title: Blocking TNF-α enhances Pseudomonas aeruginosa-induced mortality in burn mice through induction of IL-1β.
abstract: OBJECTIVE
  Tumor necrosis factor (TNFα) is a proinflammatory cytokine and has been a target for intervention in human sepsis. However, inhibition of TNF-α with a high dose of a TNF-receptor fusion protein in patients with septic shock worsened patient survival. This study was designed to investigate whether blocking TNF-α enhances mortality in infected burn mice through the induction of IL-1β.
  
  
  METHODS
  WT or Tnfrsf1a(-/-) mice received Pseudomonas aeruginosa injection in the back at 8h after burn injury. The animals were sacrificed at 24h after burn and lung tissues were harvested and examined for determining myeloperoxidase (MPO) activity, pulmonary microvascular dysfunction, NF-κB DNA binding activity, and IL-1β expression. Also, the lung and blood were harvested for bacterial count assay.
  
  
  RESULTS
  Thermal injury alone induced NF-κB DNA binding activity and neutrophil infiltration in the lung in WT but not in Tnfrsf1a(-/-) mice. A 50% total body surface area (TBSA) burn induced a significant increase of mortality in WT compared with Tnfrsf1a(-/-) mice. In contrast, P. aeruginosa injection with a 30% TBSA burn pretreatment enhanced IL-1β expression, bacterial counts in lung and blood, pulmonary microvascular dysfunction, and mortality in Tnfrsf1a(-/-) mice compared with WT mice. Injection of the IL-1 receptor antagonist, Anakinra, reduced P. aeruginosa infection with burn pretreatment-induced blood bacterial counts, IL-1β levels as well as permeability of lung, and mortality in Tnfrsf1a(-/-) mice.
  
  
  CONCLUSIONS
  Our findings suggest that thermal injury induces lung NF-κB activation and neutrophil sequestration through TNFα signaling. However, blocking TNF-α enhances P. aeruginosa infection-induced lung damage in burn mice via induction of IL-1β. Using an IL-1 receptor antagonist combined with the neutralization of TNF-α could be a useful strategy for decreasing P. aeruginosa infection-induced mortality in burn patients.
authors.affiliation: Department of Surgery, Zuoying Armed Forces General Hospital, Kaohsiung, Taiwan.
authors.forename: Tzyy-Bin
authors.initials: TB
authors.lastname: Tsay
authors.affiliation: Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
authors.forename: Ming-Chieh
authors.initials: MC
authors.lastname: Yang
authors.affiliation: Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
authors.forename: Pei-Hsuan
authors.initials: PH
authors.lastname: Chen
authors.affiliation: Department of Surgery, Zuoying Armed Forces General Hospital, Kaohsiung, Taiwan.
authors.forename: Kuan-Hung
authors.initials: KH
authors.lastname: Lai
authors.affiliation: Department of Anatomy, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Hung-Tu
authors.initials: HT
authors.lastname: Huang
authors.affiliation: Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan. Electronic address: chingmei@mail.nsysu.edu.tw.
authors.forename: Ching-Mei
authors.initials: CM
authors.lastname: Hsu
authors.affiliation: Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; Institute of Emergency and Critical Care Medicine, National Yang-Ming University, Taipei, Taiwan. Electronic address: chenlw2001@yahoo.com.tw.
authors.forename: Lee-Wei
authors.initials: LW
authors.lastname: Chen
mesh_terms: D000818:Animals; D002056:Burns / Q000382:microbiology* / Q000473:pathology*; D015169:Colony Count, Microbial; D004247:DNA / Q000378:metabolism; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000382:microbiology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011552:Pseudomonas Infections / Q000097:blood / Q000382:microbiology / Q000473:pathology / Q000503:physiopathology; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000502:physiology*; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013696:Temperature; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D016328:NF-kappa B; D017472:Receptors, Interleukin-1; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D004247:DNA; D009195:Peroxidase