high-density lipoprotein-cholesterol (HDL-C), in most mammalian species. However, the relationship between inflammation and low-density lipoprotein-cholesterol (LDL-C) concentrations is less clear. Most reports indicate that systemic inflammation, as observed during sepsis or following high dose experimental endotoxaemia, lowers total, and LDL-C in man. However, isolated reports have suggested that certain inflammatory conditions are associated with increased LDL-C. In this review, we summarize the emerging evidence that low-grade inflammation specifically of intestinal origin may be associated with increased serum LDL-C levels. Preliminary insights into potential mechanisms that may mediate these effects, including those connecting inflammation to trans-intestinal cholesterol efflux (TICE), are considered. We conclude that this evidence supports the potential downregulation of major mediators of TICE by inflammatory mediators in vitro and during intestinal inflammation in vivo. The TICE-inflammation axis therefore merits further study in terms of its potential to regulate serum LDL-C, and as a readily druggable target for hypercholesterolaemia.
Assuntos
Reação de Fase Aguda/sangue , LDL-Colesterol/sangue , Enterite/sangue , Enterócitos/metabolismo , Mediadores da Inflamação/sangue , Intestino Delgado/metabolismo , Reação de Fase Aguda/tratamento farmacológico , Reação de Fase Aguda/imunologia , Reação de Fase Aguda/microbiologia , Animais , Anti-Inflamatórios/farmacologia , HDL-Colesterol/sangue , Enterite/tratamento farmacológico , Enterite/imunologia , Enterite/microbiologia , Enterócitos/efeitos dos fármacos , Enterócitos/imunologia , Enterócitos/microbiologia , Microbioma Gastrointestinal , Humanos , Hipolipemiantes/farmacologia , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/imunologia , Intestino Delgado/microbiologia , Triglicerídeos/sangueRESUMO
The paraoxonases (PON1, PON2 and PON3) are an enzyme family with a high structural homology. All of them have lactonase activity and degrade lipid peroxides in lipoproteins and cells. As such, they play a role in protection against oxidation and inflammation. Infectious diseases are often associated with oxidative stress and an inflammatory response. Infection and inflammation trigger a cascade of reactions in the host, known as the acute-phase response. This response is associated with dramatic changes in serum proteins and lipoproteins, including a decrease in serum PON1 activity. These alterations have clinical consequences for the infected patient, including an increased risk for cardiovascular diseases, and an impaired protection against the formation of antibiotic-resistant bacterial biofilms. Several studies have investigated the value of serum PON1 measurement as a biomarker of the infection process. Low serum PON1 activities are associated with poor survival in patients with severe sepsis. In addition, preliminary studies suggest that serum PON1 concentration and/or enzyme activity may be useful as markers of acute concomitant infection in patients with an indwelling central venous catheter. Investigating the associations between paraoxonases and infectious diseases is a recent, and productive, line of research.
Assuntos
Arildialquilfosfatase/metabolismo , Doenças Transmissíveis/enzimologia , Imunidade Inata , Modelos Biológicos , Estresse Oxidativo , Reação de Fase Aguda/sangue , Reação de Fase Aguda/enzimologia , Reação de Fase Aguda/imunologia , Reação de Fase Aguda/microbiologia , Animais , Arildialquilfosfatase/sangue , Arildialquilfosfatase/química , Arildialquilfosfatase/genética , Biomarcadores/sangue , Cateteres de Demora/efeitos adversos , Cateteres de Demora/microbiologia , Cateteres Venosos Centrais/efeitos adversos , Cateteres Venosos Centrais/microbiologia , Doenças Transmissíveis/sangue , Doenças Transmissíveis/imunologia , Doenças Transmissíveis/microbiologia , Infecção Hospitalar/sangue , Infecção Hospitalar/enzimologia , Infecção Hospitalar/imunologia , Infecção Hospitalar/microbiologia , Humanos , Polimorfismo Genético , Regiões Promotoras Genéticas , Sepse/sangue , Sepse/enzimologia , Sepse/imunologia , Sepse/microbiologia , Homologia Estrutural de ProteínaRESUMO
Microbial translocation, characterized by elevated levels of lipopolysaccharide (LPS) and related markers, is a common occurrence in HIV and some parasitic infections. This is usually associated with extensive inflammation and immune activation. To examine the occurrence of microbial translocation and the associated inflammatory response in asymptomatic Strongyloides stercoralis infection, we measured the plasma levels of LPS and other microbial translocation markers, acute-phase proteins, inflammatory markers, and proinflammatory cytokines in individuals with (infected [INF]) or without (uninfected [UN]) S. stercoralis infections. Finally, we also measured the levels of all of these markers in INF individuals following treatment of S. stercoralis infection. We show that INF individuals exhibit significantly higher plasma levels of microbial translocation markers (LPS, soluble CD14 [sCD14], intestinal fatty acid-binding protein [iFABP], and endotoxin core IgG antibody [EndoCAb]), acute-phase proteins (α-2 macroglobulin [α-2M], C-reactive protein [CRP], haptoglobin, and serum amyloid protein A [SAA]), inflammatory markers (matrix metalloproteinase 1 [MMP-1] and heme oxygenase 1 [HO-1]), and proinflammatory cytokines (interleukin-6 [IL-6], IL-8, monocyte chemoattractant protein 1 [MCP-1], and IL-1ß) than do UN individuals. INF individuals exhibit significantly decreased levels of tissue inhibitor of metalloproteinases 4 (TIMP-4). Following treatment of S. stercoralis infection, the elevated levels of microbial translocation markers, acute-phase proteins, and inflammatory markers were all diminished. Our data thus show that S. stercoralis infection is characterized by microbial translocation and accompanying increases in levels of acute-phase proteins and markers of inflammation and provide data to suggest that microbial translocation is a feature of asymptomatic S. stercoralis infection and is associated with an inflammatory response.
Assuntos
Reação de Fase Aguda/metabolismo , Translocação Bacteriana/fisiologia , Heme Oxigenase-1/metabolismo , Inflamação/metabolismo , Metaloproteinase 1 da Matriz/metabolismo , Strongyloides stercoralis/metabolismo , Strongyloides stercoralis/fisiologia , Proteínas de Fase Aguda/metabolismo , Reação de Fase Aguda/microbiologia , Adulto , Animais , Biomarcadores/sangue , Biomarcadores/metabolismo , Proteína C-Reativa/metabolismo , Proteínas de Ligação a Ácido Graxo/metabolismo , Feminino , Humanos , Imunoglobulina G/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Lipopolissacarídeos/sangue , Masculino , Pessoa de Meia-Idade , Estrongiloidíase/sangue , Estrongiloidíase/metabolismo , Estrongiloidíase/microbiologia , Adulto JovemRESUMO
The aim of this study was to define the in vivo immunomodulatory properties of the macrolide antibiotic gamithromycin in calves, with respect to the acute phase response. Additionally, the corticosteroid dexamethasone was included as a positive control immunomodulatory drug. Both drugs, as well as their combination,were studied in a previously developed inflammation model,which was initiated by an intravenous lipopolysaccharide (LPS) challenge (0.5 µg/kg body weight). Twenty-four 4-week-old male Holstein Friesian calves were randomized into four groups: no pharmacological treatment (n = 6) or a pharmacological treatment with gamithromycin (n= 6), dexamethasone (n= 6) or their combination (n= 6) 1 h prior to LPS administration. Blood collection and clinical scoring were performed at regular time points until 72 h post LPS challenge. Plasma concentrations of selected cytokines (tumour necrosis factor-α (TNF-α) and interleukin 6 (IL-6)) and acute phase proteins (serum amyloid A and haptoglobin) were subsequently determined. Gamithromycin did not have any beneficial effect on the LPS-induced clinical signs (dyspnea, fever, anorexia and depression), nor on the studied inflammatory mediators. In the dexamethasone and combination groups, the occurrence of dyspnea and fever was not prominently influenced, although the calves recovered significantly faster from the challenge. Moreover, dexamethasone significantly inhibited the levels of TNF-α and IL-6, suggesting a key role for these cytokines in sickness behaviour. In conclusion, unlike dexamethasone, gamithromycin did not directly reduce cytokine release in an LPS inflammation model in calves.
Assuntos
Antibacterianos/farmacologia , Anti-Inflamatórios/farmacologia , Doenças dos Bovinos/tratamento farmacológico , Dexametasona/farmacologia , Imunomodulação , Inflamação/tratamento farmacológico , Macrolídeos/farmacologia , Proteínas de Fase Aguda/metabolismo , Reação de Fase Aguda/tratamento farmacológico , Reação de Fase Aguda/etiologia , Reação de Fase Aguda/microbiologia , Animais , Bovinos , Doenças dos Bovinos/microbiologia , Citocinas/sangue , Combinação de Medicamentos , Inflamação/microbiologia , Lipopolissacarídeos/farmacologia , MasculinoRESUMO
The effect of ß-glucans as feed additive on the profile of C-reactive protein (CRP) and complement acute phase responses was studied in common carp Cyprinus carpio after exposition to a bacterial infection with Aeromonas salmonicida. Carp were orally administered with ß-glucan (MacroGard®) for 14 days with a daily ß-glucan intake of 6 mg per kg body weight. Fish were then intraperitoneally injected with either PBS or 1 × 108 bacteria per fish and sampled at time 0, 6, 12, 24, 48, 72, 96 and 120 h post-injection (p.i.) for serum and head kidney, liver and mid-gut tissues. CRP levels and complement activity were determined in the serum samples whilst the gene expression profiles of CRP and complement related genes (crp1, crp2, c1r/s, bf/c2, c3 and masp2) were analysed in the tissues by quantitative PCR. Results obtained showed that oral administration of ß-glucan for 14 days significantly increased serum CRP levels up to 2 fold and serum alternative complement activity (ACP) up to 35 fold. The bacterial infection on its own (i.e. not combined with a ß-glucan feeding) did have significant effects on complement response whilst CRP was not detectably induced during the carp acute phase reaction. However, the combination of the infection and the ß-glucan feeding did show significant effects on both CRP and complement profiles with higher serum CRP levels and serum ACP activity in the ß-glucan fed fish than in the control fed fish. In addition, a distinct organ and time dependent expression profile pattern was detected for all the selected genes: a peak of gene expression first occurred in the head kidney tissue (6 h p.i. or 12 h p.i.), then an up-regulation in the liver several hours later (24 h p.i.) and finally up- or down-regulations in the mid-gut at 24 h p.i. and 72 h p.i. In conclusion, the results of this study suggest that MacroGard® stimulated CRP and complement responses to A. salmonicida infection in common carp.
Assuntos
Reação de Fase Aguda/veterinária , Proteína C-Reativa/metabolismo , Carpas , Doenças dos Peixes/imunologia , Infecções por Bactérias Gram-Negativas/veterinária , beta-Glucanas/imunologia , Reação de Fase Aguda/imunologia , Reação de Fase Aguda/microbiologia , Aeromonas salmonicida/imunologia , Animais , Suplementos Nutricionais/análise , Doenças dos Peixes/microbiologia , Perfilação da Expressão Gênica/veterinária , Regulação da Expressão Gênica , Infecções por Bactérias Gram-Negativas/imunologia , Infecções por Bactérias Gram-Negativas/microbiologia , Imunidade Inata , Injeções Intraperitoneais/veterinária , Reação em Cadeia da Polimerase em Tempo Real/veterináriaRESUMO
The pathogenicity of Haemoplasma spp. in cats varies with 'Candidatus Mycoplasma haemominutum' (CMhm) causing subclinical infection while Mycoplasma haemofelis (Mhf) often induces haemolytic anaemia. The aims of this study were to characterise the acute phase response (APR) of the cat to experimental infection with Mhf or CMhm, and to determine whether chronic feline immunodeficiency virus (FIV) infection influences this response. The acute phase proteins serum amyloid A (SAA), haptoglobin (Hp) and α-1-acid glycoprotein (AGP) concentrations were measured pre-infection and every 7-14 days up to day 100 post-infection (pi) in cats infected with either Mhf or CMhm. Half of each group of cats (6/12) were chronically and subclinically infected with FIV. Marbofloxacin treatment was given on days 16-44 pi to half of the Mhf-infected cats, and on days 49-77 pi to half of the CMhm-infected cats. FIV-infected animals had significantly lower AGP concentrations, and significantly greater Hp concentrations than non-FIV-infected cats when infected with CMhm and Mhf, respectively. Both CMhm and Mhf infection were associated with significant increases in SAA concentrations, while AGP concentrations were only significantly increased by Mhf infection. Mhf-infected cats had significantly greater SAA concentrations than CMhm-infected animals. Both Mhf and CMhm infections were associated with an APR, with Mhf infection inducing a greater response. Chronic FIV infection appeared to modify the APR, which varied with the infecting Haemoplasma species.
Assuntos
Proteínas de Fase Aguda/metabolismo , Reação de Fase Aguda/veterinária , Doenças do Gato/microbiologia , Doenças do Gato/virologia , Infecções por Lentivirus/veterinária , Infecções por Mycoplasma/veterinária , Reação de Fase Aguda/microbiologia , Animais , Antibacterianos/uso terapêutico , Doenças do Gato/tratamento farmacológico , Gatos , Doença Crônica , Coinfecção/veterinária , Esquema de Medicação/veterinária , Fluoroquinolonas/uso terapêutico , Haptoglobinas/metabolismo , Vírus da Imunodeficiência Felina/fisiologia , Infecções por Lentivirus/virologia , Mycoplasma/efeitos dos fármacos , Mycoplasma/isolamento & purificação , Mycoplasma/patogenicidade , Infecções por Mycoplasma/tratamento farmacológico , Infecções por Mycoplasma/microbiologia , Nefelometria e Turbidimetria/veterinária , Orosomucoide/metabolismo , Proteína Amiloide A Sérica/metabolismo , Especificidade da Espécie , Organismos Livres de Patógenos EspecíficosRESUMO
The acute phase response is an evolutionarily conserved reaction in which physiological stress triggers the liver to remodel the blood proteome. Although thought to be involved in immune defense, the net biological effect of the acute phase response remains unknown. As the acute phase response is stimulated by diverse cytokines that activate either NF-κB or STAT3, we hypothesized that it could be eliminated by hepatocyte-specific interruption of both transcription factors. Here, we report that the elimination in mice of both NF-κB p65 (RelA) and STAT3, but neither alone, abrogated all acute phase responses measured. The failure to respond was consistent across multiple different infectious, inflammatory, and noxious stimuli, including pneumococcal pneumonia. When the effects of infection were analyzed in detail, pneumococcal pneumonia was found to alter the expression of over a thousand transcripts in the liver. This outcome was inhibited by the combined loss of RelA and STAT3. Moreover, this interruption of the acute phase response increased mortality and exacerbated bacterial dissemination during pneumonia, possibly as a result of acute humoral enhancement of macrophage opsonophagocytosis, which was impaired in the mutant mice. Thus, we conclude that RelA and STAT3 are essential for stress-induced transcriptional remodeling in the liver and the subsequent activation of the acute phase response, whose functional role includes compartmentalization of local infection.
Assuntos
Reação de Fase Aguda/microbiologia , Hepatócitos/metabolismo , Pneumonia Pneumocócica/imunologia , Fator de Transcrição STAT3/genética , Fator de Transcrição RelA/genética , Reação de Fase Aguda/sangue , Reação de Fase Aguda/genética , Animais , Regulação da Expressão Gênica , Técnicas de Inativação de Genes , Imunidade Inata , Fígado/metabolismo , Fígado/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pneumonia Pneumocócica/sangue , Pneumonia Pneumocócica/genética , Fator de Transcrição STAT3/metabolismo , Proteína Amiloide A Sérica/metabolismo , Componente Amiloide P Sérico/metabolismo , Streptococcus pneumoniae , Fator de Transcrição RelA/metabolismo , TranscriptomaRESUMO
The existence of an immunological homunculus has been proposed, but evidence for location-specific response of the central nervous system to immunological stimulation is lacking. In this study, we show that inflammation induced by injection of casein into one of the causes c-fos expression in the paraventricular nucleus of the hypothalamus (PVN) in an asymmetrical manner: much stronger activation is always induced in the contralateral PVN. Unilateral sciatic nerve transection abolished the casein-induced PVN activation if casein was injected into the hindlimb with the nerve transection, but had no effect if casein was injected into the hindlimb with intact nerve innervation. Injection of casein into one the forelimbs also caused contralateral PNV activation. Further, stronger PVN activation was found in the anterior PVN after the forelimb injection, but in the posterior PVN after the hindlimb injection. Casein-induced PVN activation is absent in IL-1R1 KO, IL-6 KO, TNFα KO, and in C3H/HeJ (TLR4 mutant) animals. In comparison, injection of LPS, a systemic inflammagen, into one hindlimb induced bilateral PVN activation but injection of live Escherichia coli into one hindlimb induced contralateral PVN activation. These results support the notion that local inflammation may activate the PVN by neural routes in a location-specific manner.
Assuntos
Reação de Fase Aguda/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Núcleo Hipotalâmico Paraventricular/patologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Reação de Fase Aguda/induzido quimicamente , Reação de Fase Aguda/imunologia , Reação de Fase Aguda/microbiologia , Animais , Caseínas , Escherichia coli , Membro Anterior/efeitos dos fármacos , Membro Anterior/imunologia , Membro Posterior/efeitos dos fármacos , Membro Posterior/imunologia , Imuno-Histoquímica , Injeções Intramusculares , Interleucina-6/deficiência , Interleucina-6/genética , Lipopolissacarídeos , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos , Camundongos Knockout , Mutação , Receptores Tipo I de Interleucina-1/deficiência , Receptores Tipo I de Interleucina-1/genética , Nervo Isquiático/efeitos dos fármacos , Fatores de Tempo , Receptor 4 Toll-Like/genética , Fator de Necrose Tumoral alfa/deficiência , Fator de Necrose Tumoral alfa/genéticaRESUMO
Enterococcus faecium is an emerging pathogen that causes infections in hospitalized patients with various co-morbid diseases. These underlying diseases are often associated with an acute-phase response that renders patients vulnerable to nosocomial infections. To study the influence of the acute-phase response induced by sterile tissue injury on host defence against E. faecium, mice were injected subcutaneously with either turpentine or casein 1 day before intraperitoneal infection with E. faecium. Control mice were subcutaneously injected with saline or sodium bicarbonate, respectively. Turpentine and casein induced an acute-phase response as reflected by increases in the plasma concentrations of interleukin-6, serum amyloid P and C3. A pre-existent acute-phase response in mice was associated with a strongly reduced capacity to clear E. faecium, resulting in prolonged bacteraemia for several days. The inflammatory response to E. faecium was impaired in mice with an acute-phase response, as shown by reduced capacity to mount a neutrophilic leucocytosis in peripheral blood and by decreased local cytokine concentrations. These data indicate that the acute-phase response impairs host defence against E. faecium, suggesting that this condition may contribute to the increased vulnerability of critically ill patients to enterococcal infections.
Assuntos
Reação de Fase Aguda/imunologia , Enterococcus faecium/imunologia , Infecções por Bactérias Gram-Positivas/imunologia , Neutrófilos/imunologia , Peritonite/imunologia , Reação de Fase Aguda/induzido quimicamente , Reação de Fase Aguda/metabolismo , Reação de Fase Aguda/microbiologia , Animais , Caseínas/farmacologia , Quelantes/farmacologia , Complemento C3/agonistas , Complemento C3/imunologia , Complemento C3/metabolismo , Citocinas/efeitos dos fármacos , Citocinas/imunologia , Citocinas/metabolismo , Enterococcus faecium/efeitos dos fármacos , Feminino , Infecções por Bactérias Gram-Positivas/metabolismo , Infecções por Bactérias Gram-Positivas/microbiologia , Interleucina-6/agonistas , Interleucina-6/sangue , Irritantes/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Peritonite/metabolismo , Peritonite/microbiologia , Componente Amiloide P Sérico/agonistas , Componente Amiloide P Sérico/imunologia , Componente Amiloide P Sérico/metabolismo , Terebintina/farmacologiaRESUMO
The effect of experimentally induced fever on the pharmacokinetics of cefepime administered intravenously at a dose of 75 mg/kg bw was studied in six healthy rabbits. The study was conducted in two consecutive phases, separated by a washout period of 2 weeks. Infection was induced by the intravenous inoculation of 5 x 10(8) cfu of Escherichia coli 24 h before the pharmacokinetic investigation was carried out. Serial blood samples for cefepime concentration determination were obtained for 48 h following drug administration. The concentrations of cefepime in the plasma were determined by a quantitative microbiological assay using an agar-gel diffusion method employing Bacillus subtilis ATCC 6633 as the test organism, with a level of detectability of approximately 0.10 microg/ml. Cefepime plasma concentrations versus time were evaluated by non-compartmental methods using WinNonLin. Cefepime was well tolerated and no serious adverse events were observed. Rectal temperature increased 1 degree C 24 h post injection in infected animals. Highly significant differences in the blood plasma concentrations of cefepime were observed between febrile and healthy animals at all the sampling times. This could explain the greater area under the plasma level-time curve of the drug in febrile compared with healthy animals. The results from pharmacokinetic calculations showed that both the distribution volume at steady state (V (dss)) and body clearance (CL(tot)) were affected in febrile as compared to healthy animals. The mean values of V (dss) and CL(tot) of cefepime in healthy rabbits were 1.168 L/kg and 0.303 L/kg/h, respectively. As compared with healthy animals, the mean estimates of V (dss) (0.917 L/kg) and CL(tot) (0.205 L/kg per h) of cefepime were significantly lower, whereas t (1/2lambda), MRT and AUMC were significantly higher in febrile rabbits. It is concluded that, although experimental infection had an effect on the disposition kinetics of cefepime in healthy and febrile rabbits, this was not sufficiently pronounced to require alteration of the dosage during disease.
Assuntos
Reação de Fase Aguda/metabolismo , Reação de Fase Aguda/veterinária , Antibacterianos/farmacocinética , Cefalosporinas/farmacocinética , Coelhos/metabolismo , Reação de Fase Aguda/microbiologia , Animais , Antibacterianos/sangue , Área Sob a Curva , Cefepima , Cefalosporinas/sangue , Escherichia coli , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/metabolismo , Infecções por Escherichia coli/veterinária , Febre/metabolismo , Febre/microbiologia , Febre/veterinária , Meia-Vida , Injeções Intravenosas/veterinária , Masculino , Coelhos/sangueRESUMO
BACKGROUND: Salmonellosis and systemic endotoxaemia affect intestinal function. However, little is known about the functional importance of luminal Salmonella (S.) endotoxin during intestinal infection. METHODS: Pigs were either given or not given lipopolysaccharide (LPS, 30 mg day(-1)) of S. Typhimurium DT-104 orally for 14 days. Blood samples were taken weekly. After slaughter (day 14), epithelia of the proximal colon were investigated in Ussing chambers. Bacterial translocations to lung, liver, spleen and several lymph nodes were determined by culture. RESULTS: Endotoxin feeding increased plasma C-reactive protein (CRP) and histamine levels without evoking clinical signs. Postmortem, proximal colonic epithelia of LPS-treated animals showed both a decreased histamine release after mast cell stimulation with A23187 and a smaller increase in short-circuit current after A23187 application. Addition of the nitric oxide donor, sodium nitroprusside (SNP), also elicited lower increases in short-circuit current in the proximal colon of endotoxin-treated pigs. Endotoxin pre-feeding decreased colonic ion conductance, although mannitol and histamine fluxes were high in some epithelia of this group. Luminal Salmonella endotoxin increased bacterial translocation to proximal jejunal lymph nodes. LPS applied to colonic epithelia in vitro had no electrophysiological effects. CONCLUSIONS: Luminal endotoxin elicits an acute phase response and affects intestinal electrolyte transport and mast cell function. Furthermore, LPS induces epithelial spots of increased mannitol permeability that could be identical to spots of enhanced bacterial translocation.
Assuntos
Toxinas Bacterianas/farmacologia , Colo/efeitos dos fármacos , Endotoxinas/farmacologia , Enterotoxinas/farmacologia , Células Epiteliais/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Mastócitos/efeitos dos fármacos , Salmonella typhimurium/fisiologia , Reação de Fase Aguda/sangue , Reação de Fase Aguda/microbiologia , Reação de Fase Aguda/fisiopatologia , Animais , Toxinas Bacterianas/sangue , Translocação Bacteriana/efeitos dos fármacos , Translocação Bacteriana/fisiologia , Proteína C-Reativa/análise , Proteína C-Reativa/efeitos dos fármacos , Colo/fisiopatologia , Modelos Animais de Doenças , Endotoxinas/sangue , Enterotoxinas/sangue , Células Epiteliais/fisiologia , Feminino , Histamina/sangue , Mucosa Intestinal/fisiopatologia , Mastócitos/fisiologia , Infecções por Salmonella/sangue , Infecções por Salmonella/microbiologia , Infecções por Salmonella/fisiopatologia , Suínos , Fatores de TempoRESUMO
BACKGROUND: There is increasing evidence that chronic inflammation plays a pivotal role in the development of atherosclerosis. Whether inflammation is the cause or consequence of vascular damage is unclear. Also, the source of inflammation is unknown, but may well be infection by Cytomegalovirus (CMV) or Chlamydia pneumoniae (C. pneumoniae). Infection of the liver by CMV or C. pneumoniae may induce a general inflammatory reaction contributing to accelerated atherogenesis. In this study we investigated the production of interleukin-6 (IL-6), fibrinogen and plasminogen activator inhibitor-1 (PAI-1) by hepatocytes after infection with CMV or C. pneumoniae. METHODS: HepG2 cell monolayers were grown to confluence in 48-well tissue culture plates. Hepatocytes were infected with 50 microL or 100 microL of suspension of CMV (10(2.70) TCID50 mL(-1)) and C. pneumoniae (10(4.75) TCID50 mL(-1)). The medium of the inoculated cells was collected every 24 h, from day 1 to day 4, for determination of IL-6, PAI-1 and fibrinogen concentrations. RESULTS: Fibrinogen production was increased significantly in a dose-dependent manner after infection with CMV (50 microL: P=0.022 and 100 microL: P<0.001) and C. pneumoniae (P=0.012). Cytomegalovirus infection resulted in an increase of IL-6 production compared with uninfected cells (P=0.048). Cytomegalovirus and C. pneumoniae infection did not result in a significantly increase of PAI-1 production by hepatocytes. CONCLUSION: We conclude that in addition to direct vascular wall infection by C. pneumoniae and CMV, virus-related development of atherosclerosis might also be initiated by chronic liver infection and subsequent production of inflammatory and procoagulant mediators released in the circulation. This may be another pathophysiological link for the observed relation between infections and the development of atherosclerosis.
Assuntos
Reação de Fase Aguda/microbiologia , Infecções por Chlamydophila/complicações , Chlamydophila pneumoniae , Infecções por Citomegalovirus/complicações , Hepatócitos/metabolismo , Reação de Fase Aguda/etiologia , Reação de Fase Aguda/metabolismo , Linhagem Celular , Infecções por Chlamydophila/metabolismo , Infecções por Citomegalovirus/metabolismo , Fibrinogênio/biossíntese , Humanos , Interleucina-6/biossíntese , Microscopia de Contraste de Fase , Inibidor 1 de Ativador de Plasminogênio/biossínteseRESUMO
The possibility to use acute phase proteins to monitor the elimination of a bacterial infection in pigs would facilitate an objective assessment of treatment with various antimicrobial substances. To examine this possibility, the acute phase response (IL-6, serum amyloid A (SAA), and haptoglobin) elicited by Actinobacillus pleuropneumoniae and its reduction on treatment with various antibiotics was studied in serum from specific pathogen free (SPF) pigs. Pigs were infected intranasally with A. pleuropneumoniae serotype 2, and either left as non-treated control pigs or treated with different antibiotics intramuscularly at onset of respiratory disease (20h post-infection). Pigs responded to the infection with prominent increases in activity and concentrations of IL-6, SAA, and haptoglobin. These responses were to a certain extent overlapping and covered the time span from a few hours after infection until development of detectable levels of specific antibodies (7-10 days post-infection in untreated pigs). The haptoglobin response lasted until the end of the study on day 17 and thereby partly coincided with the antibody response. Treatment with antimicrobials that effectively reduced establishment of the infection with A. pleuropneumoniae also reduced the duration of all three acute phase responses, and reduced the concentration of serum haptoglobin. In contrast, less efficacious treatments did not reduce these acute phase responses. Thus, acute phase reactants can be applied to monitor therapeutic effects of antimicrobial drugs in the pig and measurements of IL-6, SAA and haptoglobin could add valuable information about the stage of infection during a disease outbreak.
Assuntos
Infecções por Actinobacillus/veterinária , Actinobacillus pleuropneumoniae/crescimento & desenvolvimento , Antibacterianos/farmacologia , Apolipoproteínas/sangue , Haptoglobinas/metabolismo , Interleucina-6/sangue , Pleuropneumonia/veterinária , Doenças dos Suínos/sangue , Infecções por Actinobacillus/sangue , Infecções por Actinobacillus/tratamento farmacológico , Infecções por Actinobacillus/microbiologia , Reação de Fase Aguda/sangue , Reação de Fase Aguda/tratamento farmacológico , Reação de Fase Aguda/microbiologia , Reação de Fase Aguda/veterinária , Animais , Antibacterianos/uso terapêutico , Anticorpos Antibacterianos/sangue , Feminino , Pulmão/microbiologia , Pulmão/patologia , Masculino , Pleuropneumonia/sangue , Pleuropneumonia/tratamento farmacológico , Pleuropneumonia/microbiologia , Proteína Amiloide A Sérica , Organismos Livres de Patógenos Específicos , Suínos , Doenças dos Suínos/tratamento farmacológico , Doenças dos Suínos/microbiologiaRESUMO
The synthesis of the common and well-documented Siaalpha 2,6 to Galbeta 1,4GlcNAc structure (Sia6LacNAc) is principally mediated by the sialyltransferase ST6Gal I, which is particularly highly expressed in liver, lactating mammary gland, intestinal epithelia of newborn animals, and B cells. Multiple independent promoters govern the expression of Siat1, the ST6Gal I gene. In liver, elevation of hepatic and serum ST6Gal is part of the acute phase reaction, the hepatic response to systemic trauma, and is governed by the inducible, liver-specific promoter-regulatory region, P1. A constitutive and nontissue-specific promoter, P3, mediates low-level, basal hepatic Siat1 transcription. We generated a mouse specifically unable to use the transcriptional initiation site uniquely used in P1-mediated ST6Gal I expression. These animals, Siat1deltaP1, are viable and display reduced ST6Gal I mRNA in liver with concomitantly reduced sialyltransferase activities in liver and in serum. Siat1deltaP1 animals are unable to elevate hepatic Siat1 mRNA as part of the inflammatory response induced by turpentine. Surprisingly, serum glycoprotein components exhibit normal extent of sialylation, with no noticeable difference in binding to SNA, the alpha2,6-sialyl-specific lectin. Siat1deltaP1 animals also exhibit an outwardly normal B cell response. On intraperitoneal challenge with the pathogen Salmonella typhimurium, a significantly greater accumulation of neutrophils within the peritoneal space was observed in Siat1deltaP1 animals compared to wild-type mice. Siat1deltaP1 mice also exhibit a greater bacterial burden in liver and spleen, accompanied by more pronounced spleno-/hepatomegaly and greater leukocyte infiltration into affected organs than their wild-type counterparts.
Assuntos
Regulação Enzimológica da Expressão Gênica , Regiões Promotoras Genéticas/genética , Sialiltransferases/genética , Sialiltransferases/metabolismo , Reação de Fase Aguda/enzimologia , Reação de Fase Aguda/imunologia , Reação de Fase Aguda/microbiologia , Animais , Feminino , Fígado/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/imunologia , Especificidade de Órgãos , Recombinação Genética/genética , Infecções por Salmonella/enzimologia , Infecções por Salmonella/imunologia , Infecções por Salmonella/microbiologia , Salmonella typhimurium/imunologia , Deleção de Sequência/genética , Sialiltransferases/imunologia , Baço/microbiologia , beta-D-Galactosídeo alfa 2-6-SialiltransferaseRESUMO
Mice mounting an acute phase response, induced by sterile inflammation after a single s.c. injection of casein 24 h beforehand, were remarkably protected against lethal infection with Gram-positive or Gram-negative bacteria. This was associated with enhanced early clearance of bacteremia, greater phagocytosis and oxidative burst responses by neutrophils, and enhanced recruitment of neutrophils into tissues compared with control, nonacute phase mice. Casein-induced inflammation was also associated with increased concentrations of G-CSF in serum, and administration of neutralizing Ab to this cytokine completely abrogated protection against Escherichia coli infection after casein pretreatment. Injection of recombinant murine G-CSF between 3 and 24 h before infection conferred the same protection as casein injection. In contrast, the casein-induced acute phase response affected neither serum values of TNF-alpha, IL-1 beta, or IL-6 after E. coli infection nor susceptibility to LPS toxicity. Furthermore, protection against infection was unaffected in IL-1R knockout mice, which have deficient acute phase plasma protein responses, or after nonspecific inhibition of acute phase protein synthesis by D-galactosamine or specific depletion of complement C3 by cobra venom factor. Increased production of G-CSF in the acute phase response is thus a key physiological component of host defense, and pretreatment with G-CSF to prevent bacterial infection in at-risk patients now merits further study, especially in view of increasing bacterial resistance to antibiotics.
Assuntos
Reação de Fase Aguda/imunologia , Infecções por Escherichia coli/imunologia , Infecções por Escherichia coli/prevenção & controle , Fator Estimulador de Colônias de Granulócitos/biossíntese , Infecções Estreptocócicas/imunologia , Infecções Estreptocócicas/prevenção & controle , Proteínas de Fase Aguda/biossíntese , Proteínas de Fase Aguda/farmacologia , Proteínas de Fase Aguda/fisiologia , Reação de Fase Aguda/microbiologia , Animais , Anticorpos Bloqueadores/administração & dosagem , Caseínas/administração & dosagem , Infecções por Escherichia coli/mortalidade , Fator Estimulador de Colônias de Granulócitos/antagonistas & inibidores , Fator Estimulador de Colônias de Granulócitos/imunologia , Fator Estimulador de Colônias de Granulócitos/fisiologia , Imunidade Inata/genética , Injeções Subcutâneas , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/imunologia , Neutrófilos/microbiologia , Infecções Estreptocócicas/mortalidade , Streptococcus pyogenes/imunologiaRESUMO
BACKGROUND: Many early epidemiologic studies reported an association between periodontal disease and cardiovascular disease. However, other studies found no association or nonsignificant trends. This report summarizes the evidence from epidemiologic studies and studies that focused on potential contributing mechanisms to provide a more complete picture of the association between periodontal and heart disease. TYPES OF STUDIES REVIEWED: The authors summarize the longitudinal studies reported to date, because they represent the highest level of evidence available regarding the connection between periodontal disease and heart disease. The authors also review many of the case-control and cross-sectional studies published, as well as findings from clinical, animal and basic laboratory studies. RESULTS: The evidence suggests a moderate association--but not a causal relationship--between periodontal disease and heart disease. Results of some case-control studies indicate that subgingival periodontal pathogenic infection may be associated with myocardial infarction. Basic laboratory studies point to the biological plausibility of this association, since oral bacteria have been found in carotid atheromas and some oral bacteria may be associated with platelet aggregation, an event important for thrombosis. Animal studies have shown that atheroma formation can be enhanced by exposure to periodontal pathogens. CONCLUSIONS: The accumulation of epidemiologic, in vitro, clinical and animal evidence suggests that periodontal infection may be a contributing risk factor for heart disease. However, legitimate concerns have arisen about the nature of this relationship. These are early investigations. Since even a moderate risk contributed by periodontal disease to heart disease could contribute to significant morbidity and mortality, it is imperative that further studies be conducted to evaluate this relationship. One particularly important study to be carried out is the investigation of a possible clinically meaningful reduction in heart disease resulting from the prevention or treatment of periodontal disease.
Assuntos
Doenças Cardiovasculares/etiologia , Doenças Periodontais/complicações , Reação de Fase Aguda/microbiologia , Aggregatibacter actinomycetemcomitans/isolamento & purificação , Animais , Arteriosclerose/microbiologia , Bacteroides/isolamento & purificação , Estudos de Casos e Controles , Estudos Transversais , Humanos , Estudos Longitudinais , Doenças Periodontais/microbiologia , Agregação Plaquetária , Porphyromonas gingivalis/isolamento & purificação , Prevotella intermedia/isolamento & purificação , Acidente Vascular Cerebral/etiologiaRESUMO
In a prospective clinical study, we investigated the inflammatory response in 88 neonatal subjects (43 boys and 45 girls) who underwent major abdominal surgery owing to congenital malformation involving the gastrointestinal tract and compared it with the response in 20 infants (8 boys, 12 girls; mean age, 4 mo) who underwent elective surgery for resolution of an existing temporary stoma. In both groups, plasma levels of endotoxin, IL-6, and C-reactive protein as well as leukocyte counts were determined during and after surgery. Endotoxin was measured by the Limulus amebocyte test, IL-6 by ELISA, and C-reactive protein by nephelometry. Statistical analyses were performed using the Wilcoxon signed-rank test. A significant increase in circulating endotoxin and a leukocyte shift was observed in the infant group only. Postoperatively, IL-6 levels peaked between 2 and 6 h and C-reactive protein after 24 h in the infant group. In contrast, no significant increase in the levels of endotoxin, IL-6, and C-reactive protein in plasma were observed during and after surgery in the neonatal subjects, except those with gastroschisis. Newborns with gastroschisis developed an inflammatory response after surgery that was less pronounced than the response of infants older than 4 mo. The finding that endotoxemia in newborns does not follow surgical trauma is most likely because of the absence of bacterial colonization of the gastrointestinal tract.
Assuntos
Abdome/cirurgia , Reação de Fase Aguda/imunologia , Reação de Fase Aguda/microbiologia , Biomarcadores , Proteína C-Reativa/metabolismo , Endotoxemia/imunologia , Endotoxemia/microbiologia , Endotoxinas/sangue , Feminino , Humanos , Lactente , Recém-Nascido , Interleucina-6/sangue , Intestinos/microbiologia , Masculino , Estudos Prospectivos , Resultado do TratamentoRESUMO
Changes in the activities of serum cytokines and in acute phase response were observed in dairy cows with naturally occurring coliform mastitis. Seven cows with severe mastitis showed systemic and mammary inflammatory response throughout the observation period, and 11 cows with mild mastitis recovered and were able to be milked within 3 days of onset of mastitis. Serum interleukin (IL)-I and tumor necrosis factor (TNF) activities were higher in the severe group than in the mild group at the first appearance of symptoms. Elevated IL-1 activity was evident in the severe group throughout the observation period. Serum alpha-1-acidglycoprotein (alpha1AG) concentration began to rise with the beginning of mastitis in the severe group, and peaked at 9 days. Serum haptoglobin (Hp) concentrations peaked at 3 days, and decreased gradually after 3 days in the severe group. These results showed that there are dynamic changes in serum IL-1 activity and in serum alpha1AG and Hp concentrations in cows with severe coliform mastitis.