TY - JOUR
T1 - Distinct responses between healthy and cirrhotic human livers upon lipopolysaccharide challenge
T2 - possible implications for acute-on-chronic liver failure
AU - Suriguga, Su
AU - Li, Mei
AU - Luangmonkong, Theerut
AU - Boersema, Miriam
AU - de Jong, Koert P.
AU - Oosterhuis, Dorenda
AU - Gorter, A. R.
AU - Beljaars, Leonie
AU - Olinga, Peter
PY - 2022/8/1
Y1 - 2022/8/1
N2 - Patients with acute-on-chronic liver failure (ACLF) are at risk of developing acute hepatic decompensation and organ failures with an unraveled complex mechanism. An altered immune response toward insults in cirrhotic compared with healthy livers may contribute to the ACLF development. Therefore, we aim to investigate the differences in inflammatory responses between cirrhotic and healthy livers using human precision-cut liver slices (PCLSs) upon the lipopolysaccharide (LPS) challenge. PCLSs prepared from livers of patients with cirrhosis or healthy donors of liver transplantation were incubated ex vivo with or without LPS for up to 48 h. Viability test, qRT-PCR, and multiplex cytokine assay were performed. Regulation of the LPS receptors during incubation or with LPS challenge differed between healthy versus cirrhotic PCLSs. LPS upregulated TLR-2 in healthy PCLSs solely (P < 0.01). Culturing for 48 h induced a stronger inflammatory response in the cirrhotic than healthy PCLS. Upon LPS stimulation, cirrhotic PCLSs secreted more proinflammatory cytokines (IL-8, IL-6, TNF-α, eotaxin, and VEGF) significantly and less anti-inflammatory cytokine (IL-1ra) than those of healthy. In summary, cirrhotic PCLSs released more proinflammatory and less anti-inflammatory cytokines after LPS stimuli than healthy, leading to dysregulated inflammatory response. These events could possibly resemble the liver immune response in ACLF.NEW & NOTEWORTHY Precision-cut liver slices (PCLSs) model provides a unique platform to investigate the different immune responses of healthy versus cirrhotic livers in humans. Our data show that cirrhotic PCLSs exhibit excessive inflammatory response accompanied by a lower anti-inflammatory cytokine release in response to LPS; a better understanding of this alteration may guide the novel therapeutic approaches to mitigate the excessive inflammation during the onset of acute-on-chronic liver failure.
AB - Patients with acute-on-chronic liver failure (ACLF) are at risk of developing acute hepatic decompensation and organ failures with an unraveled complex mechanism. An altered immune response toward insults in cirrhotic compared with healthy livers may contribute to the ACLF development. Therefore, we aim to investigate the differences in inflammatory responses between cirrhotic and healthy livers using human precision-cut liver slices (PCLSs) upon the lipopolysaccharide (LPS) challenge. PCLSs prepared from livers of patients with cirrhosis or healthy donors of liver transplantation were incubated ex vivo with or without LPS for up to 48 h. Viability test, qRT-PCR, and multiplex cytokine assay were performed. Regulation of the LPS receptors during incubation or with LPS challenge differed between healthy versus cirrhotic PCLSs. LPS upregulated TLR-2 in healthy PCLSs solely (P < 0.01). Culturing for 48 h induced a stronger inflammatory response in the cirrhotic than healthy PCLS. Upon LPS stimulation, cirrhotic PCLSs secreted more proinflammatory cytokines (IL-8, IL-6, TNF-α, eotaxin, and VEGF) significantly and less anti-inflammatory cytokine (IL-1ra) than those of healthy. In summary, cirrhotic PCLSs released more proinflammatory and less anti-inflammatory cytokines after LPS stimuli than healthy, leading to dysregulated inflammatory response. These events could possibly resemble the liver immune response in ACLF.NEW & NOTEWORTHY Precision-cut liver slices (PCLSs) model provides a unique platform to investigate the different immune responses of healthy versus cirrhotic livers in humans. Our data show that cirrhotic PCLSs exhibit excessive inflammatory response accompanied by a lower anti-inflammatory cytokine release in response to LPS; a better understanding of this alteration may guide the novel therapeutic approaches to mitigate the excessive inflammation during the onset of acute-on-chronic liver failure.
KW - acute-on-chronic liver failure
KW - cirrhosis
KW - human liver
KW - lipopolysaccharide
KW - precision-cut liver slices
U2 - 10.1152/ajpgi.00243.2021
DO - 10.1152/ajpgi.00243.2021
M3 - Article
C2 - 35727919
AN - SCOPUS:85134854493
SN - 1522-1547
VL - 323
SP - G114-G125
JO - American journal of physiology. Gastrointestinal and liver physiology
JF - American journal of physiology. Gastrointestinal and liver physiology
IS - 2
ER -