RESUMO
Caffeine is a regular part of the diet of many adults (coffee, tea, soft drinks, and energy drinks). Multiple molecular effects of caffeine suggest that it may promote bone loss. Given the extensive consumption of caffeine worldwide, any impact of caffeine consumption on bone strength and/or density would have large population health implications. The most well-established pharmacological effect of caffeine is non-specific antagonism of adenosine receptors. Adenosine regulates bone metabolism in a complex manner, with in vitro studies suggesting that direct stimulation of adenosine A2A and A2B receptors induces bone formation by activating osteoblasts and suppressing osteoclast differentiation and function. Thus, competitive inhibition of adenosine A2 receptors by caffeine may inhibit bone formation and promote bone resorption. However, antagonism of adenosine A1 receptors may have opposing effects. Caffeine has also been suggested to affect bone through derangement of calcium metabolism, alteration of vitamin D responses, and other mechanisms. In clinical and population-based studies, the impact of caffeine consumption on bone metabolism offers a mixed picture, with some but not all studies suggesting a potential link between caffeine intake and reduced bone mineral density or increased fracture risk. Differences in methodology, selected populations, and duration/timing of the studies may account for study outcome discrepancies. The in vitro effects of caffeine on cells involved in bone metabolism suggest that caffeine intake may promote osteoporosis, and some but not all clinical studies support a modest adverse caffeine impact. Herein, we describe the basic biology of caffeine as it pertains to bone, review the clinical literature to date, and consider the implications of the current data on clinical practice and future studies.
Assuntos
Fraturas Ósseas , Osteoporose , Adenosina , Adulto , Densidade Óssea , Cafeína/efeitos adversos , Café , Humanos , Osteoporose/epidemiologia , Osteoporose/etiologiaRESUMO
OBJECTIVE: Intra-articular (IA) injections of glucocorticoids (GCs) have been shown to decrease pain, increase mobility, and improve quality of life in patients with osteoarthritis (OA) of the knee. Concerns about cartilage loss with IA GCs have prompted reconsideration of their use in knee OA. This review has three objectives: 1) critically review the clinical, molecular, and structural effects of IA GCs in knee OA; 2) provide a design for a clinical trial aimed at improving our understanding of the long-term consequences of IA GCs; and 3) provide practical guidance on the use of IA GCs in patients with knee OA based on current information. DESIGN: A narrative review of current literature on the use of IA GCs for OA of the knee. RESULTS: Important questions remain to be fully answered with respect to IA GCs, including long-term effects on all aspects of the structural and molecular environment of the knee, and identification of factors that can reliably predict a positive or negative response to IA GCs. CONCLUSIONS: While awaiting results from an appropriately designed study, several provisional statements regarding IA GCs can be put forward: 1) IA GCs appear to be a relatively safe option that is effective in specific patients with symptomatic knee OA; 2) there is no definitive evidence that IA GCs accelerate joint deterioration to an important extent or hastens the requirement for knee replacement; and 3) there are few contraindications to IA GCs and injection-associated complications are rare when IA GCs are delivered with proper technique.
Assuntos
Glucocorticoides/administração & dosagem , Osteoartrite do Joelho/tratamento farmacológico , Artroplastia do Joelho , Humanos , Injeções Intra-Articulares , Osteoartrite do Joelho/patologia , Osteoartrite do Joelho/fisiopatologia , Resultado do TratamentoRESUMO
OBJECTIVE: In vitro and clinical studies suggest that urate may contribute to osteoarthritis (OA) risk. We tested the associations between hyperuricemia and knee OA, and examined the role of obesity, using a cross-sectional, nationally representative dataset. METHOD: National Health and Nutrition Examination Survey (NHANES) III used a multistage, stratified probability cluster design to select USA civilians from 1988 to 1994. Using NHANES III we studied adults >60 years, with or without hyperuricemia (serum urate > 6.8 mg/dL), excluding individuals with gout (i.e., limiting to asymptomatic hyperuricemia (AH)). Radiographic knee OA (RKOA) was defined as Kellgren-Lawrence grade ≥ 2 in any knee, and symptomatic radiographic knee osteoarthritis (RKOA) (sRKOA) was defined as RKOA plus knee pain (most days for 6 weeks) in the same knee. RESULTS: AH prevalence was 17.9% (confidence interval (CI) 15.3-20.5). RKOA prevalence was 37.7% overall (CI 35.0-40.3), and was 44.0% for AH vs 36.3% for normouricemic adults (p = 0.056). symptomatic radiographic knee osteoarthritis (sRKOA) was more prevalent in AH vs normouricemic adults (17.4% vs 10.9%, p = 0.046). In multivariate models adjusting for obesity, model-based associations between AH and knee OA were attenuated (for RKOA, prevalence ratio (PR) = 1.14, 95% CI 0.95, 1.36; for sRKOA, PR = 1.40, 95% CI 0.98, 2.01). In stratified multivariate analyses, AH was associated with sRKOA in adults without obesity (PR = 1.66, 95% CI 1.02, 2.71) but not adults with obesity (PR = 1.21, 95% CI 0.66, 2.23). CONCLUSIONS: Among adults aged 60 or older, AH is associated with knee OA risk that is more apparent in adults without obesity.
Assuntos
Hiperuricemia/complicações , Osteoartrite do Joelho/etiologia , Idoso , Idoso de 80 Anos ou mais , Doenças Assintomáticas , Estudos Transversais , Feminino , Humanos , Hiperuricemia/epidemiologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Obesidade/complicações , Osteoartrite do Joelho/epidemiologia , Prevalência , Fatores de Risco , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Gout patients do not routinely achieve optimal outcomes related in part to suboptimal administration of urate lowering therapy (ULT) including first-line xanthine oxidase inhibitors allopurinol or febuxostat. Studies leading to the approval of febuxostat compared this agent to allopurinol in inappropriately low, fixed doses. We will compare allopurinol with febuxostat in gout using appropriately titrated doses of both agents and a "treat-to-target" strategy congruent with specialty guidelines. METHODS: We have planned and initiated the Veterans Affairs (VA) Cooperative Study Program (CSP) 594, Comparative Effectiveness in Gout: Allopurinol vs Febuxostat study. This large double-blind, non-inferiority trial will enroll 950 gout patients randomized to receive allopurinol or febuxostat. Patients will be followed for a total of 72â¯weeks encompassing 3 distinct 24-week study phases. During Phase I (0-24â¯weeks), participants will undergo gradual dose titration of ULT until achievement of serum uric acid (sUA) <6.0â¯mg/dL or <5.0â¯mg/dL if tophi are present. Dose escalation will not be allowed during final three study visits of Phase 2 (24-48â¯weeks) and during Phase 3 (48-72â¯weeks). The primary study outcome is the proportion of participants experiencing at least one gout flare during Phase 3. Subsequent to the 72-week study, participants will be followed passively for up to 10â¯years after the study to assess long-term health outcomes. CONCLUSION: With its completion, the VA Comparative Effectiveness in Gout: Allopurinol vs Febuxostat study will demonstrate the central role of gradual ULT dose escalation and a treat-to-target strategy in gout management.
Assuntos
Alopurinol , Cálculos da Dosagem de Medicamento , Febuxostat , Gota , Saúde dos Veteranos , Adulto , Alopurinol/administração & dosagem , Alopurinol/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Monitoramento de Medicamentos/métodos , Febuxostat/administração & dosagem , Febuxostat/efeitos adversos , Gota/sangue , Gota/tratamento farmacológico , Supressores da Gota/administração & dosagem , Supressores da Gota/efeitos adversos , Humanos , Masculino , Conduta do Tratamento Medicamentoso/normas , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Resultado do Tratamento , Estados Unidos , United States Department of Veterans Affairs , Ácido Úrico/sangueAssuntos
Sulfatos de Condroitina/efeitos adversos , Suplementos Nutricionais/efeitos adversos , Glucosamina/efeitos adversos , Policondrite Recidivante/radioterapia , Idoso de 80 Anos ou mais , Anti-Inflamatórios/uso terapêutico , Pavilhão Auricular/patologia , Humanos , Masculino , Policondrite Recidivante/tratamento farmacológico , Policondrite Recidivante/patologia , Prednisolona/uso terapêuticoAssuntos
Anticorpos Anticitoplasma de Neutrófilos/imunologia , Antitireóideos/efeitos adversos , Autoimunidade/efeitos dos fármacos , Propiltiouracila/efeitos adversos , Vasculite/induzido quimicamente , Animais , Modelos Animais de Doenças , Doença de Graves/tratamento farmacológico , Doença de Graves/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Peroxidase/imunologia , Vasculite/imunologiaRESUMO
OBJECTIVE: Adenosine regulates inflammation and tissue repair, and adenosine A2A receptors promote wound healing by stimulating collagen matrix production. We therefore examined whether adenosine A2A receptors contribute to the pathogenesis of dermal fibrosis. METHODS: Collagen production by primary human dermal fibroblasts was analyzed by real-time polymerase chain reaction, 14C-proline incorporation, and Sircol assay. Intracellular signaling for dermal collagen production was investigated using inhibitors of MEK-1 and by demonstration of ERK phosphorylation. In vivo effects were studied in a bleomycin-induced dermal fibrosis model using adenosine A2A receptor-deficient wild-type littermate mice, C57BL/6 mice, and mice treated with adenosine A2A receptor antagonist. Morphometric features and levels of hydroxyproline were determined as measures of dermal fibrosis. RESULTS: Adenosine A2A receptor occupancy promoted collagen production by primary human dermal fibroblasts, which was blocked by adenosine A2A, but not A1 or A2B, receptor antagonism. Adenosine A2A receptor ligation stimulated ERK phosphorylation, and A2A receptor-mediated collagen production by dermal fibroblasts was blocked by MEK-1 inhibitors. Adenosine A2A receptor-deficient and A2A receptor antagonist-treated mice were protected from developing bleomycin-induced dermal fibrosis. CONCLUSION: These results demonstrate that adenosine A2A receptors play an active role in the pathogenesis of dermal fibrosis and suggest a novel therapeutic target in the treatment and prevention of dermal fibrosis in diseases such as scleroderma.
Assuntos
Derme/metabolismo , Fibroblastos/metabolismo , Fibrose/metabolismo , Receptor A2A de Adenosina/metabolismo , Esclerodermia Difusa/metabolismo , Animais , Células Cultivadas , Colágeno/genética , Colágeno/metabolismo , Derme/efeitos dos fármacos , Derme/patologia , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Fibrose/patologia , Fibrose/prevenção & controle , Expressão Gênica , Humanos , Hidroxiprolina/metabolismo , MAP Quinase Quinase 1/antagonistas & inibidores , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Mensageiro/metabolismo , Receptor A2A de Adenosina/deficiência , Receptor A2A de Adenosina/genética , Esclerodermia Difusa/induzido quimicamente , Esclerodermia Difusa/patologia , Esclerodermia Difusa/prevenção & controle , Triazinas/uso terapêutico , Triazóis/uso terapêuticoRESUMO
The neutrophil is a critical effector cell in humoral and innate immunity and plays vital roles in phagocytosis and bacterial killing. Discussed here are the neutrophil components necessary for these processes and the diseases in which these components are either lacking or dysfunctional, illustrating that normal neutrophil function is vital for health.
Assuntos
Imunidade , Neutrófilos/fisiologia , Animais , Adesão Celular , Grânulos Citoplasmáticos/fisiologia , Humanos , Inflamação/imunologia , Proteínas Quinases Ativadas por Mitógeno/fisiologia , NADPH Oxidases/fisiologia , Oxirredução , Fagocitose , Fosfatidilinositol 3-Quinases/fisiologiaRESUMO
Cellular adherens junctions are formed by cadherins linked to proteins of the catenin family. In endothelial cells, not only vascular endothelial cadherin but also platelet endothelial cell adhesion molecule-1 localizes into junctions and associates with beta-catenin. To explore a putative cooperation of platelet endothelial cell adhesion molecule-1 and vascular endothelial cadherin, we analyzed transfectants expressing either platelet endothelial cell adhesion (CD31 cells) or vascular endothelial cadherin (CD144 cells) or both molecules (CD31/CD144 cells), and, for comparison, human umbilical vein endothelial cells. Basic fibroblast growth factor completely dissociated vascular endothelial cadherin/beta-catenin complexes and robustly moved beta-catenin into the nucleus in CD144 cells, whereas in CD31/CD144 cells as well as in human umbilical vein endothelial cells, fibroblast growth factor only partially dissociated the junctional complex followed by a significantly reduced nuclear translocation of beta-catenin. In contrast, in CD31 cells, the subcellular distribution of beta-catenin remained unaffected by fibroblast growth factor. As a functional consequence, fibroblast growth factor induced a complete collapse of the F-actin network in CD144 cells, a limited rearrangement of F-actin fibers in CD31/CD144 cells and no F-actin rearrangement in CD31 cells. We also analyzed the effect of fibroblast growth factor-induced rearrangement of junctions on junction permeability for leukocytes: in line with our observation that vascular endothelial cadherin was required for cells to respond to fibroblast growth factor, only in CD31/CD144 cells, but not in CD31 cells, leukocyte transmigration was significantly enhanced by fibroblast growth factor. In conclusion platelet endothelial cell adhesion molecule-1 cooperates with vascular endothelial cadherin in a mutual fashion; platelet endothelial cell adhesion molecule-1 reduces and temporarily limits fibroblast growth factor-induced dissociation of vascular endothelial cadherin/beta-catenin complexes, but requires vascular endothelial cadherin to control leukocyte transmigration in dependence of fibroblast growth factor.
Assuntos
Junções Aderentes/efeitos dos fármacos , Junções Aderentes/fisiologia , Plaquetas/química , Caderinas/farmacologia , Moléculas de Adesão Celular/sangue , Moléculas de Adesão Celular/farmacologia , Transativadores , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/farmacologia , Endotélio Vascular/química , Fatores de Crescimento de Fibroblastos/farmacologia , Translocação Genética/efeitos dos fármacos , beta CateninaRESUMO
Fumaric acid esters are thought to improve psoriasis by altering leukocyte, keratinocyte, and/or endothelial functions. To determine specificity, kinetics, and molecular mechanisms of different fumaric acid esters in their ability to inhibit endothelial cell activation, we analyzed CD62E and CD54 expression in endothelial cells in vivo and in vitro. In lesional skin of psoriatic patients, oral fumaric acid ester treatment resulted in a marked reduction of CD62E but not CD54 expression on dermal microvessels. Using human umbilical vein endothelial cells, dimethylfumarate almost completely inhibited tumor-necrosis-factor-induced CD62E, but not CD54 expression at concentrations < or = 70 microM, mimicking the situation in vivo. A 60 min dimethylfumarate preincubation was sufficient to block tumor-necrosis-factor-induced CD62E expression for up to 24 h. In contrast, equimolar concentrations of methylhydrogenfumarate, the hydrolysis product of dimethylfumarate, did not suppress tumor-necrosis-factor-induced CD62E expression. Likewise, all fumaric acid esters other than dimethylfumarate were ineffective. Using CD62E, NF-kappa B, or AP-1-responsive promoter constructs, dimethylfumarate inhibited tumor-necrosis-factor-induced activation of the CD62E and the NF-kappa B but not the AP-1 promoter construct. In summary, at a dose range < or = 70 microM, dimethylfumarate appeared to be a specific inhibitor of CD62E expression in an NF-kappa B-dependent manner.
Assuntos
Fármacos Dermatológicos/farmacologia , Selectina E/genética , Fumaratos/farmacologia , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Capilares/química , Capilares/efeitos dos fármacos , Capilares/fisiologia , Células Cultivadas , Fumarato de Dimetilo , Selectina E/análise , Endotélio Vascular/química , Endotélio Vascular/citologia , Endotélio Vascular/fisiologia , Expressão Gênica/efeitos dos fármacos , Humanos , Molécula 1 de Adesão Intercelular/análise , Molécula 1 de Adesão Intercelular/genética , Psoríase/tratamento farmacológico , Psoríase/fisiopatologia , RNA Mensageiro/análise , Pele/irrigação sanguínea , Veias Umbilicais/citologiaRESUMO
GM-CSF has a major role in the immune and inflammatory milieu of the airway. Airway epithelial cells (AEC) are among the first targets of environmental stimuli and local cytokines, in response to which they can produce GM-CSF. The regulation of GM-CSF is only minimally understood in AEC. We hypothesized that GM-CSF expression in AEC would result from activation of protein kinase C (PKC) and subsequent activation of the extracellular signal-regulated kinase (MAPKerk1/2) pathway, so we investigated signal transduction pathways in human primary culture bronchial epithelial cells (HBECs). TNF-alpha, IL-1beta, and PMA induced the release of GM-CSF in HBECs. The robust response to PMA was not detected in SV40 adenovirus-transformed normal human bronchial epithelial cells (BEAS-2B). PMA and TNF-alpha stimulation of GM-CSF required activation of PKC (inhibition by staurosporine and bisindolylmaleimide I). GM-CSF expression was up-regulated by a nonphorbol PKC activator, but not by an inactive PMA analogue. PMA-induced GM-CSF production in HBECs did not require a Ca2+ ionophore and was not inhibited by cyclosporin A. Activation of MAPKerk1/2 via PKC was associated with and was required for GM-CSF production induced by PMA and TNF-alpha. The data demonstrate regulation of GM-CSF in HBECs by PKC pathways converging on the MAPKerk1/2 pathway and further define cell-specific regulation critical for local airway responses.
Assuntos
Brônquios/metabolismo , Células Epiteliais/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/biossíntese , Proteínas Quinases Ativadas por Mitógeno/fisiologia , Proteína Quinase C/fisiologia , Brônquios/efeitos dos fármacos , Brônquios/enzimologia , Brônquios/imunologia , Cálcio/fisiologia , Células Cultivadas , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/imunologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/enzimologia , Células Epiteliais/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Humanos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/fisiologia , Proteína Quinase 3 Ativada por Mitógeno , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteína Quinase C/metabolismo , RNA Mensageiro/biossíntese , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Acetato de Tetradecanoilforbol/farmacologia , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
Recent studies have suggested that aspirin and aspirin-like compounds have a variety of actions in addition to their well-studied ability to inhibit cyclooxygenases. These actions include inhibition of the uncoupling of oxidative phosphorylation, decreases in adenosine triphosphate stores. increases in extracellular adenosine, downregulation of the expression and activity of inducible nitric oxide synthetase, inhibition and/or stimulation of various mitogen-activated protein kinase activities and inhibition of nuclear factor binding kappaB site (NF-kappaB) activation. Moreover, aspirin-like compounds have recently been shown to have previously unappreciated clinical and biological effects, some apparently independent of cyclooxygenase. In this review we discuss the various mechanisms of action of aspirin-like compounds and their relevance to clinical disease and therapy.
Assuntos
Aspirina/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Fibrinolíticos/farmacologia , Humanos , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase Tipo IIRESUMO
CONTEXT: The use of propylthiouracil (PTU) in patients with Graves' disease has been associated with multiple complications including rash, leukocytoclastic vasculitis, pulmonary hemorrhage, glomerulonephritis, and the presence of perinuclear antineutrophilic cytoplasmic antibodies (pANCA). OBJECTIVES: To report the association of Wegener's granulomatosis (WG) with the use of PTU in a patient with Graves' disease and to review the spectrum of systemic vasculitis seen in patients with Graves' disease taking PTU. DESIGN: Retrospective review of data collected in a patient with WG. In addition, a Medline search (1980 to present) for PTU-associated vasculitis was conducted. RESULTS: We report WG in a patient treated with PTU who fulfilled the criteria of the American College of Rheumatology for this disease. Furthermore, his serum was positive for cytosolic antineutrophil cytoplasmic antibodies (cANCA) and anti-proteinase-3 (PR3) antibodies by indirect immunofluorescence and enzyme linked immunosorbent assay (ELISA), respectively. WG is associated with high morbidity and mortality and usually requires extensive therapy with prednisone and cyclophosphamide. Our patient, however, did not need specific therapy except discontinuation of PTU to make a full recovery. In previous reports, PTU has been associated with different forms of vasculitis, but this is a the first description of classic WG in a patient treated with PTU. CONCLUSIONS: PTU is capable of causing WG in susceptible patients with Graves' disease. Our patient did not require specific therapy for vasculitis and improved after discontinuation of PTU.
Assuntos
Antitireóideos/efeitos adversos , Granulomatose com Poliangiite/induzido quimicamente , Doença de Graves/tratamento farmacológico , Propiltiouracila/efeitos adversos , Anticorpos Anticitoplasma de Neutrófilos/sangue , Granulomatose com Poliangiite/imunologia , Doença de Graves/imunologia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
The anti-inflammatory effects of high-dose salicylates are well recognized, incompletely understood and unlikely due entirely to cyclooxygenase (COX) inhibition. We have previously reported a role for activation of the kinase Erk in CD11b/CD18 integrin-dependent adhesiveness of human neutrophils, a critical step in inflammation. We now report the effects of salicylates on neutrophil Erk and adhesion. Exposure of neutrophils to aspirin or sodium salicylate (poor COX inhibitor) inhibited Erk activity and adhesiveness of formylmethionyl-leucyl-phenylalanine- and arachidonic acid-stimulated neutrophils, consistent with anti-inflammation but not COX inhibition (IC50s = 1-8 mM). In contrast, indomethacin blocked neither Erk nor adhesion. Inhibition of Mek (proximal activator of Erk) also blocked stimulation of Erk and adhesion by formylmethionyl-leucyl-phenylalanineand arachidonic acid. Salicylate inhibition of Erk was independent of protein kinase A activation and generation of extracellular adenosine. These data are consistent with a role for Erk in stimulated neutrophil adhesion, and suggest that anti-inflammatory effects of salicylates may be mediated via inhibition of Erk signaling required for integrin-mediated responses.
Assuntos
Aspirina/análogos & derivados , Aspirina/farmacologia , Proteínas Quinases Dependentes de Cálcio-Calmodulina/sangue , Proteínas Quinases Ativadas por Mitógeno , Neutrófilos/fisiologia , Salicilato de Sódio/farmacologia , Acetaminofen/farmacologia , Antígenos CD/fisiologia , Ácido Araquidônico/farmacologia , Antígenos CD18/fisiologia , Adesão Celular/efeitos dos fármacos , Adesão Celular/fisiologia , Agregação Celular/efeitos dos fármacos , Agregação Celular/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase/farmacologia , Humanos , Técnicas In Vitro , Antígeno de Macrófago 1/fisiologia , Proteína Quinase 1 Ativada por Mitógeno , Proteína Quinase 3 Ativada por Mitógeno , N-Formilmetionina Leucil-Fenilalanina/farmacologia , Neutrófilos/citologia , Neutrófilos/efeitos dos fármacos , Acetato de Tetradecanoilforbol/farmacologiaRESUMO
AA stimulates integrin-dependent neutrophil adhesion, a critical early step in acute inflammation. However, neither the signaling pathway(s) of AA-stimulated adhesion, nor whether AA acts directly or through the generation of active metabolites, has been elucidated. Previously, we have observed a tight association between neutrophil Erk activation and homotypic adhesion in response to chemoattractants acting through G protein-linked receptors. We now report a similar association between homotypic adhesion and Erk activation in response to AA. Erk activation was cyclooxygenase independent and required AA metabolism to 5(S)- hydroperoxyeicosatetraenoic acid (5-HpETE) via 5-lipoxygenase, but not the further lipoxygenase-dependent metabolism of 5-HpETE to leukotrienes. AA stimulation of Erk was accompanied by Raf-1 activation and was sensitive to inhibitors of Raf-1 and Mek. Whereas activation of Erk by AA was pertussis toxin sensitive, [3H]-AA binding to neutrophils was not saturable, suggesting that an AA metabolite activates a G protein. Consistent with this hypothesis, Erk activation by 5(S)-hydroxyeicosatetraenoic acid (5-HETE; lipoxygenase-independent metabolite of 5-HpETE) was also pertussis toxin sensitive. These data suggest that a 5-lipoxygenase metabolite of AA, e.g., 5-HETE, is released from AA-treated cells to engage a plasma membrane-associated, pertussis toxin-sensitive, G protein-linked receptor, leading to activation of Erk and adhesion via the Raf-1/Mek signal transduction pathway.
Assuntos
Araquidonato 5-Lipoxigenase/fisiologia , Ácido Araquidônico/farmacologia , Integrinas/fisiologia , MAP Quinase Quinase Quinase 1 , Proteínas Quinases Ativadas por Mitógeno/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Neutrófilos/fisiologia , Proteínas Serina-Treonina Quinases/fisiologia , Proteínas Proto-Oncogênicas c-raf/fisiologia , Adesão Celular , Agregação Celular/efeitos dos fármacos , AMP Cíclico/fisiologia , Ativação Enzimática , Humanos , Ácidos Hidroxieicosatetraenoicos/farmacologia , Proteína Básica da Mielina/metabolismo , Toxina Pertussis , Fosforilação , Fatores de Virulência de Bordetella/farmacologiaRESUMO
OBJECTIVE: To assess the incidence of Reiter's syndrome aboard The Golden Venture, a ship carrying illegal immigrants from China to the United States. METHODS: After identification of an index case, we conducted telephone interviews with medical staff at immigrant detention centers in Pennsylvania, New York, and Virginia. When a potential case was identified at one facility, we performed a site inspection, reviewing the medical records of all detainees and performing histories and physicals on all those with joint and/or ocular complaints. RESULTS: We identified two patients, both HLA B27 positive, with Reiter's syndrome. The observed incidence (0.87%) approximated the predicted incidence but may have underestimated the actual incidence. We review the history of shipboard Reiter's syndrome, and discuss the pathogenic roles of HLA B27 and particular infectious agents. CONCLUSION: Continued transportation of illegal immigrants from China and other parts of the world is likely to result in occasional clusters of Reiter's syndrome. Physicians treating immigrant populations should remain aware of the possibility of reactive arthritis.
Assuntos
Artrite Reativa/epidemiologia , Surtos de Doenças , Emigração e Imigração , Adulto , Artrite Reativa/sangue , Artrite Reativa/patologia , Crime , Antígeno HLA-B27/sangue , Humanos , Incidência , Masculino , Navios , Síndrome , Membrana Sinovial/patologia , Estados Unidos/epidemiologiaRESUMO
We examined the role of phosphatidylinositol 3-kinase (PI 3-K) in FMLP-stimulated cell-cell adhesion of human neutrophils. The specific PI 3-K inhibitors wortmannin and LY294002 inhibited neutrophil homotypic aggregation stimulated by chemoattractants such as FMLP (50% inhibitory concentration (IC50) approximately 11 nM and 13 microM, respectively) but not PMA. Wortmannin also inhibited FMLP-stimulated adhesion of neutrophils to human endothelial cell monolayers, suggesting a common signaling pathway for homotypic and heterotypic adhesion. Neither CD11b/CD18 expression nor expression of an activation-specific epitope of CD11b/CD18 was affected by wortmannin in FMLP-stimulated cells. Moreover, wortmannin also inhibited the aggregation of egranulate neutrophil cytoplasts that lack the capacity for CD11b/CD18 up-regulation. Although wortmannin inhibited neutrophil lysosomal enzyme release, it had no effect on FMLP-stimulated up-regulation of CD35 in intact neutrophils, suggesting discrepant signaling pathways for specific granule degranulation and secretory vesicle release. Aggregation of human neutrophils is associated with activation of the mitogen-activated protein kinases Erk1 and -2, and Erk is activated in response to PI 3-K in some cell types. However, wortmannin inhibited FMLP stimulation of neutrophil Erk only at concentrations (IC50 > or = 1 microM) inconsistent with an effect on PI 3-K. Our data indicate that PI 3-K mediates neutrophil adhesion by a mechanism independent of CD11b/CD18 up-regulation, suggesting that PI 3-K acts either parallel to, or downstream of, Erk.