HMGB1-associated necroptosis and Kupffer cells M1 polarization underlies remote liver injury induced by intestinal ischemia/reperfusion in rats.
FASEB J
; 34(3): 4384-4402, 2020 03.
Article
in En
| MEDLINE
| ID: mdl-31961020
ABSTRACT
Reperfusion of the ischemic intestine often leads to drive distant organ injury, especially injuries associated with hepatocellular dysfunction. The precise molecular mechanisms and effective multiple organ protection strategies remain to be developed. In the current study, significant remote liver dysfunction was found after 6 hours of reperfusion according to increased histopathological scores, serum lactate dehydrogenase (LDH), alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels, as well as enhanced bacterial translocation in a rat intestinal ischemia/reperfusion (I/R) injury model. Moreover, receptor-interacting protein kinase 1/3 (RIP1/3) and phosphorylated-MLKL expressions in tissue were greatly elevated, indicating that necroptosis occurred and resulted in acute remote liver function impairment. Inhibiting the necroptotic pathway attenuated HMGB1 cytoplasm translocation and tissue damage. Meanwhile, macrophage-depletion study demonstrated that Kupffer cells (KCs) are responsible for liver damage. Blocking HMGB1 partially restored the liver function via suppressed hepatocyte necroptosis, tissue inflammation, hepatic KCs, and circulating macrophages M1 polarization. What's more, HMGB1 neutralization further protects against intestinal I/R-associated liver damage in microbiota-depleted rats. Therefore, intestinal I/R is likely associated with acute liver damage due to hepatocyte necroptosis, and which could be ameliorated by Nec-1 administration and HMGB1 inhibition with the neutralizing antibody and inhibitor. Necroptosis inhibition and HMGB1 neutralization/inhibition, may emerge as effective pharmacological therapies to minimize intestinal I/R-induced acute remote organ dysfunction.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Reperfusion Injury
/
Intestines
/
Kupffer Cells
/
Liver
Type of study:
Prognostic_studies
/
Risk_factors_studies
Limits:
Animals
Language:
En
Journal:
FASEB J
Journal subject:
BIOLOGIA
/
FISIOLOGIA
Year:
2020
Type:
Article
Affiliation country:
China