Inhibition of the Interaction of TREM-1 and eCIRP Attenuates Inflammation and Improves Survival in Hepatic Ischemia/Reperfusion.
Shock
; 57(2): 246-255, 2022 02 01.
Article
em En
| MEDLINE
| ID: mdl-34864782
ABSTRACT
INTRODUCTION:
Triggering receptor expressed on myeloid cells-1 (TREM-1) has important implications in sepsis and inflammation and is a novel receptor for extracellular cold-inducible RNA-binding protein (eCIRP). We hypothesize that the inhibition of TREM-1 via its interaction with eCIRP by novel peptide inhibitor M3 or knockout gene will attenuate the inflammation and injury associated with severe hepatic ischemia/reperfusion (I/R).METHODS:
Wild-type (WT) C57BL/6 and TREM-1-/- mice underwent 60âmin of 70% hepatic ischemia, with 24âh of reperfusion. Additionally, WT mice underwent hepatic I/R and were treated with M3 (10âmg/kg body weight) or vehicle (normal saline) at the start of reperfusion. Blood and ischemic liver tissues were collected, and analysis was performed using enzymatic assays, enzyme-linked immunosorbent assay, reverse-transcription quantitative polymerase chain reaction, and pathohistology techniques. For survival surgery, mice additionally underwent resection of non-ischemic lobes of the liver and survival was monitored for 10âdays.RESULTS:
There was an increase in serum levels of tissue markers including aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase as well as cytokine levels (IL-6) and histological scoring of hematoxylin and eosin sections in WT I/R mice. These markers decreased substantially in TREM-1-/- mice. Additionally, neutrophil infiltration markers and markers of local inflammation (myeloperoxidase, macrophage inflammatory protein-2, cyclooxygenase-2) were attenuated in TREM-1-/- mice. Similarly, we show a significant decrease in injury and inflammation markers with M3 treatment. Additionally, we demonstrate decreased apoptosis with TREM-1 inhibition. Finally, M3 treatment improved the survival rate from 42% to 75% after hepatic I/R.CONCLUSION:
TREM-1 is an important eCIRP receptor in the inflammatory response of hepatic I/R, and deficiency of TREM-1 via knockout gene or peptide inhibition attenuated liver injury and inflammation, and improved survival. Inhibition of the TREM-1 and eCIRP interaction in hepatic I/R may have important therapeutic potential.
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Base de dados:
MEDLINE
Assunto principal:
Traumatismo por Reperfusão
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Proteínas de Ligação a RNA
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Receptor Gatilho 1 Expresso em Células Mieloides
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Inflamação
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Fígado
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article