Abstract
Antibiotic-induced endotoxin release is associated with high mortality rate even when appropriate antibiotics are used for the treatment of severe infections in intensive care units. Since liver is involved in systemic clearance and detoxification of endotoxin hence it becomes a primary target organ for endotoxin mediated inflammation. Currently available anti-inflammatory drugs give rise to serious side effects. Hence, there is an urgent need for safe and effective anti-inflammatory therapy. It is likely that anti-inflammatory phytochemicals and neutraceutical agents may have the potential to reduce the endotoxin mediated inflammation and complications associated with endotoxin release. Keeping this in mind, the present study was planned to evaluate the hepatoprotective potential of zingerone (active compound of zingiber officinale) against liver inflammation induced by antibiotic mediated endotoxemia. The selected antibiotics capable of releasing high content of endotoxin were employed for their in vivo efficacy in P.aeruginosa peritonitis model. Released endotoxin induced inflammation and zingerone as co-anti-inflammatory therapy significantly reduced inflammatory response. Improved liver histology and reduced inflammatory markers MDA, RNI, MPO, tissue damage markers (AST, ALT, ALP) and inflammatory cytokines (MIP-2, IL-6 and TNF-α) were indicative of therapeutic potential of zingerone. The mechanism of action of zingerone may be related to significant inhibition of the mRNA expression of inflammatory markers (TLR4, RelA, NF-kB2, TNF- α, iNOS, COX-2) indicating that zingerone interferes with cell signalling pathway and suppresses hyper expression of cell signaling molecules of inflammatory pathway. Zingerone therapy significantly protected liver from endotoxin induced inflammatory damage by down regulating biochemical as well as molecular markers of inflammation. In conclusion, this study provides evidence that zingerone is a potent anti-inflammatory phytomedicine against hepatic inflammation induced by antibiotic mediated endotoxemia. These results thus suggest that zingerone treatment can be used as a co-therapy with antibiotics to reduced endotoxin induced inflammation during treatment of severe P.aeruginosa infections.
Highlights
Gram negative nosocomial pathogen Pseudomonas aeruginosa causes a variety of infections including spontaneous bacterial peritonitis pyogenic liver abscess, sepsis and septic shock [1,2,3]
LPS binding proteins (LBP) binds to endotoxin and activates CD14, toll-like receptor (TLR) 4 and MD2 surface receptor complex of macrophages, monocytes, hepatocytes and kupffer cells [10] resulting in potent inflammatory response
Endotoxin binds with TLR4 receptor which is highly expressed in cells that respond to endotoxin, such as macrophages, monocytes, hepatocytes and kupffer cells and induces expression of inflammatory genes through TLR4/NF-kB signaling pathway
Summary
Gram negative nosocomial pathogen Pseudomonas aeruginosa causes a variety of infections including spontaneous bacterial peritonitis pyogenic liver abscess, sepsis and septic shock [1,2,3]. LBP (endotoxin binding protein) binds to endotoxin and activates CD14, toll-like receptor (TLR) 4 and MD2 surface receptor complex of macrophages, monocytes, hepatocytes and kupffer cells [10] resulting in potent inflammatory response. Ligand induced activation of NF-kB is due to activation of NFkB-2, leading to liberation of p52/RelB [14]. Both these pathways activate transcription of array of different genes. TLR4 may have a role in non-canonical NF-kB signaling since its ligand (endotoxin) induces P100 processing in a B-cell line [15]. Further NF-kB regulates the production of pro-inflammatory mediators, such as TNF-a, COX-2 and iNOS and IL-12 which are mainly responsible for endotoxin induced tissue injury
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