Colaboração entre quimiocinas e peptídeos mitocondriais no recrutamento e ativação de neutrófilos durante a lesão hepática estéril

Abstract

Conditions that affect liver physiology and function have a severe effect on homeostasis and frequently lead to death. Paracetamol (APAP), a widely used analgesic and antipyretic drug, can cause liver injury when ingested at high doses, leading to acute liver failure, a disorder responsible for thousands of deaths per year and 50% of all liver transplants. In this disease, a phenomenon named sterile inflammation occurs, in which many leukocytes participate, but neutrophils have been featured as tissue-damaging cells, aggravating any tissue injury already in process. Considering this, our objectives were to determine if neutrophils are involved in this type of liver injury and which molecules participate in neutrophil recruitment to the site of damage. Our data indicate that neutrophils participate in the pathogenesis of APAP-induced liver injury, because they are recruited during the process of tissue injury and its depletion protects mice from APAP-induced liver damage. Moreover, we observed a large increase in chemokine and cytokine production in the liver, and interestingly, an increase in circulating mitochondrial DNA in the serum of APAP-treated mice, highlighting the role of Damage-Associated Molecular Patterns such as formyl-peptides and mitochondrial DNA in this type of injury. In this context, drugs that block neutrophil recruitment, such as the chemokine receptor CXCR2 antagonist DF2156 and the formyl-peptide receptor antagonist BOC-1, are capable of not only reducing neutrophil influx to the liver, but also to significantly decrease liver injury and inflammation when applied simultaneously to mice. Considering this, we can conclude that the regulation of neutrophil recruitment and the inflammatory process occurring in the necrotic liver, by the CXCR2 and FPR1 antagonists, has great therapeutic potential for acute liver failure treatment and also for many other diseases characterized by sterile inflammation.