LATE PROTECTIVE EFFECTS OF NETRIN-1 AND ADENOSINE A2B RECEPTOR ACTIVATION IN THE MURINE ACETAMINOPHEN HEPATOTOXICITY MODEL

Acetaminophen (APAP) overdose causes severe hepatotoxicity and the current antidote N-acetylcysteine (NAC), has a narrow early therapeutic window. Since most patients present late to the clinic, novel late acting therapeutic options are needed. The neuronal guidance cue netrin-1 has been shown to promote hepatic repair and regeneration during liver ischemia/reperfusion injury, but its effects in APAP hepatotoxicity is unknown. The primary objective of this dissertation was to explore the role of netrin-1 and its receptor adenosine A2B in APAP hepatotoxicity. In the first study, we explored the mechanisms behind the mice sub-strain susceptibility to APAP toxicity. We demonstrated that C57BL/6N mice were more susceptible to APAP-induced hepatotoxicity than C57BL/6J mice; the higher susceptibility of C57BL/6N mice was caused by forming more APAP-protein adducts and subsequent enhanced mitochondrial dysfunction associated with aggravated nuclear DNA fragmentation. In the second study, we demonstrated that the neuronal guidance protein netrin-1 could attenuate APAP hepatotoxicity in mice at late time points but it did not influence APAP metabolism, JNK activation and translocation; in contrast, netrin-1 promoted macrophage migration and liver regeneration. Its receptor adenosine A2B receptor (A2BAR) was highly induced at late time points and blocking its receptor could remove its late protective effects, indicating that netrin-1 through its receptor A2BAR, attenuated APAP hepatotoxicity by promoting macrophage migration and liver regeneration. In the third study, we explored the role of A2BAR in APAP hepatotoxicity. We found that activating A2BAR at early time could protect APAP hepatotoxicity in mice by attenuating mitochondrial dysfunction. However, when the A2BAR was activated by its agonist BAY 606583 at 6 h after APAP overdose, BAY 606583 showed superior protective effects compared to NAC. Again, the protective effects were caused by promoting macrophage migration and liver regeneration. Even a 9 h delay in activating the A2BAR with BAY 606583 after an APAP overdose promoted liver recovery after 48 h without having any effect on the injury. In summary, this dissertation demonstrated that through A2BAR, netrin-1 could attenuate APAP hepatotoxicity by attenuating mitochondrial dysfunction and promoting macrophage migration and liver regeneration. However, activating A2BAR at late time points could selectively promote the liver recovery. Thus, targeting A2BAR may be a promising therapeutic approach for patients with APAP overdose.

Grantor dc:publisher

University of Kansas

Year dc:date.issued

2020

Author dc:creator

• Duan, Luqi

Advisor dc:contributor.advisor

• Jaeschke, Hartmut

• Pharmacology
• Molecular biology
• acetaminophen
• adenosine A2B receptor
• liver damage
• liver regeneration
• macrophage
• Netrin-1

Statement dc:rights

• Copyright held by the author.

Language dc:language.iso

en

Dc Identifier Other

http://dissertations.umi.com/ku:17413

OAI identifier oai:identifier

oai:kuscholarworks.ku.edu:1808/39302