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OBJECTIVE: The University of California (UC) leadership sought to develop a robust educational response to the epidemic of opioid-related deaths. Because the contributors to this current crisis are multifactorial, a comprehensive response requires educating future physicians about safe and effective management of pain, safer opioid prescribing, and identification and treatment of substance use disorder (SUD). METHODS: The six UC medical schools appointed an opioid crisis workgroup to develop educational strategies and a coordinated response to the opioid epidemic. The workgroup had diverse specialty and disciplinary representation. This workgroup focused on developing a foundational set of educational competencies for adoption across all UC medical schools that address pain, SUD, and public health concerns related to the opioid crisis. RESULTS: The UC pain and SUD competencies were either newly created or adapted from existing competencies that addressed pain, SUD, and opioid and other prescription drug misuse. The final competencies covered three domains: pain, SUD, and public health issues related to the opioid crisis. CONCLUSIONS: The authors present a novel set of educational competencies as a response to the opioid crisis. These competencies emphasize the subject areas that are fundamental to the opioid crisis: pain management, the safe use of opioids, and understanding and treating SUD.
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Epidemias , Trastornos Relacionados con Opioides , Trastornos Relacionados con Sustancias , Analgésicos Opioides/efectos adversos , Humanos , Epidemia de Opioides , Trastornos Relacionados con Opioides/tratamiento farmacológico , Trastornos Relacionados con Opioides/epidemiología , Trastornos Relacionados con Opioides/prevención & control , Dolor/tratamiento farmacológico , Pautas de la Práctica en Medicina , Facultades de Medicina , Trastornos Relacionados con Sustancias/epidemiologíaRESUMEN
PURPOSE: This exploratory study examines affiliate physician-faculty perceptions and attitudes regarding a teaching incentive programme at a free-standing children's hospital in the United States. We describe the compensation model and present faculty interpretations of its influence on the institutional culture. METHODS: A case study methodology was applied to understand the sociological aspects of academic productivity interventions. In-depth interviews, direct observation of leadership meetings, teaching activity logs, organisational theoretical lens and survey results were used for methodological triangulation. Data from these multiple sources were coded and discussed between investigators iteratively to identify core themes. RESULTS: Of the faculty eligible for the incentive, 32 engaged in in-depth interviews (N = 32/107; 30%) and 88 (interviewees included) in the survey (N = 88/107; 82%). Findings suggest that while the implementation made some strides in mitigating barriers for some, for others gaps were identified that suggest further exploration within this domain of study is warranted. The incentive implementation was perceived as strategic, intending to encourage the academic culture of the hospital, though participants commonly expressed confusion about the rationale behind the omission of teaching allocations in formal contracts. However, high satisfaction levels for the programme as a conduit to change were evident. There was a perception of a shift in the collective faculty morale that reflected an evolving institutional culture that increased enthusiasm for teaching. Finally, faculty noted their perception that institutions that employ teaching incentives could positively influence faculty recruitment. CONCLUSION: We found a modest incentive-based reward for teaching activity was successful in informing the perceptions of faculty regarding their institution's academic prestige goals and teaching recognition. Such programmes, while requiring a small investment of time and resources by institutional leadership, can convey that the educational mission remains a priority in this era of increasing clinical and administrative pressure and an institutional culture that may positively influence faculty morale and dedication to teaching.
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Motivación , Médicos , Niño , Docentes Médicos , Hospitales , Humanos , Percepción , Enseñanza , Estados UnidosRESUMEN
PURPOSE: (1) To characterise changes in dead space fraction during the first 120 post-operative hours in neonates undergoing stage 1 palliation for hypoplastic left heart syndrome, including hybrid procedure; (2) to document whether dead space fraction varied by shunt type (Blalock-Taussig shunt and Sano) and hybrid procedure; and (3) to determine the association between dead space fraction and outcomes. METHODS: Retrospective chart review in neonates undergoing stage 1 palliation for hypoplastic left heart syndrome in a cardiac intensive care unit over a consecutive 30-month period. A linear mixed model was used to determine the differences in dead space over time. Multivariable linear regression and a multivariable linear mixed model were used to assess the association between dead space and outcomes at different time points and over time, respectively. RESULTS: Thirty-four neonates received either a Blalock-Taussig shunt (20.5%), Sano shunt (59%), or hybrid procedure (20.5%). Hospital mortality was 8.8%. Dead space fractions in patients undergoing the hybrid procedure were significantly lower on day 1 (p = 0.01) and day 2 (p = 0.02) and increased over time. A dead space fraction >0.6 on post-operative days 3-5 was significantly associated with decreased duration of mechanical ventilation in all surgical groups (p 0.6 on post-operative days 3-5 was associated with lower duration of mechanical ventilation in all surgical groups. A more comprehensive, prospective assessment of dead space in this delicate patient population would likely be beneficial in improving outcomes.
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Ventrículos Cardíacos/anomalías , Mortalidad Hospitalaria , Síndrome del Corazón Izquierdo Hipoplásico/fisiopatología , Síndrome del Corazón Izquierdo Hipoplásico/cirugía , Cuidados Paliativos/métodos , Procedimientos Quirúrgicos Cardíacos/métodos , Femenino , Ventrículos Cardíacos/cirugía , Humanos , Recién Nacido , Modelos Lineales , Masculino , Análisis Multivariante , Evaluación de Resultado en la Atención de Salud , Periodo Posoperatorio , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Utilization of electrically conductive nanomaterials for developing nanocomposite scaffolds has been at the center of attention for engineering functional cardiac tissues. The primary motive in the use of conductive nanomaterials has been to develop biomimetic scaffolds to recapitulate the extracellular matrix (ECM) of the native heart and to promote cardiac tissue maturity, excitability and electrical signal propagation. Alternatively, it is well accepted that the inclusion of nanomaterials also alters the stiffness and nano-scale topography of the scaffolds. However, what is missing in the literature is that to what extent the sole presence of nanomaterials within a scaffold, regardless of their conductivity, influences the maturation and excitability of engineered cardiac tissues. To address this knowledge gap, we developed four different classes of gelatin methacrylate (GelMA) hydrogels, with varied concentrations, embedded electrically conductive gold nanorods (GNRs) and non-conductive silica nanomaterials (SNPs), to assess the influence of matrix stiffness and the presence of nanomaterials on cardiac cell adhesion, protein expression (i.e. maturation), and tissue-level excitability. Our results demonstrated that either embedding nanomaterials (i.e. GNRs and SNPs) or increasing the matrix stiffness significantly promoted cellular retention and the expression of cardiac-specific markers, including sarcomeric α-actinin (SAC), cardiac troponin I (cTnI) and connexin43 (Cx43) gap junctions. Notably, excitation voltage thresholds at a high frequency (i.e. 2 Hz and higher), in both coupled and uncoupled gap junctions induced by heptanol, were lower for scaffolds embedded conductive GNRs or non-conductive SNPs, independent of matrix stiffness. Overall, our findings demonstrated that the sole presence of nanomaterials within the scaffolding matrix had a more pronounced influence as compared to the scaffold stiffness on the cell-cell coupling, maturation and excitability of engineered cardiac tissues.
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Materiales Biocompatibles/farmacología , Conductividad Eléctrica , Fenómenos Electrofisiológicos/efectos de los fármacos , Corazón/efectos de los fármacos , Nanocompuestos , Ingeniería de Tejidos , Andamios del Tejido , Animales , Corazón/fisiología , RatasRESUMEN
OBJECTIVES: 1) Determine the correlation between pulmonary dead space fraction and extubation success in postoperative pediatric cardiac patients; and 2) document the natural history of pulmonary dead space fractions, dynamic compliance, and airway resistance during the first 72 hours postoperatively in postoperative pediatric cardiac patients. DESIGN: A retrospective chart review. SETTING: Cardiac ICU in a quaternary care free-standing children's hospital. PATIENTS: Twenty-nine with balanced single ventricle physiology, 61 with two ventricle physiology. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We collected data for all pediatric patients undergoing congenital cardiac surgery over a 14-month period during the first 72 hours postoperatively as well as prior to extubation. Overall, patients with successful extubations had lower preextubation dead space fractions and shorter lengths of stay. Single ventricle patients had higher initial postoperative and preextubation dead space fractions. Two-ventricle physiology patients had higher extubation failure rates if the preextubation dead space fraction was greater than 0.5, whereas single ventricle patients had similar extubation failure rates whether preextubation dead space fractions were less than or equal to 0.5 or greater than 0.5. Additionally, increasing initial dead space fraction values predicted prolonged mechanical ventilation times. Airway resistance and dynamic compliance were similar between those with successful extubations and those who failed. CONCLUSIONS: Initial postoperative dead space fraction correlates with the length of mechanical ventilation in two ventricle patients but not in single ventricle patients. Lower preextubation dead space fractions are a strong predictor of successful extubation in two ventricle patients after cardiac surgery, but may not be as useful in single ventricle patients.
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Extubación Traqueal/métodos , Procedimientos Quirúrgicos Cardíacos/estadística & datos numéricos , Pulmón/fisiopatología , Espacio Muerto Respiratorio/fisiología , Femenino , Humanos , Lactante , Recién Nacido , Unidades de Cuidado Intensivo Pediátrico , Masculino , Respiración Artificial/estadística & datos numéricos , Estudios RetrospectivosRESUMEN
OBJECTIVES: To determine the optimal vancomycin dosing regimen to achieve empirical goal trough concentrations in pediatric patients with congenital heart disease and to examine the impact of cardiopulmonary bypass on vancomycin dosing requirements. METHODS: Patients younger than 18 years admitted to the pediatric cardiovascular intensive care unit (CVICU) at our institution from October 1, 2012-December 31, 2014, who received at least one dose of vancomycin, were reviewed retrospectively. Included patients had a steady-state vancomycin trough concentration drawn during the study period. The first steady-state vancomycin trough drawn after being initiated on empirical vancomycin therapy was analyzed for each patient. Excluded patients were those who received mechanical circulatory support, any form of renal replacement therapy, or had a serum creatinine result greater than 1.0 mg/dl on the day of vancomycin initiation. RESULTS: Overall, 77 patients met inclusion criteria, of which 57.1% had undergone cardiopulmonary bypass (CPB) before CVICU admission. Median age was 62 days (interquartile range [IQR] 8.3-176 days). Median daily vancomycin dose was 36.25 mg/kg/day (IQR 29-40 mg/kg/day), resulting in a median steady-state trough of 10.0 µg/ml (IQR 6.3-12.9 µg/ml). Therapeutic troughs occurred in 50.6% of patients; supratherapeutic and subtherapeutic concentrations were attained in 18.2% and 31.2% of patients, respectively. A subgroup analysis of patients who were post-CPB revealed that the only additional variable to affect vancomycin trough concentrations was aortic cross-clamp time (median 56 min, IQR 0-123.3 min, p=0.02). CONCLUSIONS: Empirical vancomycin dosing to achieve troughs of 8-15 µg/dl in patients with congenital heart disease without evidence of significant acute kidney injury should be 30 mg/kg/day for neonates, 35-40 mg/kg/day for infants, and 45 mg/kg/day in children, with adjustments required for patients with elevated creatinine or significant aortic cross-clamp time. The receipt and duration of CPB did not affect total daily vancomycin dose requirements.
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Antibacterianos/administración & dosificación , Puente Cardiopulmonar/métodos , Cardiopatías Congénitas/cirugía , Vancomicina/administración & dosificación , Factores de Edad , Antibacterianos/farmacocinética , Preescolar , Creatinina/sangre , Relación Dosis-Respuesta a Droga , Monitoreo de Drogas/métodos , Femenino , Humanos , Lactante , Recién Nacido , Unidades de Cuidado Intensivo Pediátrico , Masculino , Estudios Retrospectivos , Vancomicina/farmacocinéticaRESUMEN
BACKGROUND: The objective of this work was to examine current oxygenation index (OI) data and outcomes using electronic medical record data to identify a specific OI value associated with mortality. METHODS: This study was a retrospective electronic medical record data review from the pediatric ICU of Phoenix Children's Hospital, with data mining for variables to calculate OIs on subjects age 1 month to 20 y mechanically ventilated > 24 h, excluding those with known intracardiac shunts or cyanotic heart disease. Age, length of hospital stay, duration of mechanical ventilation, and outcomes were also assessed. The Wilcoxon signed-rank test was used to compare continuous variables, receiver operating characteristic analysis was used in determining discriminant ability, and logistic regression was conducted to determine the odds ratio (OR) for risk of death with increasing OI. RESULTS: OI was calculated on 65 subjects, of whom 6 died (9%). The median maximum OI was 10 for all subjects, 17 for non-survivors, and 8 for survivors (P = .14 via Wilcoxon rank-sum test). ORs indicated a 2.4-fold increase in the odds of death (P = .09, 95% CI 0.9-6.6) for each increasing point in maximum OI. Mean OI OR revealed a 1.9-fold increase in the odds of death (P = .25, 95% CI 0.6-5.9). Receiver operating characteristic analysis indicated a higher discriminate ability for maximum OI (area under the curve = 0.68) than mean OI (area under the curve = 0.58). OI cut-points for mortality were established. Mortality was unchanged until maximum OI > 17, for which mortality nearly tripled at a value of 18% versus 6-7% for range 0-17. CONCLUSIONS: Limitations exist in obtaining serial OI values from current electronic medical records. Serial assessment of OI values may allow creation of alert values for increased mortality risk. Consideration of escalation of therapies for respiratory failure, such as high-frequency ventilation, inhaled nitric oxide, or extracorporeal membrane oxygenation may be warranted at lower OIs than historically reported.
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Análisis de los Gases de la Sangre/estadística & datos numéricos , Oxígeno/análisis , Insuficiencia Respiratoria/mortalidad , Enfermedad Aguda , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Modelos Logísticos , Masculino , Oportunidad Relativa , Curva ROC , Valores de Referencia , Respiración Artificial/estadística & datos numéricos , Insuficiencia Respiratoria/fisiopatología , Estudios Retrospectivos , Medición de Riesgo/métodos , Factores de Riesgo , Estadísticas no Paramétricas , Adulto JovenRESUMEN
Endoplasmic reticulum (ER) stress has been implicated in alveolar epithelial type II (AT2) cell apoptosis in idiopathic pulmonary fibrosis. We hypothesized that ER stress (either chemically induced or due to accumulation of misfolded proteins) is also associated with epithelial-mesenchymal transition (EMT) in alveolar epithelial cells (AECs). ER stress inducers, thapsigargin (TG) or tunicamycin (TN), increased expression of ER chaperone, Grp78, and spliced X-box binding protein 1, decreased epithelial markers, E-cadherin and zonula occludens-1 (ZO-1), increased the myofibroblast marker, α-smooth muscle actin (α-SMA), and induced fibroblast-like morphology in both primary AECs and the AT2 cell line, RLE-6TN, consistent with EMT. Overexpression of the surfactant protein (SP)-C BRICHOS mutant SP-C(ΔExon4) in A549 cells increased Grp78 and α-SMA and disrupted ZO-1 distribution, and, in primary AECs, SP-C(ΔExon4) induced fibroblastic-like morphology, decreased ZO-1 and E-cadherin and increased α-SMA, mechanistically linking ER stress associated with mutant SP to fibrosis through EMT. Whereas EMT was evident at lower concentrations of TG or TN, higher concentrations caused apoptosis. The Src inhibitor, 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4]pyramidine) (PP2), abrogated EMT associated with TN or TG in primary AECs, whereas overexpression of SP-C(ΔExon4) increased Src phosphorylation, suggesting a common mechanism. Furthermore, increased Grp78 immunoreactivity was observed in AT2 cells of mice after bleomycin injury, supporting a role for ER stress in epithelial abnormalities in fibrosis in vivo. These results demonstrate that ER stress induces EMT in AECs, at least in part through Src-dependent pathways, suggesting a novel role for ER stress in fibroblast accumulation in pulmonary fibrosis.
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Retículo Endoplásmico/metabolismo , Epitelio/patología , Regulación de la Expresión Génica , Mesodermo/patología , Alveolos Pulmonares/metabolismo , Proteína C Asociada a Surfactante Pulmonar/química , Animales , Apoptosis , Chaperón BiP del Retículo Endoplásmico , Fibroblastos/metabolismo , Humanos , Masculino , Ratones , Mutación , Desnaturalización Proteica , Fibrosis Pulmonar/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
OBJECTIVE: Obliterative bronchiolitis is the predominant histopathologic finding in patients with chronic rejection after lung transplant. This fibroproliferative transformation within small airways of lung allograft is poorly understood; however, studies suggest epithelial-mesenchymal transition plays a role. Transplant immunosuppressive therapy has been shown to cause epithelial-mesenchymal transition in renal tubular epithelial cells, with subsequent fibrosis. This study explored whether immunosuppressive therapy contributes to epithelial-mesenchymal transition in airway epithelial cells. METHODS: Bronchial epithelial cell line RL-65 was treated 3 to 5 days with several immunosuppressive agents, including cyclosporine (INN ciclosporin), tacrolimus, azathioprine, mycophenolic acid, sirolimus, prednisone, and transforming growth factor ß1 as control. We then analyzed cells for presence of mesenchymal morphology and protein markers. RESULTS: Treatment with cyclosporine, azathioprine, mycophenolate, and sirolimus resulted in elongated and irregular cell shape, and all but azathioprine showed loss of cell-cell adhesions relative to vehicle-treated cells. Expressions of extracellular matrix proteins, fibronectin and collagen, along with mesenchymal marker, vimentin, were significantly upregulated. Immunofluorescence showed loss of E-cadherin at cell membranes and cytoskeletal rearrangements typical of epithelial-mesenchymal transition. These immunosuppressive agents also increased transforming growth factor produced by cells; however, tacrolimus- and prednisone-treated cells maintained epithelial morphology, baseline levels of matrix protein expression, and transforming growth factor production levels. CONCLUSIONS: Overall, we found that certain immunosuppressive agents may contribute to partial epithelial-mesenchymal transition in bronchial epithelial cells, specifically increasing production of excessive extracellular matrix proteins. This may provide novel insights into the pathogenesis of obliterative bronchiolitis after lung transplant.
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Bronquios/efectos de los fármacos , Bronquiolitis Obliterante/inducido químicamente , Células Epiteliales/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Inmunosupresores/toxicidad , Animales , Biomarcadores/metabolismo , Bronquios/metabolismo , Bronquios/patología , Bronquiolitis Obliterante/metabolismo , Bronquiolitis Obliterante/patología , Cadherinas/metabolismo , Adhesión Celular/efectos de los fármacos , Línea Celular , Forma de la Célula/efectos de los fármacos , Colágeno/metabolismo , Citoesqueleto/efectos de los fármacos , Citoesqueleto/metabolismo , Células Epiteliales/metabolismo , Células Epiteliales/patología , Fibronectinas/metabolismo , Fibrosis , Ratas , Factor de Crecimiento Transformador beta1/metabolismo , Vimentina/metabolismoRESUMEN
We examined the hypothesis that persistent pulmonary hypertension of the newborn (PPHN) associated with ibuprofen is due to alterations in biochemical and molecular regulators of oxidative stress and NO signaling. Newborn rats breathing 50% O2 or room air from the first day of life (P1), received early IP injections of: 1) indomethacin (0.2 mg/kg) on P1 and 0.1 mg/kg on P2 and P3; 2) ibuprofen (10 mg/kg) on P1 and 5 mg/kg on P2 and P3; or 3) saline on P1, P2 and P3, then euthanized on P4; or late treatment on P4, P5 and P6, then euthanized on P7. Lung biomarkers for oxidative stress (8- epi-PGF2a), DNA damage (8-hydroxy-2'-deoxyguanosine) and pulmonary hypertension (ET-1, big ET-1, and total NO) were assessed. Despite timing of the dose and oxygen exposure, both drugs resulted in increased alveolar size. Both drugs had no beneficial effects on oxidative stress. Indomethacin treatment in O2 resulted in higher pulmonary levels of 8-epi-PGF2alpha which was associated with downregulation of most antioxidant genes with early treatment and overexpression of GPX5 and 6 with late treatment. Early and late ibuprofen treatment suppressed hyperoxia-induced NOx production and downregulated iNOS. Postponing treatment had no significant beneficial effects on biomolecular regulators of oxidative stress and NO signaling. The effect of ibuprofen on pulmonary NOx may explain in part, the transient PPHN seen in ibuprofen-treated preterm infants.
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RATIONALE: Nitric oxide (NO) plays an important role in lung development and perinatal lung function, and pulmonary NO synthases (NOS) are decreased in bronchopulmonary dysplasia (BPD) following preterm birth. Fetal estradiol levels increase during late gestation and estradiol up-regulates NOS, suggesting that after preterm birth estradiol deprivation causes attenuated lung NOS resulting in impaired pulmonary function. OBJECTIVE: To test the effects of postnatal estradiol administration in a primate model of BPD over 14 days after delivery at 125 days of gestation (term = 185 d). METHODS: Cardiopulmonary function was assessed by echocardiography and whole body plethysmography. Lung morphometric and histopathologic analyses were performed, and NOS enzymatic activity and abundance were measured. MEASUREMENTS AND MAIN RESULTS: Estradiol caused an increase in blood pressure and ductus arteriosus closure. Expiratory resistance and lung compliance were also improved, and this occurred before spontaneous ductal closure. Furthermore, both oxygenation and ventilation indices were improved with estradiol, and the changes in lung function and ventilatory support requirements persisted throughout the study period. Whereas estradiol had negligible effect on indicators of lung inflammation and on lung structure assessed after the initial 14 days of ventilatory support, it caused an increase in lung neuronal and endothelial NOS enzymatic activity. CONCLUSIONS: In a primate model of BPD, postnatal estradiol treatment had favorable cardiovascular impact, enhanced pulmonary function, and lowered requirements for ventilatory support in association with an up-regulation of lung NOS. Estradiol may be an efficacious postnatal therapy to improve lung function and outcome in preterm infants.
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Displasia Broncopulmonar/terapia , Estradiol/farmacología , Estrógenos/farmacología , Óxido Nítrico Sintasa/metabolismo , Regulación hacia Arriba , Animales , Animales Recién Nacidos , Presión Sanguínea/efectos de los fármacos , Líquido del Lavado Bronquioalveolar/química , Modelos Animales de Enfermedad , Conducto Arterial/efectos de los fármacos , Elastina/genética , Elastina/metabolismo , Estradiol/sangre , Femenino , Humanos , Recién Nacido , Pulmón/metabolismo , Pulmón/patología , Rendimiento Pulmonar , Masculino , Oxígeno/sangre , Papio , Surfactantes Pulmonares/metabolismo , ARN Mensajero/metabolismo , Distribución Aleatoria , Receptores de Estradiol/metabolismo , Respiración ArtificialRESUMEN
BACKGROUND: Dexmedetomidine is an alpha2-adrenergic agonist that causes sleep-like sedation and mild analgesia without narcosis or respiratory depression, and has relative cardiovascular stability. Due to these properties, it may be an effective agent for prolonged use in the sedation of patients in the paediatric cardiothoracic intensive care unit. We reviewed our experience with the drug to detail its safety and efficacy. METHODS: We conducted a retrospective chart review of all patients who received dexmedetomidine over a six month period in a dedicated paediatric cardiothoracic intensive care unit. Patients were identified from pharmacy records showing administration of drugs. We collected demographic data, information relating to doses of dexmedetomidine, physiologic parameters, and clinical outcomes. RESULTS: We identified 54 patients who received the drug. The median age of recipients was 6 months, with a range from 1 day to 16 years. The mean duration of administration was 37.3 hours, with a range from 2 to 177 hours. The mean duration of continuation of administration after extubation was 16.7 hours, with a range from zero to 112.5 hours. Physiologically, there were no clinically significant changes in mean arterial pressure, heart rate, respiratory rate, or saturations of oxygen before, during, or after utilization of the drug. Use of dexmedetomidine significantly reduced the need to administer narcotics, and scores using the COMFORT system were not different between patients who received dexmedetomidine and those who did not. CONCLUSIONS: In this limited and retrospective review, dexmedetomidine was found to be safe and efficacious. Its use as a sedative agent for extended periods of time in critically-ill children deserves investigation in a prospective and controlled manner.
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Sedación Consciente/métodos , Dexmedetomidina/administración & dosificación , Hipnóticos y Sedantes/administración & dosificación , Unidades de Cuidado Intensivo Pediátrico , Adolescente , Análisis de Varianza , Niño , Preescolar , Sedación Consciente/efectos adversos , Dexmedetomidina/efectos adversos , Femenino , Humanos , Hipnóticos y Sedantes/efectos adversos , Lactante , Recién Nacido , Masculino , Estudios RetrospectivosRESUMEN
The pulmonary renin-angiotensin system (RAS) contributes to inflammation and epithelial apoptosis in meconium aspiration. It is unclear if both angiotensin II receptors (ATR) contribute, where they are expressed and if meconium modifies subtype expression. We examined ATR subtypes in 2 wk rabbit pup lungs before and after meconium exposure and with and without captopril pretreatment or type 1 receptor (AT1R) inhibition with losartan, determining expression and cellular localization with immunoblots, RT-PCR and immunohistochemistry, respectively. Responses of cultured rat alveolar type II pneumocytes were also examined. Type 2 ATR were undetected in newborn lung before and after meconium instillation. AT1R were expressed in pulmonary vascular and bronchial smooth muscle and alveolar and bronchial epithelium. Meconium increased total lung AT1R protein approximately 3-fold (p = 0.006), mRNA 29% (p = 0.006) and immunostaining in bronchial and alveolar epithelium and smooth muscle, which were unaffected by captopril and losartan. Meconium also increased AT1R expression >3-fold in cultured type II pneumocytes and caused concentration-dependent cell death inhibited by losartan. Meconium increases AT1R expression in newborn rabbit lung and cultured type II pneumocytes and induces AT1R-mediated cell death. The pulmonary RAS contributes to the pathogenesis of meconium aspiration through increased receptor expression.
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Apoptosis , Síndrome de Aspiración de Meconio/metabolismo , Alveolos Pulmonares/metabolismo , Receptor de Angiotensina Tipo 1/metabolismo , Sistema Renina-Angiotensina , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Apoptosis/efectos de los fármacos , Captopril/farmacología , Muerte Celular , Células Cultivadas , Modelos Animales de Enfermedad , Humanos , Inmunohistoquímica , Recién Nacido , Losartán/farmacología , Masculino , Meconio/metabolismo , Síndrome de Aspiración de Meconio/patología , Alveolos Pulmonares/efectos de los fármacos , Alveolos Pulmonares/patología , ARN Mensajero/metabolismo , Conejos , Ratas , Ratas Sprague-Dawley , Receptor de Angiotensina Tipo 1/efectos de los fármacos , Receptor de Angiotensina Tipo 1/genética , Receptor de Angiotensina Tipo 2/metabolismo , Sistema Renina-Angiotensina/efectos de los fármacos , Regulación hacia ArribaRESUMEN
Epithelial-mesenchymal transition (EMT), a process whereby fully differentiated epithelial cells undergo transition to a mesenchymal phenotype giving rise to fibroblasts and myofibroblasts, is increasingly recognized as playing an important role in repair and scar formation following epithelial injury. The extent to which this process contributes to fibrosis following injury in the lung is a subject of active investigation. Recently, it was demonstrated that transforming growth factor (TGF)-beta induces EMT in alveolar epithelial cells (AEC) in vitro and in vivo, and epithelial and mesenchymal markers have been colocalized to hyperplastic type II (AT2) cells in lung tissue from patients with idiopathic pulmonary fibrosis (IPF), suggesting that AEC may exhibit extreme plasticity and serve as a source of fibroblasts and/or myofibroblasts in lung fibrosis. In this review, we describe the characteristic features of EMT and its mechanistic underpinnings. We further describe the contribution of EMT to fibrosis in adult tissues following injury, focusing especially on the critical role of TGF-beta and its downstream mediators in this process. Finally, we highlight recent descriptions of EMT in the lung and the potential implications of this process for the treatment of fibrotic lung disease. Treatment for fibrosis of the lung in diseases such as IPF has heretofore focused largely on amelioration of potential inciting processes such as inflammation. It is hoped that this review will stimulate further consideration of the cellular mechanisms of fibrogenesis in the lung and especially the role of the epithelium in this process, potentially leading to innovative avenues of investigation and treatment.
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Células Epiteliales/citología , Enfermedades Pulmonares/patología , Mesodermo/citología , Factor de Crecimiento Transformador beta/metabolismo , Animales , Fibrosis , Humanos , Pulmón/patologíaRESUMEN
Patients with interstitial lung diseases, such as idiopathic pulmonary fibrosis (IPF) and bronchopulmonary dysplasia (BPD), suffer from lung fibrosis secondary to myofibroblast-mediated excessive ECM deposition and destruction of lung architecture. Transforming growth factor (TGF)-beta1 induces epithelial-mesenchymal transition (EMT) of alveolar epithelial cells (AEC) to myofibroblasts both in vitro and in vivo. Inhaled nitric oxide (NO) attenuates ECM accumulation, enhances lung growth, and decreases alveolar myofibroblast number in experimental models. We therefore hypothesized that NO attenuates TGF-beta1-induced EMT in cultured AEC. Studies of the capacity for endogenous NO production in AEC revealed that endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) are expressed and active in AEC. Total NOS activity was 1.3 pmol x mg protein(-1) x min(-1) with 67% derived from eNOS. TGF-beta1 (50 pM) suppressed eNOS expression by more than 60% and activity by 83% but did not affect iNOS expression or activity. Inhibition of endogenous NOS with l-NAME led to spontaneous EMT, manifested by increased alpha-smooth muscle actin (alpha-SMA) expression and a fibroblast-like morphology. Provision of exogenous NO to TGF-beta1-treated AEC decreased stress fiber-associated alpha-SMA expression and decreased collagen I expression by 80%. NO-treated AEC also retained an epithelial morphology and expressed increased lamellar protein, E-cadherin, and pro-surfactant protein B compared with those treated with TGF-beta alone. These findings indicate that NO serves a critical role in preserving an epithelial phenotype and in attenuating EMT in AEC. NO-mediated regulation of AEC fate may have important implications in the pathophysiology and treatment of diseases such as IPF and BPD.
Asunto(s)
Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Mesodermo/citología , Mesodermo/efectos de los fármacos , Óxido Nítrico/farmacología , Alveolos Pulmonares/citología , Alveolos Pulmonares/efectos de los fármacos , Actinas/metabolismo , Animales , Apoptosis/efectos de los fármacos , Biomarcadores/metabolismo , Colágeno/biosíntesis , Células Epiteliales/enzimología , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Isoenzimas/genética , Isoenzimas/metabolismo , Masculino , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa/metabolismo , Alveolos Pulmonares/enzimología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Fibras de Estrés/efectos de los fármacos , Fibras de Estrés/metabolismo , Factor de Crecimiento Transformador beta1/farmacologíaRESUMEN
Endothelin-1 (ET-1) is implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF), but the cellular mechanisms underlying the role it plays in this disease are not well characterized. Epithelial-mesenchymal transition (EMT), which was recently demonstrated in alveolar epithelial cells (AEC), may play an important role in the pathogenesis of IPF and other forms of pulmonary fibrosis. Whether ET-1 contributes to the induction of EMT in AEC is unknown. The aims of this study were to evaluate AEC production of ET-1 and to determine if ET-1 induces EMT in AEC. We demonstrate that ET-1 is produced at physiologically relevant levels by primary AEC and is secreted preferentially toward the basolateral surface. We also demonstrate that AEC express high levels of endothelin type A receptors (ET-A) and, to a lesser extent, type B receptors (ET-B), suggesting autocrine or paracrine function for alveolar ET-1. In addition, ET-1 induces EMT through ET-A activation. Furthermore, TGF-beta1 synthesis is increased by ET-1, ET-1 induces Smad3 phosphorylation, and ET-1-induced EMT is attenuated by a TGF-beta1-neutralizing antibody. Thus, ET-1 is an important mediator of EMT in AEC, acting through ET-A-mediated TGF-beta1 production. These findings increase our basic understanding of the role of ET-1 in pulmonary fibrosis and suggest potential roles for AEC-derived ET-1 in the pathogenesis of other alveolar epithelial-mediated lung diseases.
Asunto(s)
Endotelina-1/fisiología , Epitelio/fisiología , Regulación de la Expresión Génica , Mesodermo/fisiología , Fibrosis Pulmonar/metabolismo , Receptor de Endotelina A/fisiología , Factor de Crecimiento Transformador beta1/fisiología , Animales , Apoptosis , Pulmón/metabolismo , Pulmón/patología , Lesión Pulmonar , Masculino , Modelos Biológicos , Fenotipo , Ratas , Ratas Sprague-Dawley , Receptor de Endotelina A/metabolismo , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
An understanding of the mechanisms underlying pulmonary fibrosis remains elusive. Once believed to result primarily from chronic inflammation, it is now clear that inflammation and chronic fibrosis, especially in diseases such as idiopathic pulmonary fibrosis/usual interstitial pneumonia, are often dissociated, and that inflammation is neither necessary nor sufficient to induce fibrosis. The origin of the primary effector cell of fibrosis in the lung, the myofibroblast, is not clearly established. Three potential sources have been hypothesized. Although conversion of resident fibroblasts and differentiation of circulating bone marrow-derived progenitors likely play a role, the possible contribution of alveolar epithelial cells (AECs), through a process termed "epithelial-mesenchymal transition" (EMT), has only recently received consideration. A process by which epithelial cells lose cell-cell attachment, polarity and epithelial-specific markers, undergo cytoskeletal remodeling, and gain a mesenchymal phenotype, EMT plays a prominent role in fibrogenesis in adult tissues such as the kidney. This review summarizes the evidence supporting a central role for EMT in the pathogenesis of lung fibrosis, the potential for EMT in AECs in vitro and in vivo and role of transforming growth factor-beta1 in this process, and the implications of epithelium-driven fibrosis on future research and treatment. Potential pathways involved in EMT are also discussed. It is hoped that a major shift in current paradigms regarding the genesis of pulmonary fibrosis and dissection of the relevant pathways may allow development of targeted interventions that could potentially reverse the process and ameliorate the debilitating effects of abnormal repair and progressive fibrosis.
Asunto(s)
Células Epiteliales/citología , Fibroblastos/patología , Alveolos Pulmonares/citología , Fibrosis Pulmonar/patología , Animales , Apoptosis , Biomarcadores/metabolismo , Línea Celular , Proteínas de la Membrana/metabolismo , Mesodermo/citología , Miocitos del Músculo Liso/patología , Ratas , Factor de Crecimiento Transformador beta/farmacología , Factor de Crecimiento Transformador beta1RESUMEN
OBJECTIVE: To compare the pressure-rate products and phase angles of children during minimal support ventilation and after extubation. DESIGN AND SETTING: Prospective, randomized single-center trial in a pediatric intensive care unit in a tertiary children's hospital. METHODS: Seventeen endotracheally intubated, mechanically ventilated children were placed on T-piece, T-piece with heliox, continuous positive airway pressure, and pressure support in random order. Esophageal pressure swings, phase angles, respiratory mechanics, and physiological parameters were measured on these modes and after extubation. MEASUREMENTS AND RESULTS: Pressure-rate product postextubation was significantly higher than on support modes. For each mode and after extubation they were: pressure support 198+/-31, continuous positive airway pressure 237+/-30, T-piece 323+/-47, T-piece/heliox 308+/-61, and extubation 378+/-43 cmH2O/min. Phase angles were significantly higher during T-piece ventilation than pressure support but not did not differ significantly from postextubation. CONCLUSIONS: Assessment of effort of breathing during even minimal mechanical ventilation may underestimate postextubation effort in children. Postextubation pressure-rate product and hence "effort of breathing" in children is best approximated by T-piece ventilation.