RESUMO
BACKGROUND: In COPD, the bronchial epithelium shows a pathologically activated Wnt pathway. Sclerostin (SOST) is a secreted glycoprotein that is associated with bone metabolism and blocks the Wnt pathway. We hypothesized that low sclerostin levels might be associated with lung function and COPD exacerbations in patients. METHODS: We studied 139 outpatients with stable COPD and normal kidney function. We assessed the serum levels of SOST and bone metabolism parameters, body composition, clinical characteristics and lung function at baseline. We followed the patients prospectively for 12 months after enrolment. Moderate exacerbations and hospital admissions were recorded during follow-up. RESULTS: The serum SOST levels were 23.98±7.6 pmol/l (men: 25.5±7.7 pmol/l, women: 20.3±5.9 pmol/l (p < 0.001)). SOST showed correlations with age (r = 0.36), FFMI (r = 0.38), FEV1 (r = 0.27), DLCO (r = 0.39), 6MWD (r = 0.19) and CAT (r = -0.24). In multivariate linear regression analysis, only age (beta=0.264) and FFMI (beta=1.241) remained significant. SOST showed a significant negative correlation with serum phosphorus (r = -0.29). Cox proportional risk analysis indicated that patients in the lower tertile of SOST levels were at higher risk of moderate COPD exacerbation (HR 2.015, CI95% 1.136-3.577, p = 0.017) and hospital admission due to COPD (HR 5.142, CI95% 1.380-19.158, p = 0.015) than the rest of the patients. CONCLUSIONS: SOST levels are associated with body composition and lung function in patients with COPD. Furthermore, lower SOST levels predict a higher risk of exacerbations and hospitalization.
RESUMO
UNLABELLED: Although the molecular basis for the pathophysiology of non-alcoholic steatohepatitis (NASH) is poorly understood, we evaluate the hepatic gene expression of cytokines, chemokines, cell receptors, growth factors, intracellular transducers and extracellular communication proteins in liver tissue of obese patients (with and without NASH), and we determine the specific intrahepatic gene expression profiles associated with histological severe NASH.Thirty-eight obese patients with BMI > 35 were analyzed, who underwent bariatric surgery. Biopsy specimen samples were snap-frozen in liquid nitrogen. Hepatic gene expression was determined in liver biopsy specimens from 3 groups: a) obese patients without NASH (n = 12); b) patients with NASH without fibrosis (n = 13); and c) patients with NASH and fibrosis (n = 13). Genes were considered to be expressed differentially in NASH only if there was a greater than 2-fold difference in abundance of mRNA when compared with each of the control group. These results were confirmed by real-time PCR. Fourteen genes were differentially expressed (10 overexpressed and 4 underexpressed) in patients with NASH. Genes that were significantly overexpressed included prohibitin, TNF, TNF RI (p55), MCSF, R2-TRAIL, b1-CTGF, FGF, VEGF, and BIGH3OBR. Insulin growth factor-1, insulin growth factor-2, interleukin-2 and tyrosine-receptor were underexpressed in NASH patients. IN CONCLUSION: 1. The obese patients with NASH without fibrosis show an overexpression of proinflammatory and proapoptotic genes. Also, the NASH patients with fibrosis show an overexpression of fibrogenic genes, including the leptin receptor Ob-Rb.2. The up-regulated gene expression of prohibitin suggests mitochondrial dysfunction in NASH patients.
Assuntos
Citocinas/genética , Fígado Gorduroso/genética , Obesidade Mórbida/genética , Adulto , Citocinas/metabolismo , Fígado Gorduroso/patologia , Feminino , Expressão Gênica , Perfilação da Expressão Gênica/métodos , Humanos , Masculino , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Reação em Cadeia da Polimerase/métodos , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
La fisiopatología de la enfermedad hepática por depósito de grasasólo se conoce de forma parcial. En este trabajo hemos analizadola expresión génica intrahepática de citoquinas, quimioquinas, receptorescelulares, factores de crecimiento, transductores de señalesintracelulares y proteínas de comunicación extracelular en el tejidohepático de sujetos obesos con y sin esteatohepatitis no alcohólica,en un intento de determinar un perfil de expresión génica asociadoa las formas severas de la esteatohepatitis no alcohólica (EHNA).Se analizó un grupo de 38 pacientes obesos con un IMC > 35,que fueron sometidos a cirugía bariátrica. La expresión génica intrahepáticase determinó en el tejido hepático dividiendo a los pacientesen tres grupos: a) pacientes obesos sin datos histológicos sugestivosde EHNA (n = 12); b) pacientes con EHNA sin fibrosis (n =13); y c) pacientes con EHNA y fibrosis (n = 13). Se consideró queexistía una sobreexpresión génica cuando la diferencia en la expresiónera, al menos, de dos veces con respecto al grupo control. Losresultados se confirmaron mediante PCR en tiempo real. Se detectóuna expresión diferencial de 14 genes (10 sobreexpresados y 4infraexpresados). Los genes sobreexpresados incluyeron prohibitina,TNF, TNF RI (p55), MCSF, R2-TRAIL, TGF-b1, CTGF, FGF,VEGF, BIGH3 y ObRb. La expresión de los genes insulin growthfactor-1, insulin growth factor-2, interleuquina-2 y tyrosine-receptorfue menor que en el grupo control.En conclusión:1. Los pacientes obesos con EHNA sin fibrosis muestran unasobreexpresión de genes proinflamatorios y proapoptóticos. Enlos pacientes con EHNA y fibrosis, se observa, además, una sobreexpresiónde genes profibrogénicos, incluyendo el gen del receptorde la leptina.2. La expresión de prohibitiva en los pacientes con EHNA,tanto con fibrosis como sin fibrosis, fue superior que en los controles,lo que sugiere una disfunción mitocondrial en los pacientescon EHNA
Although the molecular basis for the pathophysiology of nonalcoholicsteatohepatitis (NASH) is poorly understood, we evaluatethe hepatic gene expression of cytokines, chemokines, cell receptors,growth factors, intracellular transducers and extracellularcommunication proteins in liver tissue of obese patients (with andwithout NASH), and we determine the specific intrahepatic geneexpression profiles associated with histological severe NASH.Thirty-eight obese patients with BMI > 35 were analyzed, whounderwent bariatric surgery. Biopsy specimen samples were snapfrozenin liquid nitrogen. Hepatic gene expression was determinedin liver biopsy specimens from 3 groups: a) obese patientswithout NASH (n = 12); b) patients with NASH without fibrosis (n= 13); and c) patients with NASH and fibrosis (n = 13). Geneswere considered to be expressed differentially in NASH only ifthere was a greater than 2-fold difference in abundance of mRNAwhen compared with each of the control group. These resultswere confirmed by real-time PCR. Fourteen genes were differentiallyexpressed (10 overexpressed and 4 underexpressed) in patientswith NASH. Genes that were significantly overexpressed includedprohibitin, TNF, TNF RI (p55), MCSF, R2-TRAIL,b1-CTGF, FGF, VEGF, and BIGH3OBR. Insulin growth factor-1,insulin growth factor-2, interleukin-2 and tyrosine-receptor wereunderexpressed in NASH patients.In conclusion:1. The obese patients with NASH without fibrosis show anoverexpression of proinflammatory and proapoptotic genes.Also, the NASH patients with fibrosis show an overexpression offibrogenic genes, including the leptin receptor Ob-Rb.2. The up-regulated gene expression of prohibitin suggestsmitochondrial dysfunction in NASH patients
