title: Role of tumor necrosis factor-alpha and interleukin-1beta on lung dysfunction following hemorrhagic shock in rats.
abstract: BACKGROUND
  Hemorrhagic shock occasionally causes a fatal outcome following an outbreak of lung dysfunction, but the precise mechanism has not been clearly elucidated. Several studies have indicated that hemorrhagic shock causes a delayed vascular inflammatory decompensation and leads to inflammation-related organ dysfunction. Tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta are known as major proinflammatory cytokines that play an important role in excessive autolytic inflammation, finally inducing organ dysfunctions. In this study, the role of TNF-alpha and IL-1beta on lung dysfunction following hemorrhagic shock was examined by using FR167653, a potent inhibitor of TNF-alpha and IL-1beta production that acts by suppressing p38 mitogen-activated protein kinase (MAPK).
  
  
  METHODS
  Hemorrhagic shock was induced in anesthetized male rats by bleeding via a common carotid catheter for 20 minutes to 25% of total body blood volume without fluid resuscitation. Mean blood pressure, heart rate and arterial blood gas components were recorded up to 5 hours after the bleeding. The levels of TNF-alpha, IL-1beta and lactic dehydrogenase (LDH)-3 isozyme were measured in the serum of pulmonary venous blood. The lung tissue was excised for the assay of mRNA and for histopathological study.
  
  
  RESULTS
  The expressions of mRNA for TNF-alpha and IL-1beta in the lung tissue and the concentrations of both cytokines in pulmonary serum increased after a hemorrhage. Inflammation-related injuries and function deterioration were observed in the lung following hemorrhagic shock. These hemorrhagic changes were inhibited by pretreatment with FR167653.
  
  
  CONCLUSIONS
  TNF-alpha and IL-1beta play a key role in the development of inflammation-related lung dysfunction following hemorrhagic shock. Our model should be useful to explain the pathogenesis of lung dysfunction following hemorrhagic shock.
authors.affiliation: Department of Forensic Medicine, School of Medicine, University of Occupational and Environmental Health, Japan. h-sato@med.uoeh-u.ac.jp
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Sato
authors.forename: Kentaro
authors.initials: K
authors.lastname: Kasai
authors.forename: Toshiko
authors.initials: T
authors.lastname: Tanaka
authors.forename: Toshiro
authors.initials: T
authors.lastname: Kita
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D001784:Blood Gas Analysis; D006470:Hemorrhage; D006801:Humans; D007249:Inflammation; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000502:physiology*; D008168:Lung / Q000473:pathology*; D020935:MAP Kinase Signaling System; D008297:Male; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012771:Shock, Hemorrhagic / Q000473:pathology*; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000502:physiology*
chemical_list: C104334:FR 167653; D053583:Interleukin-1beta; D011720:Pyrazoles; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha