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1.
Am J Respir Crit Care Med ; 202(6): 812-821, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32584597

RESUMO

Rationale: Coronavirus disease (COVID-19) is a global threat to health. Its inflammatory characteristics are incompletely understood.Objectives: To define the cytokine profile of COVID-19 and to identify evidence of immunometabolic alterations in those with severe illness.Methods: Levels of IL-1ß, IL-6, IL-8, IL-10, and sTNFR1 (soluble tumor necrosis factor receptor 1) were assessed in plasma from healthy volunteers, hospitalized but stable patients with COVID-19 (COVIDstable patients), patients with COVID-19 requiring ICU admission (COVIDICU patients), and patients with severe community-acquired pneumonia requiring ICU support (CAPICU patients). Immunometabolic markers were measured in circulating neutrophils from patients with severe COVID-19. The acute phase response of AAT (alpha-1 antitrypsin) to COVID-19 was also evaluated.Measurements and Main Results: IL-1ß, IL-6, IL-8, and sTNFR1 were all increased in patients with COVID-19. COVIDICU patients could be clearly differentiated from COVIDstable patients, and demonstrated higher levels of IL-1ß, IL-6, and sTNFR1 but lower IL-10 than CAPICU patients. COVID-19 neutrophils displayed altered immunometabolism, with increased cytosolic PKM2 (pyruvate kinase M2), phosphorylated PKM2, HIF-1α (hypoxia-inducible factor-1α), and lactate. The production and sialylation of AAT increased in COVID-19, but this antiinflammatory response was overwhelmed in severe illness, with the IL-6:AAT ratio markedly higher in patients requiring ICU admission (P < 0.0001). In critically unwell patients with COVID-19, increases in IL-6:AAT predicted prolonged ICU stay and mortality, whereas improvement in IL-6:AAT was associated with clinical resolution (P < 0.0001).Conclusions: The COVID-19 cytokinemia is distinct from that of other types of pneumonia, leading to organ failure and ICU need. Neutrophils undergo immunometabolic reprogramming in severe COVID-19 illness. Cytokine ratios may predict outcomes in this population.


Assuntos
Reação de Fase Aguda/imunologia , Proteínas de Transporte/metabolismo , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/metabolismo , Citocinas/imunologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Ácido Láctico/metabolismo , Proteínas de Membrana/metabolismo , Pneumonia Viral/imunologia , Pneumonia Viral/metabolismo , Hormônios Tireóideos/metabolismo , alfa 1-Antitripsina/imunologia , Reação de Fase Aguda/metabolismo , Adulto , Idoso , Betacoronavirus , Western Blotting , Estudos de Casos e Controles , Infecções Comunitárias Adquiridas/imunologia , Infecções Comunitárias Adquiridas/metabolismo , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/fisiopatologia , Estado Terminal , Eletroforese em Gel de Poliacrilamida , Ensaio de Imunoadsorção Enzimática , Feminino , Hospitalização , Humanos , Unidades de Terapia Intensiva , Interleucina-10/imunologia , Interleucina-1beta/imunologia , Interleucina-6/imunologia , Interleucina-8/imunologia , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Neutrófilos/metabolismo , Pandemias , Fosforilação , Pneumonia/imunologia , Pneumonia/metabolismo , Pneumonia Viral/mortalidade , Pneumonia Viral/fisiopatologia , Receptores Tipo I de Fatores de Necrose Tumoral/imunologia , Índice de Gravidade de Doença , alfa 1-Antitripsina/metabolismo
2.
Sci Rep ; 9(1): 19065, 2019 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-31836734

RESUMO

The acute phase response (APR) is a systemic first-line defense against challenges including infection, trauma, stress, and neoplasia. Alteration of acute phase protein (APP) levels in plasma is the most important change during acute phase response. C-reactive protein (CRP), which increases dramatically during inflammation onset, is an indicator of inflammation. To monitor the process of APR, we generated human CRP promoter-driven luciferase transgenic (hCRP-Luc) mice to quantify the hCRP promoter activation in vivo. The naïve female hCRP-Luc mice express low basal levels of liver bioluminescence, but the naïve male hCRP-Luc mice do not. Thus, female hCRP-Luc mice are suitable for monitoring the process of APR. The liver bioluminescence of female hCRP-Luc mice can be induced by several toll-like receptor (TLR) ligands. The expression of liver bioluminescence was highly sensitive to endotoxin stimulation in a dose-dependent manner. On-off-on bioluminescence response was noted in female hCRP-Luc mice upon two endotoxin stimulations one month apart. The LPS-induced bioluminescence of the female hCRP-Luc mice was IL-6-mediated and associated with APP alpha-1-acid glycoprotein expression. In conclusion, the female hCRP-Luc mouse is a non-invasive, sensitive and reusable reporter tool for APR.


Assuntos
Reação de Fase Aguda/metabolismo , Genes Reporter , Receptores Toll-Like/metabolismo , Proteínas da Fase Aguda/metabolismo , Animais , Sequência de Bases , Proteína C-Reativa/metabolismo , Feminino , Hormônios Esteroides Gonadais/farmacologia , Humanos , Interleucina-6/metabolismo , Ligantes , Lipopolissacarídeos/farmacologia , Luciferases/metabolismo , Luminescência , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
3.
Res Vet Sci ; 127: 57-64, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31678454

RESUMO

The objective of this study was to evaluate the effects of in-feed clinoptilolite (CPL) on serum metabolic and antioxidative biomarkers, acute phase proteins and reproductive performance in cows during pregnancy and lactation. A total of 78 Holstein-Friesian cows were randomly assigned into two groups: the treatment group, cows fed CPL (n = 38) which received 50 g of powdered CPL twice a day from day 180 before parturition to day 60 postpartum; and the control group (n = 40). Blood samples were taken on days 180, 90, 60, 30 and 10 before parturition, on day of calving and on days 5, 12, 19, 26, 33, 40 and 60 postpartum, and were analysed for metabolic biomarkers: glucose, triglycerides, total cholesterol, high density lipoprotein cholesterol, non-esterified fatty acids, beta-hydroxybutyrate (BHB), antioxidative biomarkers and acute phase proteins: paraoxonase-1 (PON1), apolipoprotein A-I, haptoglobin (Hp) and serum amyloid A (SAA). CPL supplementation increased concentration of glucose and significantly decreased (P < .05) level of BHB during puerperium. The SAA concentration in CPL-fed cows was significantly decreased (P < .05) on days 33, 40 and 60 postpartum as well as Hp concentration on days 0 and 12 postpartum. The results of this study suggest that the CPL-fed cows may have improved metabolic status due to the tendency of greater glucose levels and decreased BHB values during early lactation. In addition, acute phase response was lower (P < .05) in CPL-fed cows. Such an outcome might be attributed to the effect of dietary CPL on intensity and severity of the negative energy balance and inflammatory response in dairy cows.


Assuntos
Reação de Fase Aguda/veterinária , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Doenças dos Bovinos/tratamento farmacológico , Zeolitas/metabolismo , Reação de Fase Aguda/tratamento farmacológico , Reação de Fase Aguda/metabolismo , Ração Animal/análise , Animais , Bovinos , Doenças dos Bovinos/metabolismo , Dieta/veterinária , Suplementos Nutricionais/análise , Feminino , Lactação/fisiologia , Gravidez , Distribuição Aleatória , Soro/metabolismo , Zeolitas/administração & dosagem
4.
Front Immunol ; 10: 1220, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31191557

RESUMO

The term "acute phase response" (APR) is referred to a nonspecific and complex reaction of an organism that occurs shortly after any tissue damage, such as infection, trauma, neoplasia, inflammation, and stress. The APR can be identified and monitored with some laboratory tests, such as the concentration of several plasma proteins, the acute phase proteins (APPs). The APPs are components of the non-specific innate immune response, and their plasma concentration is proportional to the severity and/or the extent of tissue damage. The evaluation of health status of marine mammals is difficult because the classical clinical signs of illness used for human and domestic animals are difficult to recognize and understand. For this reason, in the past years, several efforts were done to identify laboratory markers of disease in these animals. The APPs have demonstrated their role as early markers of inflammation in veterinary medicine, thus several APPs were tested in marine mammals, such as C-reactive protein (CRP), serum amyloid-A (SAA), and Haptoglobin (Hp). However, the difficulty to extrapolate the knowledge about APPs in one species to another, the lack of specie-specific reagents, the absence of data about negative APPs have hampered their extent use in marine mammals. Herein, the state of art of APPs in marine mammals is reviewed, with particular attention to pre-analytical and analytical factors that should be taken into account in validation and interpretation of APPs assays. Moreover, the current application, potential utility and the future developments of APPs in marine mammals is highlighted and discussed.


Assuntos
Proteínas da Fase Aguda/imunologia , Proteínas da Fase Aguda/metabolismo , Organismos Aquáticos/imunologia , Organismos Aquáticos/metabolismo , Mamíferos/imunologia , Mamíferos/metabolismo , Proteínas da Fase Aguda/genética , Reação de Fase Aguda/genética , Reação de Fase Aguda/imunologia , Reação de Fase Aguda/metabolismo , Animais , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Imunidade Inata
5.
Mediators Inflamm ; 2019: 6518308, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31049027

RESUMO

The aim of the study was to evaluate the inflammatory reaction in children with pseudocroup and compare it with other laryngological diseases according to the available literature data. The study group included 51 children hospitalized because of pseudocroup. The measurements of the acute phase proteins (APP), such as C-reactive protein (CRP), alpha-1-antitrypsin (AT), alpha-1-antichymotrypsin (ACT), alpha-1-acid glycoprotein (AGP), ceruloplasmin (Cp), transferrin (Tf), alpha-2-macroglobulin (A2M), and haptoglobin (Hp) were obtained at 3 time points. The glycosylation profiles of AGP, ACT, and Tf were completed. An increased AGP level was observed in girls. The AGP glycosylation revealed the advantage of the W0 variant over the W1 variant. W1 and W2 were decreased in boys. W3 emerged in boys. The Tf concentration and T4 variant were lower compared to the control group. The A2M level was lower after treatment. The Hp and AT levels were decreased a few weeks later. The ACT glycosylation revealed a decrease of the A4 variant in boys. In conclusion, the inflammatory reaction during pseudocroup was of low intensity. The APP glycosylation suggested a chronic process. In a follow-up investigation, no normalization of the parameters was noted, but signs of persistent inflammation were observed.


Assuntos
Reação de Fase Aguda/metabolismo , Crupe/metabolismo , Laringite/metabolismo , Proteínas da Fase Aguda/metabolismo , Proteína C-Reativa/metabolismo , Ceruloplasmina/metabolismo , Haptoglobinas/metabolismo , Humanos , Orosomucoide/metabolismo , Transferrina/metabolismo , alfa 1-Antiquimotripsina/metabolismo , alfa 1-Antitripsina/metabolismo
6.
Sci Rep ; 9(1): 3102, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30816210

RESUMO

Complex associations exist between inflammation and thrombosis, with the inflammatory state tending to promote coagulation. Fibrinogen, an acute phase protein, has been shown to interact with the amyloidogenic ß-amyloid protein of Alzheimer's disease. However, little is known about the association between fibrinogen and serum amyloid A (SAA), a highly fibrillogenic protein that is one of the most dramatically changing acute phase reactants in the circulation. To study the role of SAA in coagulation and thrombosis, in vitro experiments were performed where purified human SAA, in concentrations resembling a modest acute phase response, was added to platelet-poor plasma (PPP) and whole blood (WB), as well as purified and fluorescently labelled fibrinogen. Results from thromboelastography (TEG) suggest that SAA causes atypical coagulation with a fibrin(ogen)-mediated increase in coagulation, but a decreased platelet/fibrin(ogen) interaction. In WB scanning electron microscopy analysis, SAA mediated red blood cell (RBC) agglutination, platelet activation and clumping, but not platelet spreading. Following clot formation in PPP, the presence of SAA increased amyloid formation of fibrin(ogen) as determined both with auto-fluorescence and with fluorogenic amyloid markers, under confocal microcopy. SAA also binds to fibrinogen, as determined with a fluorescent-labelled SAA antibody and correlative light electron microscopy (CLEM). The data presented here indicate that SAA can affect coagulation by inducing amyloid formation in fibrin(ogen), as well as by propelling platelets to a more prothrombotic state. The discovery of these multiple and complex effects of SAA on coagulation invite further mechanistic analyses.


Assuntos
Reação de Fase Aguda/metabolismo , Amiloide/metabolismo , Plaquetas/metabolismo , Fibrinogênio/metabolismo , Proteína Amiloide A Sérica/fisiologia , Trombose/metabolismo , Adulto , Aglutinação , Doença de Alzheimer/metabolismo , Coagulação Sanguínea , Plaquetas/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Ativação Plaquetária , Agregação Plaquetária , Ligação Proteica
7.
J Trace Elem Med Biol ; 52: 270-287, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30732893

RESUMO

Zinc oxide nanoparticles (ZnO NPs) are one of the most widely used nanomaterials. Following oral exposure, these NPs can accumulate in various organs and induce the toxicity due to their physiochemical characteristics. In present study to reduce the toxicity, surface engineered ZnO NPs (c-ZnO NPs) were in-situ synthesized by using polyacrylamide grafted guar gum (PAm-g-GG) polymer in alkaline media. Further, the comparative effect of bared ZnO NPs (b-ZnO NPs) and c-ZnO NPs were assessed on secondary target organ liver and kidneys of Swiss mice at doses of 10, 50 and 300 mg/kg following 28 days repeated oral treatment. The b-ZnO NPs were incited severe damages in liver and kidney tissue than c-ZnO NPs as seen by transmission electron microscopy and histopathology. The increased levels of serum biomarkers (AST, ALT, ALP, creatinine, uric acid, and urea) were also observed, that remarking a disturbance in the function of liver and kidney. After sub-acute oral treatment of b-ZnO NPs, the hepatic pro-inflammatory cytokines (IL-6, TNF-α, and MMP-9) were up-regulated that causes the activation of acute phase response (APR). We also observed significantly increased in expression of hepatic acute phase proteins (hepcidin and haptoglobin) and altered interlinked iron (Fe) signaling biomarkers (hephaestin, TF, TFR-1, LDH, and ferroportin). This study emphasizes that exposure to ZnO NPs may cause inflammation mediated APR through ultra-structural damage of tissue that could escort the progression of anemia. Nevertheless, the capping with PAm-g-GG in c- ZnO NPs has reduced the toxicity by altering the surface reactive property of ZnO NPs.


Assuntos
Reação de Fase Aguda/metabolismo , Homeostase/efeitos dos fármacos , Ferro/metabolismo , Nanopartículas/toxicidade , Óxido de Zinco/toxicidade , Administração Oral , Animais , Biomarcadores/sangue , Citocinas/metabolismo , Feminino , Camundongos , Nanopartículas/administração & dosagem , Propriedades de Superfície , Óxido de Zinco/administração & dosagem
8.
Int J Mol Sci ; 21(1)2019 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-31892161

RESUMO

(1) Background: Sepsis-induced acute kidney injury (AKI) is the most common form of acute kidney injury (AKI). We studied the temporal profile of the sepsis-induced renal proteome changes. (2) Methods: Male mice were injected intraperitoneally with bacterial lipopolysaccharide (LPS) or saline (control). Renal proteome was studied by LC-MS/MS (ProteomeXchange: PXD014664) at the early phase (EP, 1.5 and 6 h after 40 mg/kg LPS) and the late phase (LP, 24 and 48 h after 10 mg/kg LPS) of LPS-induced AKI. Renal mRNA expression of acute phase proteins (APP) was assessed by qPCR. (3) Results: Renal proteome change was milder in EP vs. LP. APPs dominated the proteome in LP (proteins upregulated at least 4-fold (APPs/all): EP, 1.5 h: 0/10, 6 h: 1/10; LP, 24 h: 22/47, 48 h: 17/44). Lipocalin-2, complement C3, fibrinogen, haptoglobin and hemopexin were the most upregulated APPs. Renal mRNA expression preceded the APP changes with peak effects at 24 h, and indicated renal production of the majority of APPs. (4) Conclusions: Gene expression analysis revealed local production of APPs that commenced a few hours post injection and peaked at 24 h. This is the first demonstration of a massive, complex and coordinated acute phase response of the kidney involving several proteins not identified previously.


Assuntos
Lesão Renal Aguda/patologia , Reação de Fase Aguda/patologia , Rim/metabolismo , Rim/patologia , Proteoma/metabolismo , Sepse/metabolismo , Sepse/patologia , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/metabolismo , Proteínas da Fase Aguda/metabolismo , Reação de Fase Aguda/induzido quimicamente , Reação de Fase Aguda/metabolismo , Animais , Complemento C3/metabolismo , Modelos Animais de Doenças , Interleucina-6/metabolismo , Rim/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Sepse/induzido quimicamente , Fator de Necrose Tumoral alfa/metabolismo
9.
J Dairy Sci ; 102(1): 365-376, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30487053

RESUMO

In dairy cows, administration of high dosages of niacin (nicotinic acid, NA) was found to cause antilipolytic effects, which are mediated by the NA receptor hydroxyl-carboxylic acid receptor 2 (HCAR2) in white adipose tissue (WAT), and thereby an altered hepatic lipid metabolism. However, almost no attention has been paid to possible direct effects of NA in cattle liver, despite evidence that HCAR2 is also expressed in the liver and is even more abundant than in WAT. Because of this, we hypothesized that feeding a high dosage of rumen-protected NA to dairy cows influences critical metabolic or signaling pathways in the liver by inducing changes in the hepatic transcriptome. To identify these pathways, we applied genome-wide transcript profiling in liver biopsies obtained at d 7 postpartum (p.p.) from dairy cows used in our recent study; cows received either no NA (control group, n = 9) or 79 mg of rumen-protected NA/kg of body weight daily (NA group, n = 9) from 21 d before calving until 3 wk p.p. Hepatic transcript profiling revealed that 487 transcripts were differentially expressed (filter criteria: fold change >1.2 or <-1.2 and P < 0.05) in the liver at d 7 p.p. between cows fed NA and control cows. Substantially more transcripts were downregulated (n = 338), whereas only 149 transcripts were upregulated by NA in the liver of cows. Gene set enrichment analysis for the upregulated transcripts revealed that the most-enriched gene ontology biological process terms were exclusively related to immune processes, such as leukocyte differentiation, immune system process, activation of immune response, and acute inflammatory response. Gene set enrichment analysis of the downregulated transcripts showed that the most-enriched biological process terms were related to metabolic processes, such as cellular metabolic process, small molecule metabolic process, lipid catabolic process, organic cyclic compound metabolic process, small molecule biosynthetic process, and cellular lipid catabolic process. In conclusion, hepatic transcriptome analysis showed that rumen-protected NA induces genes that are involved mainly in immune processes, including acute phase response and stress response, in dairy cows at d 7 p.p. Thus, supplementation of a high dosage of rumen-protected NA to dairy cows in the periparturient period may induce or amplify the systemic inflammation-like condition that is typically observed in the liver of high-yielding dairy cows in the p.p. period.


Assuntos
Bovinos/genética , Suplementos Nutricionais , Perfilação da Expressão Gênica/veterinária , Niacina/administração & dosagem , Reação de Fase Aguda/metabolismo , Animais , Peso Corporal , Bovinos/fisiologia , Dieta/veterinária , Feminino , Lactação , Lipólise , Fígado/metabolismo , Período Pós-Parto , Gravidez , Rúmen/metabolismo
10.
Brain Behav Immun ; 69: 486-498, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29355821

RESUMO

Perinatal inflammation is known to contribute to neurodevelopmental diseases. Animal models of perinatal inflammation have revealed that the inflammatory response within the brain is age dependent, but the regulators of this variation remain unclear. In the adult, the peripheral acute phase response (APR) is known to be pivotal in the downstream recruitment of leukocytes to the injured brain. The relationship between perinatal brain injury and the APR has not been established. Here, we generated focal inflammation in the brain using interleukin (IL)-1ß at postnatal day (P)7, P14, P21 and P56 and studied both the central nervous system (CNS) and hepatic inflammatory responses at 4 h. We found that there is a significant window of susceptibility in mice at P14, when compared to mice at P7, P21 and P56. This was reflected in increased neutrophil recruitment to the CNS, as well as an increase in blood-brain barrier permeability. To investigate phenomena underlying this window of susceptibility, we performed a dose response of IL-1ß. Whilst induction of endogenous IL-1ß or intercellular adhesion molecule (ICAM)-1 in the brain and induction of a hepatic APR were dose dependent, the recruitment of neutrophils and associated blood-brain barrier breakdown was inversely proportional. Furthermore, in contrast to adult animals, an additional peripheral challenge (intravenous IL-1ß) reduced the degree of CNS inflammation, rather than exacerbating it. Together these results suggest a unique window of susceptibility to CNS injury, meaning that suppressing systemic inflammation after brain injury may exacerbate the damage caused, in an age-dependent manner.


Assuntos
Reação de Fase Aguda/metabolismo , Barreira Hematoencefálica/metabolismo , Lesões Encefálicas/metabolismo , Encéfalo/metabolismo , Inflamação/metabolismo , Animais , Interleucina-1beta/metabolismo , Camundongos , Infiltração de Neutrófilos , Neutrófilos/metabolismo
11.
J Hepatol ; 68(5): 996-1005, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29331340

RESUMO

BACKGROUND & AIMS: Heat shock protein (Hsp) 72 is a molecular chaperone that has broad cytoprotective functions and is upregulated in response to stress. To determine its hepatic functions, we studied its expression in human liver disorders and its biological significance in newly generated transgenic animals. METHODS: Double transgenic mice overexpressing Hsp72 (gene Hspa1a) under the control of a tissue-specific tetracycline-inducible system (Hsp72-LAP mice) were produced. Acute liver injury was induced by a single injection of acetaminophen (APAP). Feeding with either a methionine choline-deficient (MCD; 8 weeks) or a 3,5-diethoxycarbonyl-1,4-dihydrocollidine-supplemented diet (DDC; 12 weeks) was used to induce lipotoxic injury and Mallory-Denk body (MDB) formation, respectively. Primary hepatocytes were treated with palmitic acid. RESULTS: Patients with non-alcoholic steatohepatitis and chronic hepatitis C infection displayed elevated HSP72 levels. These levels increased with the extent of hepatic inflammation and HSP72 expression was induced after treatment with either interleukin (IL)-1ß or IL-6. Hsp72-LAP mice exhibited robust, hepatocyte-specific Hsp72 overexpression. Primary hepatocytes from these animals were more resistant to isolation-induced stress and Hsp72-LAP mice displayed lower levels of hepatic injury in vivo. Mice overexpressing Hsp72 had fewer APAP protein adducts and were protected from oxidative stress and APAP-/MCD-induced cell death. Hsp72-LAP mice and/or hepatocytes displayed significantly attenuated Jnk activation. Overexpression of Hsp72 did not affect steatosis or the extent of MDB formation. CONCLUSIONS: Our results demonstrate that HSP72 induction occurs in human liver disease, thus, HSP72 represents an attractive therapeutic target owing to its broad hepatoprotective functions. LAY SUMMARY: HSP72 constitutes a stress-inducible, protective protein. Our data demonstrate that it is upregulated in patients with chronic hepatitis C and non-alcoholic steatohepatitis. Moreover, Hsp72-overexpressing mice are protected from various forms of liver stress.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Proteínas de Choque Térmico HSP72/metabolismo , Reação de Fase Aguda/metabolismo , Reação de Fase Aguda/patologia , Animais , Morte Celular , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Modelos Animais de Doenças , Feminino , Proteínas de Choque Térmico HSP72/genética , Hepatite C Crônica/metabolismo , Hepatite C Crônica/patologia , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Sistema de Sinalização das MAP Quinases , Masculino , Corpos de Mallory/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Estresse Oxidativo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Regulação para Cima
12.
J Lipid Res ; 59(2): 339-347, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29247043

RESUMO

Serum amyloid A (SAA) is a family of acute-phase reactants. Plasma levels of human SAA1/SAA2 (mouse SAA1.1/2.1) can increase ≥1,000-fold during an acute-phase response. Mice, but not humans, express a third relatively understudied SAA isoform, SAA3. We investigated whether mouse SAA3 is an HDL-associated acute-phase SAA. Quantitative RT-PCR with isoform-specific primers indicated that SAA3 and SAA1.1/2.1 are induced similarly in livers (∼2,500-fold vs. ∼6,000-fold, respectively) and fat (∼400-fold vs. ∼100-fold, respectively) of lipopolysaccharide (LPS)-injected mice. In situ hybridization demonstrated that all three SAAs are produced by hepatocytes. All three SAA isoforms were detected in plasma of LPS-injected mice, although SAA3 levels were ∼20% of SAA1.1/2.1 levels. Fast protein LC analyses indicated that virtually all of SAA1.1/2.1 eluted with HDL, whereas ∼15% of SAA3 was lipid poor/free. After density gradient ultracentrifugation, isoelectric focusing demonstrated that ∼100% of plasma SAA1.1 was recovered in HDL compared with only ∼50% of SAA2.1 and ∼10% of SAA3. Thus, SAA3 appears to be more loosely associated with HDL, resulting in lipid-poor/free SAA3. We conclude that SAA3 is a major hepatic acute-phase SAA in mice that may produce systemic effects during inflammation.


Assuntos
Reação de Fase Aguda/metabolismo , Proteína Amiloide A Sérica/metabolismo , Animais , Células Cultivadas , Lipopolissacarídeos/farmacologia , Lipoproteínas HDL/metabolismo , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Amiloide A Sérica/deficiência , Proteína Amiloide A Sérica/genética
13.
Mol Metab ; 6(10): 1081-1091, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-29031710

RESUMO

OBJECTIVE AND METHODS: Metabolic viscera and their vasculature are richly innervated by peripheral sensory neurons. Here, we examined the metabolic and inflammatory profiles of mice with selective ablation of all Nav1.8-expressing primary afferent neurons. RESULTS: While mice lacking sensory neurons displayed no differences in body weight, food intake, energy expenditure, or body composition compared to controls on chow diet, ablated mice developed an exaggerated inflammatory response to high-fat feeding characterized by bouts of weight loss, splenomegaly, elevated circulating interleukin-6 and hepatic serum amyloid A expression. This phenotype appeared to be directly mediated by the ingestion of saturated lipids. CONCLUSIONS: These data demonstrate that the Nav1.8-expressing afferent neurons are not essential for energy balance but are required for limiting the acute phase response caused by an obesogenic diet.


Assuntos
Reação de Fase Aguda/metabolismo , Gorduras na Dieta/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.8/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.8/fisiologia , Animais , Composição Corporal , Peso Corporal , Dieta Hiperlipídica , Ingestão de Alimentos/fisiologia , Metabolismo Energético/fisiologia , Homeostase/fisiologia , Camundongos , Neurônios Aferentes/metabolismo , Obesidade/etiologia , Células Receptoras Sensoriais/metabolismo , Vísceras/metabolismo , Perda de Peso
14.
Sci Rep ; 7(1): 9574, 2017 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-28851955

RESUMO

Brain injury elicits a systemic acute-phase response (APR), which is responsible for co-ordinating the peripheral immunological response to injury. To date, the mechanisms responsible for signalling the presence of injury or disease to selectively activate responses in distant organs were unclear. Circulating endogenous extracellular vesicles (EVs) are increased after brain injury and have the potential to carry targeted injury signals around the body. Here, we examined the potential of EVs, isolated from rats after focal inflammatory brain lesions using IL-1ß, to activate a systemic APR in recipient naïve rats, as well as the behavioural consequences of EV transfer. Focal brain lesions increased EV release, and, following isolation and transfer, the EVs were sequestered by the liver where they initiated an APR. Transfer of blood-borne EVs from brain-injured animals was also enough to suppress exploratory behaviours in recipient naïve animals. EVs derived from brain endothelial cell cultures treated with IL-1ß also activated an APR and altered behaviour in recipient animals. These experiments reveal that inflammation-induced circulating EVs derived from endothelial cells are able to initiate the APR to brain injury and are sufficient to generate the associated sickness behaviours, and are the first demonstration that EVs are capable of modifying behavioural responses.


Assuntos
Reação de Fase Aguda/metabolismo , Encefalite/metabolismo , Encefalite/fisiopatologia , Células Endoteliais/metabolismo , Vesículas Extracelulares/metabolismo , Comportamento de Doença , Animais , Comportamento Animal , Citocinas/metabolismo , Modelos Animais de Doenças , Encefalite/etiologia , Encefalite/patologia , Hepatite/etiologia , Hepatite/metabolismo , Hepatite/patologia , Mediadores da Inflamação/metabolismo , Macrófagos do Fígado/metabolismo , Masculino , Ratos
15.
J Lipid Res ; 58(10): 2051-2060, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28830907

RESUMO

Acute phase reaction (APR) is a systemic inflammation triggered by several conditions associated with lipid profile alterations. We evaluated whether APR also associates with changes in cholesterol synthesis and absorption, HDL structure, composition, and cholesterol efflux capacity (CEC). We analyzed 59 subjects with APR related to infections, oncologic causes, or autoimmune diseases and 39 controls. We detected no difference in markers of cholesterol synthesis and absorption. Conversely, a significant reduction of LpA-I- and LpAI:AII-containing HDL (-28% and -44.8%, respectively) and of medium-sized HDL (-10.5%) occurred in APR. Total HDL CEC was impaired in APR subjects (-18%). Evaluating specific CEC pathways, we found significant reductions in CEC by aqueous diffusion and by the transporters scavenger receptor B-I and ABCG1 (-25.5, -41.1 and -30.4%, respectively). ABCA1-mediated CEC was not affected. Analyses adjusted for age and gender provided similar results. In addition, correcting for HDL-cholesterol (HDL-C) levels, the differences in aqueous diffusion total and ABCG1-CEC remained significant. APR subjects displayed higher levels of HDL serum amyloid A (+20-folds; P = 0.003). In conclusion, APR does not associate with cholesterol synthesis and absorption changes but with alterations of HDL composition and a marked impairment of HDL CEC, partly independent of HDL-C serum level reduction.


Assuntos
Reação de Fase Aguda/metabolismo , Colesterol/sangue , Homeostase , Lipoproteínas HDL/sangue , Absorção Fisico-Química , Reação de Fase Aguda/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Colesterol/biossíntese , Colesterol/metabolismo , Feminino , Humanos , Lipoproteínas HDL/química , Masculino , Pessoa de Meia-Idade , Tamanho da Partícula , Proteína Amiloide A Sérica/metabolismo , Adulto Jovem
16.
Mediators Inflamm ; 2017: 7962546, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28659664

RESUMO

Infective endocarditis (IE) is a septic inflammation of the endocardium. Recognition of microbial patterns, cytokine and acute phase responses, hemostasis features, and alterations in plasma lipid and calcium profile all have been reported to affect pathogenesis and clinical course of IE. Having recruited 123 patients with IE and 300 age-, sex-, and ethnicity-matched healthy blood donors, we profiled their genomic DNA for 35 functionally significant polymorphisms within the 22 selected genes involved in the abovementioned pathways, with the further genetic association analysis. We found that the G/A genotype of the rs1143634 polymorphism within the IL1B gene, the G/T genotype of the rs3212227 polymorphism within the IL12B gene, the A/G genotype of the rs1130864 polymorphism within the CRP gene, and the G allele of the rs1801197 polymorphism within the CALCR gene were associated with a decreased risk of IE whereas the T/T genotype of the rs1205 polymorphism within the CRP gene was associated with a higher risk of IE. Furthermore, heterozygous genotypes of the rs1143634 and rs3212227 polymorphisms were associated with the higher plasma levels of IL-1ß and IL-12, respectively. Our results indicate that inherited variation in the cytokine, acute phase response, and calcium metabolism pathways may be linked to IE.


Assuntos
Reação de Fase Aguda/metabolismo , Cálcio/metabolismo , Endocardite/imunologia , Endocardite/metabolismo , Reação de Fase Aguda/imunologia , Adulto , Alelos , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Genótipo , Humanos , Interleucina-12/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética
17.
J Exp Biol ; 220(Pt 16): 2957-2964, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28606898

RESUMO

Carotenoids are finite resources that animals can allocate to self-maintenance, attractiveness or reproduction. Here we test how carotenoids affect the acute phase response (APR), an intense rapid systemic response characterized by fever, sickness behavior and production of acute phase proteins, which serves to reduce pathogen persistence. We conducted a 2×2 factorial design experiment in captive adult male and female zebra finches (Taeniopygia guttata) to determine the effects of carotenoid supplementation on the intensity of the APR. We measured changes in feeding rate, activity level and body temperature of the birds. We found that, relative to unsupplemented controls, carotenoid-supplemented birds exhibited less severe reductions in feeding and activity, smaller increases in body temperature and lower circulating levels of haptoglobin (an acute phase protein) 24 h after inducing an APR. Among supplemented individuals, those with higher blood carotenoid levels exhibited a lower reduction in activity rate after 24 h. Forty-eight hours after APR induction, birds exhibited a significant decrease in plasma carotenoid levels and a decrease in bill hue, with less reduction in hue in carotenoid-supplemented individuals. These results demonstrate that carotenoids can alleviate several important behavioral and physiological effects of an APR and that bill color can change rapidly following induction of the costly APR immune defense. In particular, immune activation may have caused birds to preferentially draw down carotenoids from the bloodstream, ostensibly for use in health. Rapid bill color changes over a 48-h period support growing evidence that bills may serve as short-term signals of health and condition.


Assuntos
Reação de Fase Aguda/veterinária , Bico/fisiologia , Carotenoides/fisiologia , Febre/veterinária , Comportamento de Doença , Aves Canoras/fisiologia , Reação de Fase Aguda/etiologia , Reação de Fase Aguda/metabolismo , Animais , Dieta , Suplementos Nutricionais/análise , Feminino , Febre/etiologia , Febre/metabolismo , Tentilhões/fisiologia , Masculino , Pigmentação
18.
J Nippon Med Sch ; 84(2): 64-72, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28502961

RESUMO

Haptoglobin exerts renal protective function by scavenging free hemoglobin from the urine and blood stream in patients with hemolytic disorders. Recent studies elucidate the relationships between haptoglobin and inflammation. In addition, coagulopathy is often induced by systemic inflammation characterized by the presence of vascular endothelial damage. We hypothesize that haptoglobin might have an anti-inflammatory effect and affect hypercoagulability using rat burn model. Thirty anesthetized rats of six-weeks of age received over 30% full-thickness scald burn on the dorsal skin surface. All rats were injected with either haptoglobin (Hpt) or normal saline (NS) intraperitoneally. The rats were divided into three groups: 1) control group (NS 20 mL/kg); 2) low concentration of Hpt group, L-Hpt, (Hpt 4 mL (80 U) /kg+NS 16 mL/kg); and 3) high concentration of Hpt group, H-Hpt, (Hpt 20 mL (400 U) /kg). While under anesthesia, all rats were euthanized by exsanguination at 6 hours (N=5) and 24 hours (N=5). Inflammatory and anti-inflammatory cytokines were measured and whole-blood viscoelastic tests were performed by thromboelastometry (ROTEM). Haptoglobin significantly reduced free hemoglobin 24 hours after the injury. Improvement of hematuria was confirmed in the H-Hpt group. There were no differences in thrombin-antithrombin complex and plasmin-α2 plasmin inhibitor complex. The haptoglobin tended to decrease interferon-gamma (IFN-γ) in H-Hpt group. ROTEM findings of the L-Hpt group showed significantly higher clot firmness and shorter time to maximum clot formation velocity than the control group. Haptoglobin reduced INF-γ, and accelerated speed of clot formation in acute phase of severe burn.


Assuntos
Reação de Fase Aguda/sangue , Reação de Fase Aguda/metabolismo , Anti-Inflamatórios , Coagulação Sanguínea , Queimaduras/sangue , Queimaduras/metabolismo , Haptoglobinas/farmacologia , Mediadores da Inflamação/sangue , Interferon gama/sangue , Animais , Coagulação Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Haptoglobinas/uso terapêutico , Hematúria/tratamento farmacológico , Hemoglobinas/metabolismo , Masculino , Ratos Sprague-Dawley , Índice de Gravidade de Doença
19.
Respir Med ; 127: 33-39, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28502416

RESUMO

BACKGROUND: Systemic inflammation in bronchiectasis is poorly studied in relation to aetiology and severity. We hypothesized that molecular patterns of inflammation may define particular aetiology and severity groups in bronchiectasis. METHOD: We assayed blood concentrations of 31 proteins from 90 bronchiectasis patients (derivation cohort) and conducted PCA to examine relationships between these markers, disease aetiology and severity. Key results were validated in two separate cohorts of 97 and 79 patients from other centres. RESULTS: There was significant heterogeneity in protein concentrations across the derivation population. Increasing severity of bronchiectasis (BSI) was associated with increasing fibrinogen (rho = 0.34, p = 0.001 -validated in a second cohort), and higher fibrinogen was associated with worse lung function, Pseudomonas colonisation and impaired health-status. There were generally similar patterns of inflammation in patients with idiopathic and post-infectious disease. However, patients with primary immunodeficiency had exaggerated IL-17 responses, validated in a second cohort (n = 79, immunodeficient 12.82 pg/ml versus idiopathic/post-infectious 4.95 pg/ml, p = 0.001), and thus IL-17 discriminated primary immunodeficiency from other aetiologies (AUC 0.769 (95%CI 0.661-0.877)). CONCLUSION: Bronchiectasis is associated with heterogeneity of systemic inflammatory proteins not adequately explained by differences in disease aetiology or severity. More severe disease is associated with enhanced acute-phase responses. Plasma fibrinogen was associated with bronchiectasis severity in two cohorts, Pseudomonas colonisation and health status, and offers potential as a useful biomarker.


Assuntos
Biomarcadores/sangue , Bronquiectasia/sangue , Fibrinogênio/metabolismo , Inflamação/sangue , Interleucina-17/metabolismo , Reação de Fase Aguda/metabolismo , Idoso , Bronquiectasia/diagnóstico por imagem , Bronquiectasia/fisiopatologia , Estudos de Coortes , Feminino , Nível de Saúde , Humanos , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/imunologia , Masculino , Pessoa de Meia-Idade , Pseudomonas/crescimento & desenvolvimento , Testes de Função Respiratória/métodos , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X/métodos
20.
PLoS One ; 12(4): e0174167, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28380028

RESUMO

Pulmonary exposure to multi-walled carbon nanotubes (MWCNTs) has been linked to an increased risk of developing cardiovascular disease in addition to the well-documented physicochemical-dependent adverse lung effects. A proposed mechanism is through a strong and sustained pulmonary secretion of acute phase proteins to the blood. We identified physicochemical determinants of MWCNT-induced systemic acute phase response by analyzing effects of pulmonary exposure to 14 commercial, well-characterized MWCNTs in female C57BL/6J mice pulmonary exposed to 0, 6, 18 or 54 µg MWCNT/mouse. Plasma levels of acute phase response proteins serum amyloid A1/2 (SAA1/2) and SAA3 were determined on day 1, 28 or 92. Expression levels of hepatic Saa1 and pulmonary Saa3 mRNA levels were assessed to determine the origin of the acute phase response proteins. Pulmonary Saa3 mRNA expression levels were greater and lasted longer than hepatic Saa1 mRNA expression. Plasma SAA1/2 and SAA3 protein levels were related to time and physicochemical properties using adjusted, multiple regression analyses. SAA3 and SAA1/2 plasma protein levels were increased after exposure to almost all of the MWCNTs on day 1, whereas limited changes were observed on day 28 and 92. SAA1/2 and SAA3 protein levels did not correlate and only SAA3 protein levels correlated with neutrophil influx. The multiple regression analyses revealed a protective effect of MWCNT length on SAA1/2 protein level on day 1, such that a longer length resulted in lowered SAA1/2 plasma levels. Increased SAA3 protein levels were positively related to dose and content of Mn, Mg and Co on day 1, whereas oxidation and diameter of the MWCNTs were protective on day 28 and 92, respectively. The results of this study reveal very differently controlled pulmonary and hepatic acute phase responses after MWCNT exposure. As the responses were influenced by the physicochemical properties of the MWCNTs, this study provides the first step towards designing MWCNT that induce less SAA.


Assuntos
Proteínas da Fase Aguda/metabolismo , Reação de Fase Aguda/metabolismo , Fenômenos Químicos/efeitos dos fármacos , Exposição por Inalação/efeitos adversos , Pulmão/efeitos dos fármacos , Nanotubos de Carbono/efeitos adversos , Animais , Feminino , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/metabolismo , RNA Mensageiro/metabolismo , Proteína Amiloide A Sérica/metabolismo
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