RESUMO
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.
Assuntos
Pulmão/metabolismo , Ativação de Macrófagos/genética , Fibrose Pulmonar/genética , Escleroderma Sistêmico/genética , 2',5'-Oligoadenilato Sintetase/genética , 2',5'-Oligoadenilato Sintetase/metabolismo , Adulto , Antígenos/genética , Antígenos/metabolismo , Antígenos CD/genética , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/genética , Antígenos de Diferenciação Mielomonocítica/metabolismo , Quimiocinas CC/genética , Quimiocinas CC/metabolismo , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Cadeia alfa 1 do Colágeno Tipo I , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Progressão da Doença , Feminino , Humanos , Pulmão/patologia , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/patologia , Fibrose Pulmonar/fisiopatologia , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Testes de Função Respiratória , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/patologia , Escleroderma Sistêmico/fisiopatologia , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismoRESUMO
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.