The Immune Response After Drug Induced Hepatotoxicity

点击翻译按钮获取中文摘要

PROJECT SUMMARY Acetaminophen (APAP) overdose is the most common cause of acute liver failure in the United States and thus is an important clinical problem. Though the current antidote N-acetylcysteine (NAC) was developed in the 1970's and is effective if administered early, its efficacy decreases if given beyond 8 hours after an APAP overdose. In spite of the significant progress in understanding mechanisms of APAP-induced liver injury in the subsequent decades, no additional therapeutic approaches to complement NAC have been developed and translated to the clinic. Part of the problem is the delayed presentation of patients to the hospital, by which time the injury process is often in progress and any drugs including NAC targeting early processes may be of limited benefit. It is now recognized that the regenerative capacity of the liver subsequent to APAP-induced injury is a critical feature dictating patient prognosis. APAP induces a late innate immune reaction in response to cell injury, and our early studies in mice and humans indicated that immune cell infiltration facilitated removal of damaged cells and was helpful in regeneration and recovery. Our recently published data now indicate that guidance cues such as the protein netrin-1 function through the adenosine A2B receptor to suppress neutrophils and enhance macrophage infiltration into the necrotic area to facilitate liver regeneration and recovery after an APAP overdose. Based on recent information that neutrophil and macrophage phenotypes can shift cell functionality from pro-inflammatory to anti-inflammatory, we hypothesize that activation of the adenosine A2B receptor enhances immune-cell mediated liver recovery after APAP overdose and this could be an effective late-acting therapeutic approach against APAP-induced hepatotoxicity. This hypothesis will be tested by 1) Elucidating molecular mechanisms involved in macrophage recruitment and liver regeneration after activation of the adenosine A2B receptor and their facilitation of recovery after APAP overdose in vivo, 2) Examining the effects of pharmacological modulation as well as deficiency of the adenosine A2B receptor on APAP-induced liver injury in vivo, and 3) Explore the role of A2BAR agonists and the innate immune response after prolonged NAC and evaluate circulating monocyte markers from patients after APAP overdose. We have advanced early acting alternative therapies for APAP overdose such as 4-methylpyrazole (4MP) through pre- clinical animal experiments and volunteer safety studies to planning of a clinical trial. While 4MP functions to prevent APAP-induced injury and would be beneficial in patients with severe overdose, it is anticipated that results from the studies proposed here will provide novel insight into the A2B receptor as a putative target for a late acting therapeutic to complement 4MP and NAC in the clinic and improve outcomes after an APAP overdose.