title: Burn plus lipopolysaccharide augments endoplasmic reticulum stress and NLRP3 inflammasome activation and reduces PGC-1α in liver.
abstract: Extensively burned patients often suffer from sepsis (especially caused by Pseudomonas aeruginosa), which may prolong metabolic derangement, contribute to multiple organ failure, and increase mortality. The molecular and cellular mechanisms of such infection-related metabolic derangement and organ dysfunction are unclear. We have previously shown that severely burned patients have significant and persisting hepatic endoplasmic reticulum (ER) stress. We hypothesized that ER stress and the unfolded protein response correlate with NOD-like receptor, pyrin domain containing 3 (NLRP3) inflammasome activation in burn. These may trigger profound metabolic changes in the liver, which form the pathological basis of liver damage and liver dysfunction after burn injury. A two-hit rat model was established by a 60% total body surface area scald burn and intraperitoneal injection of P. aeruginosa-derived lipopolysaccharide (LPS) 3 days after burn. One day later, animals were killed, and liver tissue samples were collected for gene expression and protein analysis of NLRP3 inflammasome activation, ER stress, and glucose and lipid metabolism. Liver damage was assessed by plasma markers (alanine aminotransferase and aspartate aminotransferase) and liver immunohistochemical analysis. Our results showed that burn injury and LPS injection induced inflammasome activation in liver and augmented hepatic ER stress and liver damage. Although there was an increased metabolic demand after burn, hepatic NLRP3 inflammasome activation corresponded to inhibition of PGC-1α (peroxisome proliferator-activated receptor γ-coactivator 1α) and its upstream regulators protein kinase A catalyst unit, AMP-activated protein kinase α, and sirtuin-1 may provide a mechanism for the enhanced metabolic derangement after major burn injury plus sepsis. In conclusion, burn + LPS augments inflammasome activation and ER stress in liver, which in turn contribute to postburn metabolic derangement.
authors.affiliation: *Sunnybrook Research Institute; †Department of Surgery, Division of Plastic Surgery, and Department of Immunology, University of Toronto; and ‡Ross Tilley Burn Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
authors.forename: Li
authors.initials: L
authors.lastname: Diao
authors.forename: Alexandra H
authors.initials: AH
authors.lastname: Marshall
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Dai
authors.forename: Elena
authors.initials: E
authors.lastname: Bogdanovic
authors.forename: Abdikarim
authors.initials: A
authors.lastname: Abdullahi
authors.forename: Saeid
authors.initials: S
authors.lastname: Amini-Nik
authors.forename: Marc G
authors.initials: MG
authors.lastname: Jeschke
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D002056:Burns / Q000503:physiopathology*; D002352:Carrier Proteins; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D058847:Inflammasomes / Q000502:physiology*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000378:metabolism*; D008107:Liver Diseases / Q000503:physiopathology*; D008297:Male; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011550:Pseudomonas aeruginosa / Q000737:chemistry; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C573346:Nlrp3 protein, rat; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D055372:AMP-Activated Protein Kinases; D056564:Sirtuin 1