Overdoses of acetaminophen (also known as paracetamol) account for most drug overdoses in a number of countries, including the United States. Such overdoses damage the liver, causing acute liver failure, which can be fatal.
Wajahat Mehal and colleagues, at Yale University, New Haven, have now provided new insight into the mechanisms by which acetaminophen causes liver damage in mice and determined that aspirin provides substantial protection from these toxic effects of acetaminophen.
Overdoses of acetaminophen cause two waves of liver damage. The first wave of liver cell destruction is a result of the toxic nature of acetaminophen. The second wave is mediated by molecules of the immune system, which is activated in response to the initial acetaminophen-induced liver damage. In the study, the first wave of dying mouse liver cells were found to promote the production of immune molecules known as proinflammatory cytokines by sinusoidal endothelial cells in the liver. This production of proinflammatory cytokines required two signaling pathways to be active, one initiated by the protein Tlr9 and one activated by a protein complex known as the Nalp3 inflammasome. Interestingly, aspirin was found to protect mice against acetaminophen-induced liver damage by downregulating proinflammatory cytokine production. In an accompanying commentary, Jacquelyn Maher, at the University of California, San Francisco, discusses the importance of these data for understanding the mechanisms underlying a severe clinical condition.