RESUMEN
BACKGROUND: Harmful effects of spontaneous breathing have been shown in experimental severe acute respiratory distress syndrome (ARDS). However, in the clinical setting, spontaneous respiration has been indicated only in mild ARDS. To date, no study has compared the effects of spontaneous assisted breathing with those of fully controlled mechanical ventilation at different levels of positive end-expiratory pressure (PEEP) on lung injury in ARDS. OBJECTIVE: To compare the effects of assisted pressure support ventilation (PSV) with pressure-controlled ventilation (PCV) on lung function, histology and biological markers at two different PEEP levels in mild ARDS in rats. DESIGN: Randomised controlled experimental study. SETTING: Basic science laboratory. PARTICIPANTS: Thirty-five Wistar rats (weightâ±âSD, 310â±â19)âg received Escherichia coli lipopolysaccharide (LPS) intratracheally. After 24âh, the animals were anaesthetised and randomly allocated to either PCV (n=14) or PSV (n=14) groups. Each group was further assigned to PEEPâ=â2âcmH2O or PEEPâ=â5âcmH2O. Tidal volume was kept constant (≈6âmlâkg). Additional nonventilated animals (n=7) were used as a control for postmortem analysis. MAIN OUTCOME MEASURES: Ventilatory and mechanical parameters, arterial blood gases, diffuse alveolar damage score, epithelial integrity measured by E-cadherin tissue expression, and biological markers associated with inflammation (IL-6 and cytokine-induced neutrophil chemoattractant, CINC-1) and type II epithelial cell damage (surfactant protein-B) were evaluated. RESULTS: In both PCV and PSV, peak transpulmonary pressure was lower, whereas E-cadherin tissue expression, which is related to epithelial integrity, was higher at PEEPâ=â5âcmH2O than at PEEPâ=â2âcmH2O. In PSV, PEEPâ=â5âcmH2O compared with PEEPâ=â2âcmH2O was associated with significantly reduced diffuse alveolar damage score [median (interquartile range), 11 (8.5 to 13.5) vs. 23 (19 to 26), Pâ=â0.005] and expressions of IL-6 and CINC-1 (Pâ=â0.02 for both), whereas surfactant protein-B mRNA expression increased (Pâ=â0.03). These changes suggested less type II epithelial cell damage at a PEEP of 5âcmH2O. Peak transpulmonary pressure correlated positively with IL-6 [Spearman's rho (ρ)â=â0.62, Pâ=â0.0007] and CINC-1 expressions (ρâ=â0.50, Pâ=â0.01) and negatively with E-cadherin expression (ρâ=â-0.67, Pâ=â0.0002). CONCLUSION: During PSV, PEEP of 5âcmH2O, but not a PEEP of 2âcmH2O, reduced lung damage and inflammatory markers while maintaining epithelial cell integrity.
Asunto(s)
Respiración con Presión Positiva/métodos , Síndrome de Dificultad Respiratoria/metabolismo , Síndrome de Dificultad Respiratoria/terapia , Lesión Pulmonar Inducida por Ventilación Mecánica/metabolismo , Lesión Pulmonar Inducida por Ventilación Mecánica/terapia , Animales , Cadherinas/biosíntesis , Respiración con Presión Positiva/tendencias , Distribución Aleatoria , Ratas , Ratas Wistar , Síndrome de Dificultad Respiratoria/patología , Resultado del Tratamiento , Lesión Pulmonar Inducida por Ventilación Mecánica/patologíaRESUMEN
OBJECTIVE: Systemic sclerosis (SSc)-related interstitial lung disease (ILD) is one of the leading causes of mortality. We undertook this study to analyze the gene expression of lung tissue in a prospective cohort of patients with SSc-related ILD and to compare it with that in control lungs and with 2 prospective clinical parameters in order to understand the molecular pathways implicated in progressive lung disease. METHODS: Lung tissue was obtained by open lung biopsy in 28 consecutive patients with SSc-related ILD and in 4 controls. High-resolution computed tomography (HRCT) and pulmonary function testing (PFT) were performed at baseline and 2-3 years after treatment based on lung histologic classification. Microarray analysis was performed, and the results were correlated with changes in the HRCT score (FibMax) and PFT values. Quantitative polymerase chain reaction (qPCR) and immunohistochemistry were used to confirm differential levels of messenger RNA and protein. RESULTS: Lung microarray data distinguished patients with SSc-related ILD from healthy controls. In the lungs of patients with SSc-related ILD who had nonspecific interstitial pneumonia (NSIP), expressed genes included macrophage markers, chemokines, collagen, and transforming growth factor ß (TGFß)- and interferon (IFN)-regulated genes. Expression of these genes correlated with progressive lung fibrosis defined by the change in FibMax. Immunohistochemistry confirmed increased markers of collagen (COL1A1), IFN (OAS1 and IFI44), and macrophages (CCL18 and CD163), and the positive correlation with the change in FibMax was confirmed by qPCR in a larger group of SSc patients with NSIP. Several genes correlated with both the change in FibMax (r > 0.4) and the change in % predicted forced vital capacity (r < -0.1), including IFN and macrophage markers, chemokines, and heat-shock proteins. CONCLUSION: These results highlight major pathogenic pathways relevant to progressive pulmonary fibrosis in SSc-related ILD: macrophage emigration and activation, and up-regulated expression of TGFß- and IFN-regulated genes.
Asunto(s)
Pulmón/metabolismo , Activación de Macrófagos/genética , Fibrosis Pulmonar/genética , Esclerodermia Sistémica/genética , 2',5'-Oligoadenilato Sintetasa/genética , 2',5'-Oligoadenilato Sintetasa/metabolismo , Adulto , Antígenos/genética , Antígenos/metabolismo , Antígenos CD/genética , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/genética , Antígenos de Diferenciación Mielomonocítica/metabolismo , Quimiocinas CC/genética , Quimiocinas CC/metabolismo , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Cadena alfa 1 del Colágeno Tipo I , Proteínas del Citoesqueleto/genética , Proteínas del Citoesqueleto/metabolismo , Progresión de la Enfermedad , Femenino , Humanos , Pulmón/patología , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Fibrosis Pulmonar/etiología , Fibrosis Pulmonar/patología , Fibrosis Pulmonar/fisiopatología , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Pruebas de Función Respiratoria , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/patología , Esclerodermia Sistémica/fisiopatología , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
BACKGROUND: Clinical demand for liver transplant steadily grows while organs offer has reached a plateau years ago. To expand the donor liver pool, various options have been considered including acceptance of suboptimal donors and steatotic grafts, with a risk of poorer outcomes. The latter risk and its relation to the grade of liver graft steatosis have been studied in this prospective clinical study. METHODS: One hundred eighteen consecutive liver transplantation (115 patients) performed between May 2002 and March 2008 were prospectively analyzed. According to the grade of steatosis on a 2 hr postreperfusion biopsy, four groups were considered: absence (<5%) (n=34), mild (<30%) (n=40), moderate (30%-60%) (n=23), or severe steatosis (> or = 60%) (n=21). Donors and recipients demographic data, and patients and grafts survival rates were compared among the four groups. RESULTS: Eighty-four (71%) grafts presented some degree of steatosis (macrosteatosis: 19.5%, microsteatosis: 47%, mix type: 33.5%). Patient and graft survival were significant lower in the "severe steatosis" group, as a whole. Grafts with less than 30% predominant macro-, or microsteatosis also had poorer outcomes with lower patient and graft survival rates. CONCLUSION: Steatotic liver grafts were used on a large scale (71%) in this clinical series. The analysis confirms that using grafts with moderate (>30%) and severe steatosis (>60%) have a negative impact on outcomes. The authors conclude that using these grafts allow a significant increase in organ offer that counterbalances the negative outcome for patients who are not offered a transplant, and this supports the need for further clinical research.