Abstract
Murine acetaminophen-induced acute liver injury (ALI) serves as paradigmatic model for drug-induced hepatic injury and regeneration. As major cause of ALI, acetaminophen overdosing is a persistent therapeutic challenge with N-acetylcysteine clinically used to ameliorate parenchymal necrosis. To identify further treatment strategies that serve patients with poor N-acetylcysteine responses, hepatic 3′mRNA sequencing was performed in the initial resolution phase at 24 h/48 h after sublethal overdosing. This approach disclosed 45 genes upregulated (≥5-fold) within this time frame. Focusing on C5aR1, we observed in C5aR1-deficient mice disease aggravation during resolution of intoxication as evidenced by increased liver necrosis and serum alanine aminotransferase. Moreover, decreased hepatocyte compensatory proliferation and increased caspase-3 activation at the surroundings of necrotic cores were detectable in C5aR1-deficient mice. Using a non-hypothesis-driven approach, herein pro-regenerative/-resolving effects of C5aR1 were identified during late acetaminophen-induced ALI. Data concur with protection by the C5a/C5aR1-axis during hepatectomy and emphasize the complex role of inflammation during hepatic regeneration and repair.
Highlights
Acetaminophen is an over-the-counter marketed analgetic broadly used to treat weak-to-moderate pain in clinical practice
Statistical analysis on raw data: a Mann–Whitney-U-test, raw data are shown; c Student’s t-test (IL-10, heme oxygenase-1 (HO-1), TNFα), data are shown as means ± s.e.m.; Mann–Whitney-Utest (IL-36γ), data are shown as box-plots
Non-hypothesis-driven 3′mRNA sequencing by Massive Analysis of cDNA ends (MACE) disclosed a group of 45 genes that are consistently expressed at time points 24 h/48 h after administration of APAP and can be considered as gene candidates potentially affecting resolution from intoxication
Summary
Acetaminophen (paracetamol, N-acetyl-p-aminophenol; APAP) is an over-the-counter marketed analgetic broadly used to treat weak-to-moderate pain in clinical practice. Generally well-tolerated when applied in recommended dosages, APAP is, subsequent to accidental or intentional overdosing, a leading cause of acute liver injury (ALI) world-wide. APAP is, to a significant degree, converted to highly reactive N-acetyl-p-benzoquinone imine (NAPQI) by action of hepatocyte cytochrome p450 monooxygenases, foremost CYP2e1 and CYP1a2. Unchecked excessive NAPQI activity, initiates a deleterious string of events involving oxidative stress, activation of c-jun N-terminal kinase, mitochondrial dysfunction, and DNA fragmentation— culminating in hepatocyte necrosis[3,4]. This initial phase of APAP intoxication can evolve into fatal acute liver failure. Associated compensatory parenchymal hypertrophy is driven by pro-proliferative molecules such as EGF receptor ligands, hepatocyte growth factors, and signal transducer and activator of transcription (STAT)-3-activating cytokines like interleukin (IL)-65,6
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
