# The Immune Response After Drug Induced Hepatotoxicity

> **NIH NIH R01** · UNIVERSITY OF KANSAS MEDICAL CENTER · 2022 · $339,900

## Abstract

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.

## Key facts

- **NIH application ID:** 10356936
- **Project number:** 5R01DK125465-02
- **Recipient organization:** UNIVERSITY OF KANSAS MEDICAL CENTER
- **Principal Investigator:** Anup Ramachandran
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $339,900
- **Award type:** 5
- **Project period:** 2021-04-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10356936

## Citation

> US National Institutes of Health, RePORTER application 10356936, The Immune Response After Drug Induced Hepatotoxicity (5R01DK125465-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10356936. Licensed CC0.

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