Inhibition of Drug-Induced Liver Injury in Mice Using a Positively Charged Peptide That Binds DNA.
Hepatol Commun
; 5(10): 1737-1754, 2021 10.
Article
en En
| MEDLINE
| ID: mdl-34532999
ABSTRACT
Hepatic cell death occurs in response to diverse stimuli such as chemical and physical damage. The exposure of intracellular contents such as DNA during necrosis induces a severe inflammatory response that has yet to be fully explored therapeutically. Here, we sought means to neutralize the ability of extracellular DNA to induce deleterious tissue inflammation when drug-induced liver injury had already ensued. DNA exposure and inflammation were investigated in vivo in drug-induced liver injury using intravital microscopy. The necrotic DNA debris was studied in murine livers in vivo and in DNA debris models in vitro by using a positively charged chemokine-derived peptide (MIG30; CXCL9[74-103]). Acetaminophen-induced liver necrosis was associated with massive DNA accumulation, production of CXC chemokines, and neutrophil activation inside the injured tissue. The MIG30 peptide bound the healthy liver vasculature and, to a much greater extent, to DNA-rich necrotic tissue. Moreover, MIG30 bound extracellular DNA directly in vivo in a charge-dependent manner and independently of glycosaminoglycans and chemokines. Post-treatment of mice with MIG30 reduced mortality, liver damage, and inflammation significantly. These effects were not observed with a control peptide that does not bind DNA. Mechanistically, MIG30 inhibited the interaction between DNA and histones, and promoted the dissociation of histones from necrotic debris. MIG30 also inhibited the pro-inflammatory effect of CpG DNA, as measured by a reduction in CXCL8 production, indicating that MIG30 disturbs the ability of DNA to induce hepatic inflammation. Conclusion:
The use of DNA-binding peptides reduces necrotic liver injury and inflammation, even at late timepoints.
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Péptidos
/
Degradación Necrótica del ADN
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Enfermedad Hepática Inducida por Sustancias y Drogas
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Hígado
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Antiinflamatorios
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Hepatol Commun
Año:
2021
Tipo del documento:
Article