Bloqueio da sinalização purinérgica como alternativa terapêutica para a falência hepática aguda

• Ano de defesa: 2013
• Autor(a) principal: Jayane Lais Dias Quintão
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de Minas Gerais; UFMG
• Palavras-chave em Português: Paracetamol; Inflamação estéril; Lesão hepática; Sinalização purinérgica; Sistema imune; Morte celular; Inflamação; Biologia celular
• Link de acesso: http://hdl.handle.net/1843/BUOS-978FGJ

The liver is an organ that performs functions essential to life, such as metabolic control, plasma protein synthesis and detoxification of chemicals, drugs and toxins. With that, he is subject to the occurrence of various types ofinjury, such as those induced by chemical agents. Acetaminophen (APAP), an analgesic and antipyretic in common use can cause liver damage if taken in high doses, even leading to acute liver failure (FHA), a fatal disorder that causes thousands of deaths annually and is responsible for 50% of all liver transplants in the world. It has been reported that during cell death by overdose of paracetamol there is an imbalance in the culminating in mitochondrial homeostasis hepatocyte death by necrosis and consequently release their intracellular contents, such as formylated peptides, mitochondrial DNA, HSP (heat shock protein) and ATP (adenosine triphosphate). ATP is secreted from hepatocytes under physiological conditions and plays an important role in modulating the functions of the liver, through activation of purinergic receptors. Interestingly, higher concentrations of extracellular ATP, as observed inthe necrosis, unleash activation of inflammatory responses that contribute to the progression of liver injury, but has not yet been established which purinergic receptors are involved, as well as the differential function of these receptors in acute liver failure induced by overdose of APAP. It is already known that impaired calcium homeostasis is a feature of hepatotoxicity induced by acetaminophen (APAP), since ATP induces the mobilization of intracellular stores this ion. Thus, our study evaluated whether ATP release during necrosis induced by acetaminophen could directly contribute to activation of cellular immune response, promoting increased liver injury. In accordance with our in vivo results, treatment withAPAP overdose resulted in extensive areas of necrosis in the liver and neutrophil infiltration macissa not perfused large areas and the onset of systemic inflammation. In the liver, theseeffects were significantly reversed after ATP metabolism by one or ATPase at block purinergicreceptors, but none of the treatments prevented the pulmonary inflammation, suggesting think that the purinergic signaling contributes paracrine liver. In corroboration of our findings, experiments performed in vitro have shown that treatment with APAP induces loss ofcell viability and quantitatively the real-time PCR showed that incubation of HepG2 cellswith APAP increased the expression of several purinergic receptors, which may explain thehiperesponsividade to extracellular ATP. This phenotype was confirmed by experiments using human liver biopsies of patients diagnosed with fulminant hepatic failure. Our data is leading us to think that under pathological conditions, ATP can act not only as anactivator of the immune system, but also plays an autocrine and paracrine as a DAMP cytotoxic, mainly desrregular intracellular calcium homeostasis.