Role of the Nalp3 inflammasome in acetaminophen-induced sterile inflammation and liver injury

Journal Article · Sun May 01 00:00:00 EDT 2011 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2011.03.001· OSTI ID:21535290

Williams, C David ^[1]; Antoine, Daniel J ^[2]; Shaw, Patrick J ^[3]; Benson, Craig ^[2]; Farhood, Anwar ^[4]; Williams, Dominic P ^[2]; Kanneganti, Thirumala-Devi ^[3]; Park, B Kevin ^[2]; Jaeschke, Hartmut ^[1]

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1. Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160 (United States)
2. MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool L69 3GE (United Kingdom)
3. Department of Immunology, St. Jude's Research Hospital, Memphis, TN 38104 (United States)
4. Department of Pathology, Brackenridge Hospital, Austin, TX 78701 (United States)

Acetaminophen (APAP) overdose is the leading cause of acute liver failure in the US and UK. Recent studies implied that APAP-induced injury is partially mediated by interleukin-1{beta} (IL-1{beta}), which can activate and recruit neutrophils, exacerbating injury. Mature IL-1{beta} is formed by caspase-1, dependent on inflammasome activation. The objective of this invetstigation was to evaluate the role of the Nalp3 inflammasome on release of damage associated molecular patterns (DAMPs), hepatic neutrophil accumulation and liver injury (ALT, necrosis) after APAP overdose. Mice deficient for each component of the Nalp3 inflammasome (caspase-1, ASC and Nalp3) were treated with 300 mg/kg APAP for 24 h; these mice had similar neutrophil recruitment and liver injury as APAP-treated C57Bl/6 wildtype animals. In addition, plasma levels of DAMPs (DNA fragments, keratin-18, hypo- and hyper-acetylated forms of high mobility group box-1 protein) were similarly elevated with no significant difference between wildtype and gene knockout mice. In addition, aspirin treatment, which has been postulated to attenuate cytokine formation and the activation of the Nalp3 inflammasome after APAP, had no effect on release of DAMPs, hepatic neutrophil accumulation or liver injury. Together, these data confirm the release of DAMPs and a sterile inflammatory response after APAP overdose. However, as previously reported minor endogenous formation of IL-1{beta} and the activation of the Nalp3 inflammasome have little impact on APAP hepatotoxicity. It appears that the Nalp3 inflammasome is not a promising therapeutic target to treat APAP overdose.

• OSTI ID: 21535290
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 3 Vol. 252; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ACETYLSALICYLIC ACID
ANALGESICS
ANIMALS
ANTIPYRETICS
BIOLOGICAL MATERIALS
BLOOD
BLOOD CELLS
BODY
BODY FLUIDS
BUILDUP
CARBOXYLIC ACIDS
CENTRAL NERVOUS SYSTEM AGENTS
CENTRAL NERVOUS SYSTEM DEPRESSANTS
DAMAGE
DIGESTIVE SYSTEM
DISEASES
DNA
DRUGS
GENES
GLANDS
HYDROXY ACIDS
INFLAMMATION
INJURIES
KERATIN
LEUKOCYTES
LIVER
MAMMALS
MATERIALS
MICE
NECROSIS
NEUTROPHILS
NUCLEIC ACIDS
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANS
PATHOLOGICAL CHANGES
PROTEINS
RODENTS
SCLEROPROTEINS
SYMPTOMS
VERTEBRATES