RESUMEN
OBJECTIVE: Sternoclavicular joint (SCJ) infections are rarely encountered and their management is not well standardised. We reviewed our experience with the management of this condition in order to evaluate the role of surgery in the management of the SCJ infection and to provide an algorithm for its treatment. METHODS: It is a multicentre study in which we retrospectively reviewed the data files of the patients who were referred to us for surgical management of SCI infection. RESULTS: From March 2003 to June 2009, 14 patients (12 men and two women) were treated surgically for infected SCJ. No patients were found in the paediatric age group. Mean age was 49.8 years with a range between 26 and 77 years. All patients were symptomatic. The prevalent symptom was either anterior chest wall swelling (21%) or pain (29%); while 50% of them presented with both swelling and pain. Associated risk factors were elicited in 12 patients (86%) while it could not be identified in two patients (14%). These risk factors were in the form of drug addiction in three patients, diabetes mellitus (DM) in four, chronic renal failure (CRF) in three patients and two patients had both DM and CRF. Surgical management was performed in all patients in the form of either incision and drainage in two patients (14%); or SCJ curettage in three patients (21%), while resection of the SCJ was done in nine patients (62%). Mean postoperative hospital stay period (PHS) was 8.1 days (range: 5-30 days). All of them are alive and free of symptoms in follow-up. CONCLUSION: Surgery was found to be curative with good results for those patients with SCJ infection that did not respond to a full course of intravenous antibiotic therapy. Surgical options include incision and drainage, curettage or SCJ resection. The type of surgical procedure depends on the radiological findings, presentation, severity of the infection and intra-operative findings. In our experience, complex muscle flap reconstruction was not necessary following SCJ resection.
Asunto(s)
Artropatías/cirugía , Osteomielitis/cirugía , Articulación Esternoclavicular/cirugía , Adulto , Anciano , Algoritmos , Desbridamiento/métodos , Drenaje/métodos , Farmacorresistencia Bacteriana , Femenino , Humanos , Artropatías/diagnóstico , Artropatías/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Osteomielitis/diagnóstico , Osteomielitis/tratamiento farmacológico , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Infecciones Estafilocócicas/diagnóstico , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/cirugía , Articulación Esternoclavicular/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
This study sought to assess putative pathways involved in the anti-inflammatory effects of 17,18-epoxyeicosatetraenoic acid (17,18-EpETE), as measured by a decrease in the contractile reactivity and Ca(2+) sensitivity of TNF-α-pretreated human bronchi. Tension measurements performed in the presence of 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), a soluble epoxide hydrolase (sEH)-specific inhibitor, demonstrated that 17,18-EpETE reduced the reactivity of TNF-α-pretreated tissues. The overexpression of sEH detected in patients with asthma and TNF-α-treated bronchi contributed to the maintenance of hyperresponsiveness in our models, which involved intracellular proinflammatory cascades. The inhibition of peroxisome proliferator-activated receptor (PPAR)γ by GW9662 abolished 17,18-EpETE + AUDA-mediated anti-inflammatory effects by inducing IκBα degradation and cytokine synthesis, indicating that PPARγ is a molecular target of epoxy-eicosanoids. Western blot analysis revealed that 17,18-EpETE pretreatment reversed the phosphorylation of p38 mitogen-activated protein kinase (p38-MAPK) induced by TNF-α in human bronchi. The Ca(2+) sensitivity of human bronchial explants was also quantified on ß-escin permeabilized preparations. The presence of SB203580, a p38-MAPK inhibitor, reversed the effect induced by epoxy-eicosanoid in the presence of AUDA on TNF-α-triggered Ca(2+) hypersensitivity by increasing the phosphorylation level of PKC Potentiated Inhibitor Protein-17 (CPI-17) regulatory protein. Moreover, PPARγ ligands, such as rosiglitazone and 17,18-EpETE, decreased the expression of CPI-17, both at the mRNA and protein levels, whereas this effect was countered by GW9662 treatment in TNF-α-treated bronchi. These results demonstrate that 17,18-EpETE is a potent regulator of human lung inflammation and concomitant hyperresponsiveness, and may represent a valuable asset against critical inflammatory bronchial disorder.
Asunto(s)
Antiinflamatorios/farmacología , Ácidos Araquidónicos/farmacología , Epóxido Hidrolasas/metabolismo , Pulmón/patología , PPAR gamma/metabolismo , Neumonía/enzimología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Ácido 8,11,14-Eicosatrienoico/farmacología , Ácidos Araquidónicos/antagonistas & inhibidores , Bronquios/efectos de los fármacos , Bronquios/enzimología , Bronquios/patología , Calcio/farmacología , Ciclooxigenasa 2/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular , Pulmón/efectos de los fármacos , Pulmón/enzimología , Modelos Biológicos , Proteínas Musculares , Fosfatasa de Miosina de Cadena Ligera/metabolismo , PPAR gamma/antagonistas & inhibidores , Fosfoproteínas Fosfatasas/metabolismo , Fosforilación/efectos de los fármacos , Neumonía/patología , Inhibidores de Proteínas Quinasas/farmacología , Solubilidad/efectos de los fármacos , Factor de Necrosis Tumoral alfa/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidoresAsunto(s)
Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Enfisema Pulmonar/patología , Enfisema Pulmonar/cirugía , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Humanos , Hallazgos Incidentales , Neoplasias Pulmonares/cirugía , Masculino , Persona de Mediana Edad , NeumonectomíaRESUMEN
Human cytochrome P-450 epoxygenase enzymes metabolize eicosapentaenoic acid (EPA), an omega-3-polyunsaturated fatty acid (PUFA), and leads to the production of 17(18)-epoxyeicosatetraenoic acid, or 17(18)-EpETE. The aim of the present study was to delineate the mode of action of 17(18)-EpETE on human pulmonary artery (HPA) and distal bronchi. Isometric tension measurements demonstrated that 17(18)-EpETE induced concentration-dependent relaxing effects in pulmonary artery and airway smooth muscles. Iberiotoxin (IbTx) and glyburide (Glyb), known BK(Ca) and K(ATP) channel inhibitors, respectively, reversed the relaxation induced by 17(18)-EpETE on both tissues types. Microelectrode measurements showed that exogenous addition of 17(18)-EpETE hyperpolarized the membrane potential of HPA and bronchial smooth muscle cells. These induced electrophysiological effects were reversed by the addition of 10 nM IbTx and 10 muM Glyb. Complementary experiments performed on human bronchi, using the planar lipid bilayer reconstitution technique, demonstrated that 17(18)-EpETE activated reconstituted BK(Ca) channels at low free Ca(2+) concentration. Moreover, in bronchi, the relaxing responses induced by 17(18)-EpETE were also related to reduced Ca(2+) sensitivity of the myofilaments, since free Ca(2+) concentration-response curves, performed on beta-escin-permeabilized cultured explants, were shifted toward higher Ca(2+). Together, these results provide new insight into the mode of action of 17(18)-EpETE in lung tissues and highlight this eicosanoid as a potent modulator of tone on both HPA and distal bronchi in vitro, which may be of clinical relevance in the pathophysiology of pulmonary hypertension and airway diseases.
Asunto(s)
Ácidos Araquidónicos/farmacología , Músculo Liso Vascular/fisiología , Arteria Pulmonar/fisiología , Vasodilatación/fisiología , Amidas/farmacología , Bronquios/efectos de los fármacos , Bronquios/fisiología , Calcio/metabolismo , Gliburida/farmacología , Humanos , Hipoglucemiantes/farmacología , Contracción Isométrica/efectos de los fármacos , Contracción Isométrica/fisiología , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Músculo Liso Vascular/efectos de los fármacos , Técnicas de Cultivo de Órganos , Péptidos/farmacología , Canales de Potasio/fisiología , Arteria Pulmonar/efectos de los fármacos , Factor de Necrosis Tumoral alfa/farmacología , Vasodilatación/efectos de los fármacosRESUMEN
Under pathophysiologic conditions, the modulation of Ca2+ sensitivity and reactivity of bronchial smooth muscle is controlled by protein kinase C-dependent phosphorylation of the newly described protein, CPI-17. The goal of the present study was to assess the key role of this regulatory protein in airway hyperresponsiveness (AHR) using control and TNF-alpha-treated human bronchi as well as a specific siRNA duplex against human CPI-17 transcripts. Validity of a mixed transfection strategy was assessed using the reversible permeabilization method to introduce X-TremeGene (X-TG)-siRNA complexes in an overreactive model of human bronchi treated with TNF. Data demonstrate that X-TG-siRNA complexes targeted against CPI-17 transcripts resulted in a reduction in mRNA and specific protein expression in human bronchial tissues. This approach revealed that overall reactivity of bronchial smooth muscle to methacholine was reduced, while their relaxing responses to beta2-agonist were increased, when compared with responses triggered in control TNF-alpha-treated bronchi. Quantification analysis showed that Ca2+ -sensitivity in both untreated and TNF-alpha-treated bronchi were largely reduced upon transfection with human CPI-17 siRNA-X-TremeGene complexes, while Western blot analysis corroborated the decrease in CPI-17 and MLC phosphorylation levels in pretreated human bronchi. Identical results were obtained upon treatment with an antiinflammatory eicosanoid, 14,15-EET, known to inhibit CPI-17 phosphorylation. Together these results are consistent with a key molecular role for CPI-17 in AHR, in the absence of bronchial wall remodeling.
Asunto(s)
Bronquios/efectos de los fármacos , Bronquios/enzimología , Silenciador del Gen/efectos de los fármacos , Fosfoproteínas Fosfatasas/deficiencia , Hipersensibilidad Respiratoria/enzimología , Factor de Necrosis Tumoral alfa/farmacología , Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Ácido 8,11,14-Eicosatrienoico/farmacología , Bronquios/patología , Calcio/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular , Proteínas Musculares , Fosfatasa de Miosina de Cadena Ligera/metabolismo , Permeabilidad/efectos de los fármacos , Fosfoproteínas Fosfatasas/metabolismo , Fosforilación/efectos de los fármacos , ARN Interferente Pequeño/metabolismoRESUMEN
The aim of the present study was to provide a mechanistic insight into how 20-hydroxyeicosatetraenoic acid (20-HETE) relaxes distal human pulmonary arteries (HPAs). This compound is produced by omega-hydroxylase from free arachidonic acid. Tension measurements, performed on either fresh or 1 day-cultured pulmonary arteries, revealed that the contractile responses to 1 microM 5-hydroxytryptamine were largely relaxed by 20-HETE in a concentration-dependent manner (0.01-10 microM). Iberiotoxin pretreatments (10 nM) partially decreased 20-HETE-induced relaxations. However, 10 microM indomethacin and 3 microM SC-560 pretreatments significantly reduced the relaxations to 20-HETE in these tissues. The relaxing responses induced by the eicosanoid were likely related to a reduced Ca2+ sensitivity of the myofilaments since free Ca2+ concentration ([Ca2+])-response curves performed on beta-escin-permeabilized cultured explants were shifted toward higher [Ca2+]. 20-HETE also abolished the tonic responses induced by phorbol-ester-dibutyrate (a PKC-sensitizing agent). Western blot analyses, using two specific primary antibodies against the PKC-potentiated inhibitory protein CPI-17 and its PKC-dependent phosphorylated isoform pCPI-17, confirmed that 20-HETE interferes with this intracellular process. We also investigated the effect of 20-HETE on the activation of Rho-kinase pathway-induced Ca2+ sensitivity. The data demonstrated that 20-HETE decreased U-46619-induced Ca2+ sensitivity on arteries. Hence, this observation was correlated with an increased staining of p116(Rip), a RhoA-binding protein. Together, these results strongly suggest that the 20-hydroxyarachidonic acid derivative is a potent modulator of tone in HPAs in vitro.
Asunto(s)
Citocromo P-450 CYP4A/metabolismo , Arteria Pulmonar/enzimología , Proteínas Adaptadoras Transductoras de Señales/biosíntesis , Proteínas Adaptadoras Transductoras de Señales/genética , Western Blotting , Inhibidores de la Ciclooxigenasa/farmacología , Electroforesis en Gel de Poliacrilamida , Endotelio Vascular/fisiología , Escina/metabolismo , Humanos , Ácidos Hidroxieicosatetraenoicos/metabolismo , Técnicas In Vitro , Péptidos y Proteínas de Señalización Intracelular , Contracción Isométrica/fisiología , Proteínas Musculares , Relajación Muscular/efectos de los fármacos , Músculo Liso Vascular/fisiología , Péptidos/farmacología , Fosfoproteínas Fosfatasas/metabolismo , Canales de Potasio Calcio-Activados/metabolismo , Proteína Quinasa C/metabolismo , Resistencia Vascular/fisiologíaRESUMEN
The aim of the present study was to investigate the anti-inflammatory effects of 14,15-epoxyeicosatrienoic acid (EET) on reactivity and Ca(2+) sensitivity in TNF-alpha-stimulated human bronchi. Tension measurements performed on either control, TNF-alpha-, or TNF-alpha + EET-pretreated bronchi revealed that 100 nM 14,15-EET pretreatments significantly reduced the reactivity of TNF-alpha-pretreated tissues to contractile agonists. EET also normalized the relaxing response to isoproterenol in TNF-alpha-treated bronchi. Pretreatment with 100 nM 14,15-EET prevented TNF-alpha-induced IkappaBalpha degradation, as demonstrated by an increase in IkappaBalpha protein levels on Western blot analysis. The anti-inflammatory properties of EET were mediated by the inhibition of IkappaBalpha degradation, suggesting a lower activation of NF-kappaB. The Ca(2+) sensitivity of TNF-alpha-stimulated bronchi was also evaluated on beta-escin-permeabilized preparations. Observed mean responses demonstrated that EET pretreatments abolished Ca(2+) hypersensitivity developed by TNF-alpha-stimulated bronchial explants. Moreover, 14,15-EET significantly reduced PDBu-induced Ca(2+) sensitivity in TNF-alpha-stimulated bronchi. Western blot and RT-PCR analyses revealed that CPI-17 protein and transcript levels were increased in TNF-alpha-treated bronchi, as opposed to being decreased in the presence of 14,15-EET. This eicosanoid also reduced U-46619-induced Ca(2+) sensitivity, which is related to the activation of Rho-kinase pathway. These results were also correlated with an increase in protein staining and transcription level of p116(Rip), a RhoA inhibitory-binding protein. Altogether, these data demonstrate that 14,15-EET is a potent modulator of the hyperreactivity triggered by TNF-alpha in human airway smooth muscle cells.
Asunto(s)
Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Antiinflamatorios/farmacología , Bronquios/efectos de los fármacos , Factor de Necrosis Tumoral alfa/farmacología , Ácido 8,11,14-Eicosatrienoico/farmacología , Secuencia de Bases , Western Blotting , Calcio/metabolismo , Cartilla de ADN , Electroforesis en Gel de Poliacrilamida , Humanos , Hidrólisis , Técnicas In Vitro , FN-kappa B/metabolismo , Forbol 12,13-Dibutirato/farmacología , Reacción en Cadena de la Polimerasa de Transcriptasa InversaAsunto(s)
Vértebras Cervicales , Perforación del Esófago/etiología , Mediastinitis/etiología , Traumatismos del Cuello/complicaciones , Osteofito/complicaciones , Espondiloartritis/complicaciones , Heridas no Penetrantes/complicaciones , Accidentes por Caídas , Anciano , Perforación del Esófago/diagnóstico , Humanos , Masculino , Enfisema Mediastínico/diagnóstico por imagen , Enfisema Mediastínico/etiología , Mediastinitis/cirugía , Osteofito/diagnóstico , Radiografía , Espondiloartritis/diagnóstico , Supuración/etiología , Supuración/terapia , Irrigación Terapéutica , ToracotomíaRESUMEN
Airway smooth muscle (ASM) metabolizes arachidonic acid (AA) through various enzymatic pathways, including cytochrome P-450 (CYP-450) omega-hydroxylase, which leads to the production of 20-hydroxyeicosatetraenoic acid (20-HETE). The goal of this study was to delineate the mode of action of 20-HETE in human ASM cells. Isometric tension measurements demonstrated that 20-HETE induced a concentration-dependent relaxant effect in ASM on bronchi precontracted with either methacholine or AA. Relaxing effects of 20-HETE on resting tone were prevented by 10 nM iberiotoxin (IbTx), a BK(Ca) channel inhibitor. Microelectrode measurements showed that exogenous additions of 20-HETE (0.1-10 microM) hyperpolarized the membrane potential of human ASM cells. This concentration-dependent electrophysiological effect induced by the eicosanoid was prevented by 10 nM IbTx. Complementary experiments, using the planar lipid bilayer reconstitution technique, demonstrated that 20-HETE activated reconstituted BK(Ca) channels at low free Ca(2+) concentrations. Together, these results indicate that 20-HETE-dependent activation of BK(Ca) channels is responsible for the hyperpolarization and controlled relaxation of ASM in human distal bronchi.
Asunto(s)
Bronquios/efectos de los fármacos , Bronquios/fisiología , Ácidos Hidroxieicosatetraenoicos/farmacología , Canales de Potasio de Gran Conductancia Activados por el Calcio/metabolismo , Bronquios/metabolismo , Inhibidores de la Ciclooxigenasa/farmacología , Relación Dosis-Respuesta a Droga , Electrofisiología , Humanos , Ácidos Hidroxieicosatetraenoicos/administración & dosificación , Ácidos Hidroxieicosatetraenoicos/biosíntesis , Técnicas In Vitro , Contracción Isométrica , Canales de Potasio de Gran Conductancia Activados por el Calcio/antagonistas & inhibidores , Membrana Dobles de Lípidos/metabolismo , Potenciales de la Membrana/efectos de los fármacos , Relajación Muscular , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Concentración Osmolar , Péptidos/farmacologíaRESUMEN
The present study investigated the ability of 5-oxo-EicosaTetraEnoic acid (5-oxo-ETE) for modulating airway smooth muscle (ASM) tone in human bronchi. 5-Oxo-ETE induced a concentration-dependent relaxing effect on human bronchi pre-contracted with methacholine (MCh) and arachidonic acid (AA). This relaxing response was highly sensitive to Iberiotoxin (IbTx), a large conducting Ca(2+)-activated K(+) channel (BK(Ca)) inhibitor. Furthermore, microelectrode measurements revealed that 5-oxo-ETE (0.1-10 microM) hyperpolarizes the membrane potential of human bronchial ASM cells. These hyperpolarizing effects were also inhibited in the presence of 10nM IbTx. Lastly, 5-oxo-ETE was shown to directly activate reconstituted BK(Ca) channels derived from human airway smooth muscles. In summary, the 5-oxo-ETE eicosanoid activates a specific K(+) conductance, involved in membrane hyperpolarization, which in turn reduces Ca(2+) entry and facilitates relaxation of smooth muscle cells.
Asunto(s)
Ácidos Araquidónicos/farmacología , Bronquios/efectos de los fármacos , Relajación Muscular/efectos de los fármacos , Canales de Potasio Calcio-Activados/fisiología , Bronquios/fisiología , Broncoconstrictores/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Técnicas In Vitro , Potenciales de la Membrana/efectos de los fármacos , Cloruro de Metacolina/farmacología , Músculo Liso/citología , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Péptidos/farmacología , Canales de Potasio Calcio-Activados/antagonistas & inhibidoresRESUMEN
The aim of the present study was to provide a mechanistic insight into how 14,15-epoxyeicosatrienoic acid (EET) relaxes organ-cultured human bronchi. Tension measurements, performed on either fresh or 3-d-cultured bronchi, revealed that the contractile responses to 1 microM methacholine and 10 microM arachidonic acid were largely relaxed by the eicosanoid regioisomer in a concentration-dependent manner (0.01-10 microM). Pretreatments with 14,15-epoxyeicosa-5(Z)-enoic acid, a specific 14,15-EET antagonist, prevented the relaxing effect, whereas iberitoxin pretreatments (10 nM) partially abolished EET-induced relaxations. In contrast, pretreatments with 1 microM indomethacin amplified relaxations in explants and membrane hyperpolarizations triggered by 14,15-EET on airway smooth muscle cells. The relaxing responses induced by 14,15-EET were likely related to reduced Ca2+ sensitivity of the myofilaments, because free Ca2+ concentration-response curves performed on beta-escin-permeabilized cultured explants were shifted toward higher [Ca2+] (lower pCa2+ values). 14,15-EET also abolished the tonic responses induced by phorbol-ester-dybutyrate (PDBu) (a protein kinase C [PKC]-sensitizing agent), on both fresh (intact) and beta-escin-permeabilized explants. Western blot analyses, using two specific primary antibodies against CPI-17 and its PKC-dependent phosphorylated isoform (p-CPI-17), confirmed that the eicosanoid interferes with this intracellular process. These data indicate that 14,15-EET hyperpolarizes airway smooth muscle cells and relaxes precontracted human bronchi while reducing Ca2+ sensitivity of fresh and cultured explants. The intracellular effects are related to a PKC-dependent process involving a lower phosphorylation level of CPI-17.
Asunto(s)
Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Bronquios/efectos de los fármacos , Bronquios/metabolismo , Activación del Canal Iónico/efectos de los fármacos , Relajación Muscular/efectos de los fármacos , Fosfoproteínas Fosfatasas/metabolismo , Canales de Potasio Calcio-Activados/metabolismo , Ácido 8,11,14-Eicosatrienoico/farmacología , Amidas/farmacología , Calcio/metabolismo , Humanos , Técnicas In Vitro , Péptidos y Proteínas de Señalización Intracelular , Potenciales de la Membrana/efectos de los fármacos , Proteínas Musculares , Tono Muscular/efectos de los fármacos , Miocitos del Músculo Liso/citología , Miocitos del Músculo Liso/efectos de los fármacos , Ésteres del Forbol/farmacología , Fosforilación/efectos de los fármacos , Potasio/farmacologíaRESUMEN
BACKGROUND: The efficacy of seat belts in reducing deaths from motor vehicle crashes is well documented. A unique association of injuries has emerged in adults and children with the use of seat belts. The "seat-belt syndrome" refers to the spectrum of injuries associated with lap-belt restraints, particularly flexion-distraction injuries to the spine (Chance fractures). METHODS: We describe the injuries sustained by 8 children, including 2 sets of twins, in 3 different motor vehicle crashes. RESULTS: All children were rear seat passengers wearing lap or 3-point restraints. All had abdominal lap-belt ecchymosis and multiple abdominal injuries due to the common mechanism of seat-belt compression with hyperflexion and distraction during deceleration. Five of the children had lumbar spine fractures and 4 remained permanently paraplegic. CONCLUSIONS: These incidents illustrate the need for acute awareness of the complete spectrum of intra-abdominal and spinal injuries in restrained pediatric passengers in motor vehicle crashes and for rear seat restraints that include shoulder belts with the ability to adjust them to fit smaller passengers, including older children.