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1.
JAMA Netw Open ; 2(11): e1914988, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31702802

RESUMO

Importance: Vomiting resulting from acute gastroenteritis is commonly treated with intravenous antiemetics in acute care settings. If oral treatment were beneficial, patients might not need intravenous administered hydration or medication. Furthermore, a long-acting treatment could provide sustained relief from nausea and vomiting. Objective: To determine whether an experimental long-acting bimodal release ondansetron tablet decreases gastroenteritis-related vomiting and eliminates the need for intravenous therapy for 24 hours after administration. Design, Setting, and Participants: This placebo-controlled, double-blind, randomized clinical trial included patients from 19 emergency departments and 2 urgent care centers in the United States from December 8, 2014, to February 17, 2017. Patients 12 years and older with at least 2 vomiting episodes from presumed gastroenteritis in the previous 4 hours and symptoms with less than 36 hours' duration were randomized using a 3:2 active to placebo ratio. Analyses were performed on an intent-to-treat basis and conducted from June 1, 2017, to November 1, 2017. Intervention: Bimodal release ondansetron tablet containing 6 mg of immediate release ondansetron and 18 mg of a 24-hour release matrix for a total of 24 mg of ondansetron. Main Outcomes and Measures: Treatment success was defined as no further vomiting, no need for rescue medication, and no intravenous hydration for 24 hours after bimodal release ondansetron administration. Results: Analysis included 321 patients (mean [SD] age, 29.0 [11.1] years; 195 [60.7%] women), with 192 patients in the bimodal release ondansetron group and 129 patients in the placebo group. Treatment successes were observed in 126 patients in the bimodal release ondansetron group (65.6%) compared with 70 patients in the placebo group (54.3%), with an 11.4% (95% CI, 0.3%-22.4%) absolute probability difference. The proportion of treatment success was 21% higher among patients who received bimodal release ondansetron compared with those who received a placebo (relative risk, 1.21; 95% CI, 1.00-1.46; P = .04). In an analysis including only patients with a discharge diagnosis of acute gastroenteritis and no major protocol violations, there were 123 treatment successes (69.5%) in the bimodal release ondansetron group compared with 67 treatment successes (54.9%) in the placebo group (relative risk, 1.27; 95% CI, 1.05-1.53; P = .01). Adverse effects were infrequent and similar to the known safety profile of ondansetron. Conclusions and Relevance: This randomized clinical trial found that a long-acting bimodal release oral ondansetron tablet was an effective antiemetic among adolescents and adults with moderate to severe vomiting from acute gastroenteritis. The drug benefits extended to 24 hours after administration. Bimodal release ondansetron may decrease the need for intravenous access and emergency department care to manage acute gastroenteritis. Trial Registration: ClinicalTrials.gov identifier: NCT02246439.

2.
Ann Emerg Med ; 74(1): 50-55, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30732980

RESUMO

STUDY OBJECTIVE: Methicillin-resistant Staphylococcus aureus (MRSA) transmission dynamics in the emergency department (ED) are not well defined; environmental surfaces may serve as reservoirs for transmission. This study investigates the effect of patients with a history of MRSA colonization or infection on subsequent MRSA contamination of the ED environment. METHODS: Adult ED patients with evidence of an MRSA-positive surveillance result or clinical microbiologic culture in the year preceding their current ED visit were enrolled. Cultures from 5 anatomic sites were obtained to detect active MRSA colonization. After patients' discharge and before environmental disinfection, up to 16 prespecified surfaces in their ED rooms were cultured. Strain typing was performed by repetitive-sequence polymerase chain reaction on all recovered MRSA isolates to determine concordance with the corresponding patient strain. RESULTS: Of 42 patients enrolled, 25 (60%) remained colonized with MRSA. Nineteen of the 25 ED rooms (76%) occupied by MRSA-colonized patients contained greater than or equal to 1 MRSA-contaminated environmental surface on patient discharge. Surfaces were more likely to be contaminated when rooms were occupied by patients colonized with MRSA at 1 body site (odds ratio 11.7; 95% confidence interval 1.5 to 91.5) and greater than or equal to 2 body sites (odds ratio 16.3; 95% confidence interval 3.1 to 86.8) compared with noncolonized patients. In 16 of the 19 ED rooms (84%) where MRSA was recovered, all environmental strains were concordant with the corresponding patient strain. CONCLUSION: Contamination of the ED environment with MRSA from actively colonized patients is common. Improved environmental surface disinfection may help reduce transmission of MRSA to ED health care professionals and patients during emergency care.

3.
J Pathol ; 246(1): 54-66, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29873400

RESUMO

Fibroblast growth factor (FGF) signaling has been implicated in the pathogenesis of pulmonary fibrosis. Mice lacking FGF2 have increased mortality and impaired epithelial recovery after bleomycin exposure, supporting a protective or reparative function following lung injury. To determine whether FGF2 overexpression reduces bleomycin-induced injury, we developed an inducible genetic system to express FGF2 in type II pneumocytes. Double-transgenic (DTG) mice with doxycycline-inducible overexpression of human FGF2 (SPC-rtTA;TRE-hFGF2) or single-transgenic controls were administered intratracheal bleomycin and fed doxycycline chow, starting at either day 0 or day 7. In addition, wild-type mice received intratracheal or intravenous recombinant FGF2, starting at the time of bleomycin treatment. Compared to controls, doxycycline-induced DTG mice had decreased pulmonary fibrosis 21 days after bleomycin, as assessed by gene expression and histology. This beneficial effect was seen when FGF2 overexpression was induced at day 0 or day 7 after bleomycin. FGF2 overexpression did not alter epithelial gene expression, bronchoalveolar lavage cellularity or total protein. In vitro studies using primary mouse and human lung fibroblasts showed that FGF2 strongly inhibited baseline and TGFß1-induced expression of alpha smooth muscle actin (αSMA), collagen, and connective tissue growth factor. While FGF2 did not suppress phosphorylation of Smad2 or Smad-dependent gene expression, FGF2 inhibited TGFß1-induced stress fiber formation and serum response factor-dependent gene expression. FGF2 inhibition of stress fiber formation and αSMA requires FGF receptor 1 (FGFR1) and downstream MEK/ERK, but not AKT signaling. In summary, overexpression of FGF2 protects against bleomycin-induced pulmonary fibrosis in vivo and reverses TGFß1-induced collagen and αSMA expression and stress fiber formation in lung fibroblasts in vitro, without affecting either inflammation or epithelial gene expression. Our results suggest that in the lung, FGF2 is antifibrotic in part through decreased collagen expression and fibroblast to myofibroblast differentiation. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Células Epiteliais Alveolares/metabolismo , Bleomicina , Diferenciação Celular , Colágeno/metabolismo , Fator 2 de Crescimento de Fibroblastos/metabolismo , Pulmão/metabolismo , Miofibroblastos/metabolismo , Fibrose Pulmonar/prevenção & controle , Actinas/metabolismo , Células Epiteliais Alveolares/patologia , Animais , Células Cultivadas , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fator 2 de Crescimento de Fibroblastos/genética , Humanos , Pulmão/patologia , Camundongos Transgênicos , Miofibroblastos/patologia , Fenótipo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais , Fibras de Estresse/metabolismo , Fibras de Estresse/patologia , Fatores de Tempo
4.
Thromb Res ; 166: 63-70, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29656169

RESUMO

INTRODUCTION: We sought to determine the test characteristics of an automated INNOVANCE D-dimer assay for the exclusion of pulmonary embolism (PE) and deep venous thrombosis (DVT) in emergency department (ED) patients using standard and age-adjusted cut-offs. METHODS: Cross-sectional, international, multicenter study of consecutive patients with suspected DVT or PE in 24 centers (18 USA, 6 Europe). Evaluated patients had low or intermediate Wells PE or DVT scores. For the standard cut-off, a D-dimer result <500 ng/ml was negative. For the age adjusted cut-off, we used the formula: Age (years) ∗ 10. The diagnostic standard was imaging demonstrating PE or DVT within 3 months. We calculated test characteristics using standard methods. We also explored modifications of the age adjustment multiplier. RESULTS: We included 3837 patients and excluded 251. The mean age of patients evaluated for PE (n = 1834) was 48 ±â€¯16 years, with 676 (37%) male, and 1081 (59%) white. The mean age of evaluated for DVT (n = 1752) was 53 ±â€¯16 years, with 710 (41%) male, and 1172 (67%) white. D-dimer test characteristics for PE were: sensitivity 98.0%, specificity 55.4%, negative predictive value (NPV) 99.8%, positive predictive value (PPV) 11.4%, and for DVT were: sensitivity 92.0%, specificity 44.8%, NPV 98.8%, PPV 10.3%. Age adjustment increased specificity (59.6% [PE], 51.1% [DVT]), but increasing the age-adjustment multiplier decreased sensitivity without increasing specificity. CONCLUSIONS: INNOVANCE D-dimer is highly sensitive and can exclude PE and DVT in ED patients with low- and intermediate- pre-test probability. Age-adjustment increases specificity, without increasing false negatives.


Assuntos
Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Tromboembolia Venosa/diagnóstico , Fatores Etários , Bioensaio , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Tromboembolia Venosa/patologia
5.
Am J Physiol Heart Circ Physiol ; 310(5): H559-71, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26747503

RESUMO

Fibroblast growth factor (FGF) signaling is cardioprotective in various models of myocardial infarction. FGF receptors (FGFRs) are expressed in multiple cell types in the adult heart, but the cell type-specific FGFR signaling that mediates different cardioprotective endpoints is not known. To determine the requirement for FGFR signaling in endothelium in cardiac ischemia-reperfusion injury, we conditionally inactivated the Fgfr1 and Fgfr2 genes in endothelial cells with Tie2-Cre (Tie2-Cre, Fgfr1(f/f), Fgfr2(f/f) DCKO mice). Tie2-Cre, Fgfr1(f/f), Fgfr2(f/f) DCKO mice had normal baseline cardiac morphometry, function, and vessel density. When subjected to closed-chest, regional cardiac ischemia-reperfusion injury, Tie2-Cre, Fgfr1(f/f), Fgfr2(f/f) DCKO mice showed a significantly increased hypokinetic area at 7 days, but not 1 day, after reperfusion. Tie2-Cre, Fgfr1(f/f), Fgfr2(f/f) DCKO mice also showed significantly worsened cardiac function compared with controls at 7 days but not 1 day after reperfusion. Pathophysiological analysis showed significantly decreased vessel density, increased endothelial cell apoptosis, and worsened tissue hypoxia in the peri-infarct area at 7 days following reperfusion. Notably, Tie2-Cre, Fgfr1(f/f), Fgfr2(f/f) DCKO mice showed no impairment in the cardiac hypertrophic response. These data demonstrate an essential role for FGFR1 and FGFR2 in endothelial cells for cardiac functional recovery and vascular remodeling following in vivo cardiac ischemia-reperfusion injury, without affecting the cardiac hypertrophic response. This study suggests the potential for therapeutic benefit from activation of endothelial FGFR pathways following ischemic injury to the heart.


Assuntos
Células Endoteliais/metabolismo , Infarto do Miocárdio/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Remodelação Vascular , Animais , Apoptose , Capilares/metabolismo , Capilares/patologia , Capilares/fisiopatologia , Cardiomegalia/genética , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Modelos Animais de Doenças , Células Endoteliais/patologia , Feminino , Masculino , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/metabolismo , Miocárdio/patologia , Neovascularização Fisiológica , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/deficiência , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/deficiência , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Recuperação de Função Fisiológica , Transdução de Sinais , Volume Sistólico , Fatores de Tempo , Função Ventricular Esquerda
6.
Respir Med ; 109(10): 1268-73, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26324315

RESUMO

BACKGROUND: Many patients with acute exacerbation of asthma are non-responders to inhaled ß-adrenergic agonists. The goal of this study was to evaluate the safety and efficacy of intravenous bedoradrine (MN-221), a highly selective ß2-adrenergic agonist, as adjunct to standard therapy in the management of patients with acute exacerbation of asthma who did not respond to standard therapy. METHODS: Patients (N = 167) received standard therapy and were randomized to either bedoradrine (1200 µg) or placebo. Safety and efficacy parameters were monitored hourly for 3 h, followed by a 24-h follow-up visit and an 8-day follow-up phone call. Change in %FEV1 from baseline to Hour 3 was the primary outcome. Secondary outcome measures included change in %FEV1 at 1 and 2 h, change in dyspnea score at 1, 2, and 3 h, treatment failure rate, defined as a combination of hospitalization on the index visit or return to the emergency department within 1 week, and safety monitoring. RESULTS: There was no significant difference in %FEV1 at 3 h between the 2 groups. The dyspnea scores were significantly improved for patients treated with bedoradrine compared to placebo (AUC0-2 hP < 0.005, AUC0-3 hP < 0.05). The safety profile for those treated with bedoradrine was consistent with the known mechanism of action of ß-adrenergic agonists, and included both cardiovascular and metabolic effects. CONCLUSIONS: Intravenous bedoradrine, in addition to standard therapy, did not significantly increase %FEV1 at 3 h, but it was associated with significantly improved dyspnea scores. TRIAL REGISTRATION: Clinicaltrials.gov; study name: MN-221-CL-007, registration number: NCT00838591; www.clinical trials.gov.


Assuntos
Acetamidas/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Asma/tratamento farmacológico , Naftalenos/administração & dosagem , Acetamidas/efeitos adversos , Doença Aguda , Administração por Inalação , Administração Intravenosa , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Adulto , Asma/etnologia , Broncodilatadores/administração & dosagem , Método Duplo-Cego , Dispneia/tratamento farmacológico , Feminino , Glucocorticoides/administração & dosagem , Humanos , Ipratrópio/administração & dosagem , Masculino , Pessoa de Meia-Idade , Naftalenos/efeitos adversos , Prednisona/administração & dosagem , Estudos Prospectivos , Espirometria , Resultado do Tratamento
7.
Physiol Rep ; 3(1)2015 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-25626875

RESUMO

Fibroblast growth factor 2 (FGF2) is cardioprotective in in vivo models of myocardial infarction; however, whether FGF2 has a protective role in in vivo ischemia-reperfusion (IR) injury, a model that more closely mimics acute myocardial infarction in humans, is not known. To assess the cardioprotective efficacy of endogenous FGF2, mice lacking a functional Fgf2 gene (Fgf2(-/-)) and wild-type controls were subjected to closed-chest regional cardiac IR injury (90 min ischemia, 7 days reperfusion). Fgf2(-/-) mice had significantly increased myocardial infarct size and significantly worsened cardiac function compared to wild-type controls at both 1 and 7 days post-IR injury. Pathophysiological analysis showed that at 1 day after IR injury Fgf2(-/-) mice have worsened cardiac strain patterns and increased myocardial cell death. Furthermore, at 7 days post-IR injury, Fgf2(-/-) mice showed a significantly reduced cardiac hypertrophic response, decreased cardiac vessel density, and increased vessel diameter in the peri-infarct area compared to wild-type controls. These data reveal both acute cardioprotective and a longer term proangiogenic potential of endogenous FGF2 in a clinically relevant, in vivo, closed-chest regional cardiac IR injury model that mimics acute myocardial infarction.

8.
Respir Med ; 108(9): 1284-91, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25087835

RESUMO

OBJECTIVES: (1) Compare ideal cut-off points for DS and %FEV1 at 1 and 3 h to predict hospitalization/relapse in subjects with moderate to severe asthma exacerbation (2) Develop a multivariate regression model using DS, %FEV1, demographic, and clinical variables to predict hospitalization/relapse. METHODS: Subjects with acute exacerbation of asthma (FEV1 <50% predicted following 30 min of standardized treatment: 5 mg nebulized albuterol; 0.5-1.5 mg nebulized ipratropium; and 50 mg oral prednisone) were eligible. All subjects had %FEV1 and DS obtained at baseline and hourly for 3 h. Using hospitalization/relapse as the outcome of interest; we compared the area under the receiveroperator curves (AUC) between the 1 and 3 h DS and %FEV1 measurements, and the AUC for the change in DS and %FEV1 between baseline and hour-3. We determined ideal cut-points for %FEV1 and DS to maximize sensitivity and specificity. Sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios (LR) were compared between %FEV1 and DS. We developed a multivariate regression model examining the association of specific demographic and clinical variables to hospitalization/relapse. RESULTS: 142 patients were included for analysis. The AUC was greatest for the 3-h DS (0.721), followed by the 3-h %FEV1 (0.669). Optimum cut-off values were a DS of 2, and an FEV1 of 42%. These were associated with a +LR for the composite outcome of 3.06 and 2.48 respectively. Logistic regression showed baseline DS, 3-h DS, change in DS, and oxygen use at hour 3 were all associated with the composite outcome. CONCLUSIONS: The 3-h score for %FEV1 and DS performed better than scores at any other time point and better than either parameter over time. The 3-h DS had the greatest association with the composite outcome. Neither test was a strong enough predictor to be used solely for this purpose.


Assuntos
Asma/diagnóstico , Dispneia/etiologia , Volume Expiratório Forçado/fisiologia , Hospitalização/estatística & dados numéricos , Doença Aguda , Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Adulto , Albuterol/uso terapêutico , Asma/complicações , Asma/tratamento farmacológico , Asma/fisiopatologia , Broncodilatadores/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Unidades de Terapia Intensiva/estatística & dados numéricos , Ipratrópio/uso terapêutico , Tempo de Internação/estatística & dados numéricos , Masculino , Valor Preditivo dos Testes , Prednisona/uso terapêutico , Prognóstico , Recidiva , Índice de Gravidade de Doença , Estados Unidos
10.
Chest ; 145(1): 53-59, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23949578

RESUMO

BACKGROUND: Controversy exists around the incidence and cause of hyperlactatemia during asthma exacerbations. We evaluated the incidence, potential causes, and adverse events of hyperlactatemia in patients with acute asthma exacerbation. METHODS: This study was a subanalysis of subjects receiving placebo from a prospective, randomized trial evaluating an IV b -adrenergic agonist in acute asthma exacerbation. Plasma albuterol, serum lactate, and bicarbonate concentrations were measured at baseline and 1.25 h, and dyspnea score and spirometry were measured at baseline and hourly for 3 h. All subjects had a therapeutic trial comprising 5 to 15 mg nebulized albuterol, 0.5 to 1 mg nebulized ipratropium, and at least 50 mg oral prednisone or its equivalent prior to initiation of the study. Following randomization, subjects were treated with continued albuterol and IV magnesium at the discretion of their treating physician. Subjects were followed to hospital admission or discharge with follow-up at 24 h and 1 week. RESULTS: One hundred seventy-fi ve subjects were enrolled in the parent trial, with 84 in the placebo group. Sixty-fi ve had complete data. Mean SD albuterol administration prior to baseline was 12.3 5.3 mg. Mean baseline lactate was 18.5 8.4 mg/dL vs 26.5 11.8 mg/dL at 1.25 h ( P , .001). Forty-fi ve subjects (69.2%) had hyperlactatemia. Mean baseline bicarbonate level was 22.6 2.9 mEq/L vs 21.9 4.0 mEq/L at 1.25 h ( P 5 .11). Plasma albuterol concentration correlated with lactate concentration ( b 5 0.45, P , .001) and maintained a significant association after adjusting for asthma severity ( b 5 0.41, P 5 .001). Hyperlactatemia did not increase the risk of hospitalization or relapse ( P 5 .26) or was associated with lower FEV 1 % predicted at 3 h ( P 5 .54). CONCLUSIONS: Plasma albuterol was significantly correlated with serum lactate concentration after adjusting for asthma severity. Hyperlactatemia was not associated with poorer pulmonary function as measured by 3-h FEV 1 % predicted or increased hospitalization or relapse at 1 week.


Assuntos
Albuterol/sangue , Asma/sangue , Broncodilatadores/sangue , Ácido Láctico/sangue , Adulto , Albuterol/uso terapêutico , Asma/tratamento farmacológico , Broncodilatadores/uso terapêutico , Progressão da Doença , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Volume Expiratório Forçado , Glucocorticoides/uso terapêutico , Hospitalização , Humanos , Ipratrópio/uso terapêutico , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prednisona/uso terapêutico , Espirometria
11.
PLoS One ; 8(12): e82979, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24349409

RESUMO

Fibroblast growth factors (FGFs) and their receptors are highly conserved signaling molecules that have been implicated in postnatal cardiac remodeling. However, it is not known whether cardiomyocyte-expressed FGF receptors are necessary or sufficient for ventricular remodeling in the adult heart. To determine whether cardiomyocytes were competent to respond to an activated FGF receptor, and to determine if this signal would result in the development of hypertrophy, we engineered a doxycycline (DOX)-inducible, cardiomyocyte-specific, constitutively active FGF receptor mouse model (αMHC-rtTA, TRE-caFgfr1-myc). Echocardiographic and hemodynamic analysis indicated that acute expression of caFGFR1 rapidly and directly increased cardiac contractility, while chronic expression resulted in significant hypertrophy with preservation of systolic function. Subsequent histologic analysis showed increased cardiomyocyte cross-sectional area and regions of myocyte disarray and fibrosis, classic features of hypertrophic cardiomyopathy (HCM). Analysis of downstream pathways revealed a lack of clear activation of classical FGF-mediated signaling pathways, but did demonstrate a reduction in Serca2 expression and troponin I phosphorylation. Isolated ventricular myocytes showed enhanced contractility and reduced relaxation, an effect that was partially reversed by inhibition of actin-myosin interactions. We conclude that adult cardiomyocytes are competent to transduce FGF signaling and that FGF signaling is sufficient to promote increased cardiomyocyte contractility in vitro and in vivo through enhanced intrinsic actin-myosin interactions. Long-term, FGFR overexpression results in HCM with a dynamic outflow tract obstruction, and may serve as a unique model of HCM.


Assuntos
Cardiomegalia/metabolismo , Cardiomegalia/fisiopatologia , Contração Miocárdica , Miócitos Cardíacos/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais , Animais , Cardiomegalia/diagnóstico por imagem , Cardiomegalia/genética , Cardiomegalia/patologia , Modelos Animais de Doenças , Ecocardiografia , Hemodinâmica/genética , Camundongos , Camundongos Transgênicos , Miócitos Cardíacos/patologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Remodelação Ventricular/genética
12.
Growth Factors ; 30(2): 124-39, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22304432

RESUMO

Fibroblast growth factor-2 (FGF2) protects the heart from ischemia-reperfusion (I-R) injury via a vast network of protein kinases. In the heart, downstream effectors of these FGF2-triggered signals have not yet been identified. It is hypothesized that nitric oxide (NO) signaling and ATP-sensitive potassium (K(ATP)) channel activity are key effectors of protein kinases activated by FGF2-mediated cardioprotection. Hearts with a cardiac-specific overexpression of FGF2 (FGF2 Tg) were subjected to I-R injury in the absence or the presence of selective inhibitors of NO synthase (NOS) isoforms or sarcolemmal (sarcK(ATP)) and mitochondrial (mitoK(ATP)) K(ATP) channels. Multiple NOS isoforms are necessary for FGF2-mediated cardioprotection, and nitrite levels are significantly reduced in FGF2 Tg hearts upon inhibition of protein kinase C or mitogen-activated protein kinases. Likewise, sarcK(ATP) and mitoK(ATP) channels are important for cardioprotection elicited by endogenous FGF2. These findings suggest that FGF2-induced cardioprotection occurs via protein kinase-NOS pathways as well as K(ATP) channel activity.


Assuntos
Fator 2 de Crescimento de Fibroblastos/metabolismo , Canais KATP/metabolismo , Infarto do Miocárdio/prevenção & controle , Óxido Nítrico/metabolismo , Proteínas Quinases/metabolismo , Transdução de Sinais , Regulação para Cima , Animais , Ativação Enzimática , Humanos , Camundongos , Infarto do Miocárdio/metabolismo , Óxido Nítrico Sintase/metabolismo , Canais de Potássio/metabolismo , Traumatismo por Reperfusão/metabolismo , Sarcolema/metabolismo
13.
Mol Cell Pharmacol ; 2(4): 143-154, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-21274419

RESUMO

Fibroblast growth factor 2 (basic FGF or FGF2) has been shown to affect growth and differentiation in some tissues and to be required for cardiac hypertrophy in vivo. FGF2 has been shown in vitro to signal through the mitogen-activated protein kinase (MAPK) to affect cell survival and growth. To ascertain the role of FGF2 in cardiac hypertrophy, wildtype, Fgf2 knockout, non-transgenic, and FGF2 transgenic mice were treated with isoproterenol or saline via subcutaneous mini-osmotic pump implants to induce a hypertrophic response to ß-adrenergic stimulation. Fgf2 knockout hearts are protected from isoproterenol-induced cardiac hypertrophy; whereas, FGF2 transgenic hearts show exacerbated cardiac hypertrophy as assessed by heart weight-to-body weight ratios and myocyte cross-sectional area. Echocardiography reveals significantly decreased fractional shortening in isoproterenol-treated FGF2 transgenic mice but not in Fgf2 knockout mice suggesting that FGF2 mediates the maladaptive cardiac dysfunction seen in cardiac hypertrophy induced by isoproterenol. Western blot analysis also reveals alterations in MAPK signaling in Fgf2 knockout and FGF2 transgenic hearts subjected to isoproterenol treatment, suggesting that this cascade mediates FGF2's pro-hypertrophic effect. Pharmacologic inhibition of extracellular signal-regulated kinase (ERK) signaling results in an attenuated hypertrophic response in isoproterenol-treated FGF2 transgenic mice, but this response is not seen with p38 mitogen-activated protein kinase (p38) pathway inhibition, suggesting that FGF2 activation of ERK but not p38 is necessary for FGF2's role in the mediation of cardiac hypertrophy.

14.
Am J Physiol Heart Circ Physiol ; 293(1): H354-65, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17337596

RESUMO

Elucidation of protective mechanisms against ischemia-reperfusion injury is vital to the advancement of therapeutics for ischemic heart disease. Our laboratory has previously shown that cardiac-specific overexpression of fibroblast growth factor-2 (FGF2) results in increased recovery of contractile function and decreased infarct size following ischemia-reperfusion injury and has established a role for the mitogen-activated protein kinase (MAPK) signaling cascade in the cardioprotective effect of FGF2. We now show an additional role for the protein kinase C (PKC) signaling cascade in the mediation of FGF2-induced cardioprotection. Overexpression of FGF2 (FGF2 Tg) in the heart resulted in decreased translocation of PKC-delta but had no effect on PKC-alpha, -epsilon, or -zeta. In addition, multiple alterations in PKC isoform translocation occur during ischemia-reperfusion injury in FGF2 Tg hearts as assessed by Western blot analysis and confocal immunofluorescent microscopy. Treatment of FGF2 Tg and nontransgenic (NTg) hearts with the PKC inhibitor bisindolylmaleimide (1 micromol/l) revealed the necessity of PKC signaling for FGF2-induced reduction of contractile dysfunction and myocardial infarct size following ischemia-reperfusion injury. Western blot analysis of FGF2 Tg and NTg hearts subjected to ischemia-reperfusion injury in the presence of a PKC pathway inhibitor (bisindolylmaleimide, 1 micromol/l), an mitogen/extracellular signal-regulated kinase/extracellular signal-regulated kinase (MEK/ERK) pathway inhibitor (U-0126, 2.5 micromol/l), or a p38 pathway inhibitor (SB-203580, 2 micromol/l) revealed a complicated signaling network between the PKC and MAPK signaling cascades that may participate in FGF2-induced cardioprotection. Together, these data suggest that FGF2-induced cardioprotection is mediated via a PKC-dependent pathway and that the PKC and MAPK signaling cascades are integrally connected downstream of FGF2.


Assuntos
Fator 2 de Crescimento de Fibroblastos/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Proteína Quinase C/metabolismo , Transdução de Sinais , Animais , Cardiotônicos/metabolismo , Citoproteção , Camundongos , Regulação para Cima
15.
Am J Physiol Heart Circ Physiol ; 289(5): H2167-75, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16040717

RESUMO

Our laboratory showed previously that cardiac-specific overexpression of FGF-2 [FGF-2 transgenic (Tg)] results in increased recovery of contractile function and decreased infarct size after ischemia-reperfusion injury. MAPK signaling is downstream of FGF-2 and has been implicated in other models of cardioprotection. Treatment of FGF-2 Tg and wild-type hearts with U-0126, a MEK-ERK pathway inhibitor, significantly reduced recovery of contractile function after global low-flow ischemia-reperfusion injury in FGF-2 Tg (86 +/- 2% vehicle vs. 66 +/- 4% U-0126; P < 0.05) but not wild-type (61 +/- 7% vehicle vs. 67 +/- 7% U-0126) hearts. Similarly, MEK-ERK inhibition significantly increased myocardial infarct size in FGF-2 Tg (12 +/- 3% vehicle vs. 31 +/- 2% U-0126; P < 0.05) but not wild-type (30 +/- 4% vehicle vs. 36 +/- 7% U-0126) hearts. In contrast, treatment of FGF-2 Tg and wild-type hearts with SB-203580, a p38 inhibitor, did not abrogate FGF-2-induced cardioprotection from postischemic contractile dysfunction. Instead, inhibition of p38 resulted in decreased infarct size in wild-type hearts (30 +/- 4% vehicle vs. 11 +/- 2% SB-203580; P < 0.05) but did not alter infarct size in FGF-2 Tg hearts (12 +/- 3% vehicle vs. 14 +/- 1% SB-203580). Western blot analysis of ERK and p38 activation revealed signaling alterations in FGF-2 Tg and wild-type hearts during early ischemia or reperfusion injury. In addition, MEK-independent ERK inhibition by p38 was observed during early ischemic injury. Together these data suggest that activation of ERK and inhibition of p38 by FGF-2 is cardioprotective during ischemia-reperfusion injury.


Assuntos
Fator 2 de Crescimento de Fibroblastos/fisiologia , Proteínas Quinases Ativadas por Mitógeno/fisiologia , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/metabolismo , Animais , Feminino , Fator 2 de Crescimento de Fibroblastos/biossíntese , Proteínas de Choque Térmico/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Contração Miocárdica/fisiologia , Infarto do Miocárdio/patologia , Miocárdio/patologia , Fosforilação , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
16.
Circulation ; 108(25): 3140-8, 2003 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-14656920

RESUMO

BACKGROUND: Preconditioning the heart before an ischemic insult has been shown to protect against contractile dysfunction, arrhythmias, and infarction. Pharmacological studies have suggested that fibroblast growth factor-2 (FGF2) is involved in cardioprotection. However, because of the number of FGFs expressed in the heart and the promiscuity of FGF ligand-receptor interactions, the specific role of FGF2 during ischemia-reperfusion injury remains unclear. METHODS AND RESULTS: FGF2-deficient (Fgf2 knockout) mice and mice with a cardiac-specific overexpression of all 4 isoforms of human FGF2 (FGF2 transgenic [Tg]) were compared with wild-type mice to test whether endogenous FGF2 elicits cardioprotection. An ex vivo work-performing heart model of ischemia was developed in which murine hearts were subjected to 60 minutes of low-flow ischemia and 120 minutes of reperfusion. Preischemic contractile function was similar among the 3 groups. After ischemia-reperfusion, contractile function of Fgf2 knockout hearts recovered to 27% of its baseline value compared with a 63% recovery in wild-type hearts (P<0.05). In FGF2 Tg hearts, an 88% recovery of postischemic function occurred (P<0.05). Myocardial infarct size was also reduced in FGF2 Tg hearts compared with wild-type hearts (13% versus 30%, P<0.05). There was a 2-fold increase in FGF2 release from Tg hearts compared with wild-type hearts (P<0.05). No significant alterations in coronary flow or capillary density were detected in any of the groups, implying that the protective effect of FGF2 is not mediated by coronary perfusion changes. CONCLUSIONS: These results provide evidence that endogenous FGF2 plays a significant role in the cardioprotective effect against ischemia-reperfusion injury.


Assuntos
Fator 2 de Crescimento de Fibroblastos/fisiologia , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/metabolismo , Animais , Circulação Coronária , Citoproteção , Feminino , Fator 2 de Crescimento de Fibroblastos/genética , Fator 2 de Crescimento de Fibroblastos/metabolismo , Coração/fisiopatologia , Humanos , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Contração Miocárdica , Traumatismo por Reperfusão Miocárdica/metabolismo
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