RESUMO
Once a patient is in septic shock, survival rates drop by 7.6% for every hour of delay in antibiotic therapy. Biomarkers based on the molecular mechanism of sepsis are important for timely diagnosis and triage. Here, we study the potential roles of a panel of cellular and viral miRNAs as sepsis biomarkers. We performed genome-wide microRNA (miRNA) expression profiling in leukocytes from septic patients and nonseptic controls, combined with quantitative RT-PCR in plasmas from two cohorts of septic patients, two cohorts of nonseptic surgical patients and healthy volunteers. Enzyme-linked immunosorbent assay, miRNA transfection and chromatin immunoprecipitation were used to study the effects of Kaposi sarcoma herpes virus (KSHV) miRNAs on interleukin's secretion. Differences related to sepsis etiology were noted for plasma levels of 10 cellular and 2 KSHV miRNAs (miR-K-10b and miR-K-12-12*) between septic and nonseptic patients. All the sepsis groups had high KSHV miRNAs levels compared with controls; Afro-American patients had higher levels of KSHV-miR-K12-12* than non-Afro-American patients. Both KSHV miRNAs were increased on postoperative day 1, but returned to baseline on day 7; they acted as direct agonists of Toll-like receptor 8 (TLR8), which might explain the increased secretion of the IL-6 and IL-10. Cellular and KSHV miRNAs are differentially expressed in sepsis and early postsurgical patients and may be exploited for diagnostic and therapeutic purposes. Increased miR-K-10b and miR-K12-12* are functionally involved in sepsis as agonists of TLR8, forming a positive feedback that may lead to cytokine dysregulation.
Assuntos
Herpesvirus Humano 8/genética , MicroRNAs/genética , Sarcoma de Kaposi/genética , Sepse/genética , Receptor 8 Toll-Like/genética , Ferimentos e Lesões/genética , APACHE , Negro ou Afro-Americano , Idoso , Estudos de Casos e Controles , Retroalimentação Fisiológica , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Interleucina-6/sangue , Interleucina-6/genética , Interleucina-8/sangue , Interleucina-8/genética , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Leucócitos Mononucleares/virologia , Masculino , MicroRNAs/sangue , Pessoa de Meia-Idade , Sarcoma de Kaposi/sangue , Sarcoma de Kaposi/etnologia , Sarcoma de Kaposi/mortalidade , Sepse/sangue , Sepse/etnologia , Sepse/mortalidade , Transdução de Sinais , Análise de Sobrevida , Receptor 8 Toll-Like/sangue , Ferimentos e Lesões/sangue , Ferimentos e Lesões/etnologia , Ferimentos e Lesões/mortalidadeRESUMO
MicroRNAs are non-coding RNA fragments, well characterized and well preserved along the evolution of the species and whose essential role is to regulate gene expression. MicroRNAs perform its action on messenger RNA ("target"). They induce degradation or repression of target translation with a significant decrease in the quantity and the activity of proteins. MicroRNAs are involved in normal cell function. Abnormal levels of microRNA were found in several pathological contiditions such as cancer, autoimmune diseases, viral infections, sepsis. Sepsis appears as a result of an improper inflammatory response after systemic bacterial infection. It remains a disease with a high incidence and mortality despite the evolution of diagnostic and treatment techniques. Sepsis patients have similar features to those found in the endotoxin tolerance phenomenon. Endotoxin tolerance is a state of hyporesponsivness to endotoxin challenge induced by a prior exposure. Due to its important role in repression of the pro-inflammatory cytokines translation, microRNA can be considered a new mechanism of endotoxin tolerance and a new mechanism involved in sepsis pathogenesis. In sepsis patients abnormal levels of the following types of microRNA were found: miR-146, miR-155, miR150, miR-132. Further studies are carried out to demonstrate the potential role of microRNA as biomarkers in sepsis.
