title: Soluble tumor necrosis factor receptors reduce bowel ischemia-induced lung permeability and neutrophil sequestration.
abstract: OBJECTIVE
  To evaluate the possible role of tumor necrosis factor (TNF) in the development of lung injury after bowel ischemia, and the ability of TNF-soluble receptors to negate TNF toxicity, using a rat small bowel ischemia and reperfusion model.
  
  
  METHODS
  Prospective, randomized, controlled laboratory study.
  
  
  METHODS
  Research laboratory.
  
  
  METHODS
  Forty adult male Sprague-Dawley rats weighing approximately 300 g.
  
  
  METHODS
  The rats were divided equally into four groups: a) ischemia and reperfusion alone; b) those animals receiving TNF antibodies (1 mL) before reperfusion; and c) those animals receiving 200 micrograms of human recombinant TNF soluble receptors. These 30 anesthetized rats underwent 60 mins of superior mesenteric artery occlusion per 4 hrs of reperfusion. The remaining ten animals were sham operated (laparotomy), serving as controls. Lung permeability was measured using bovine serum albumin labeled with 125I, and organ injury was assessed histologically.
  
  
  RESULTS
  Thirty and 60 mins after declamping and reperfusion, plasma TNF concentrations increased to 830 +/- 66 and 173 +/- 56 pg/mL, respectively, compared with 10 pg/mL before ischemia (p < .001). In sham-operated control rats, TNF concentrations did not increase from baseline concentrations. Four hours after reperfusion, sequestration of neutrophils in the pulmonary microcirculation was noted (319 +/- 60 vs. 84 +/- 13 neutrophils/10 high-power fields in sham-operated rats [p < .04]). Pulmonary microvascular leak also occurred, as measured by translocation of radiolabeled albumin into the bronchoalveolar space and expressed as the ratio of bronchoalveolar lavage to blood concentrations. This ratio was 5.3 +/- 0.8 in ischemic control animals compared with 1.1 +/- 0.3 in sham animals (p < .03). Treatment with antibodies to TNF before reperfusion attenuated the pulmonary injury (75 +/- 6 neutrophils/10 high-power fields, permeability index 1.6 +/- 0.1) less than in ischemic controls (p < .005). A similar protection was achieved with soluble TNF receptors, which prevented bowel ischemia-induced lung neutrophil sequestration (117 +/- 35 neutrophils/10 high-power fields, pulmonary vascular leak ratio of 2.3 +/- 0.1, p < .05).
  
  
  CONCLUSIONS
  The results of this study show that ischemia and subsequent reperfusion of the intestine in rats produce lung injury. This injury is mediated, at least in part, by TNF. Soluble TNF receptors are an effective tool in preventing lung TNF injury after intestinal ischemia.
authors.affiliation: Department of Intensive Care and Anesthesiology, Ichilov Hospital, Tel Aviv Sourasky Medical Center, Israel.
authors.forename: P
authors.initials: P
authors.lastname: Sorkine
authors.forename: A
authors.initials: A
authors.lastname: Setton
authors.forename: P
authors.initials: P
authors.lastname: Halpern
authors.forename: A
authors.initials: A
authors.lastname: Miller
authors.forename: V
authors.initials: V
authors.lastname: Rudick
authors.forename: S
authors.initials: S
authors.lastname: Marmor
authors.forename: J M
authors.initials: JM
authors.lastname: Klausner
authors.forename: G
authors.initials: G
authors.lastname: Goldman
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D002199:Capillary Permeability; D004195:Disease Models, Animal; D007421:Intestine, Small / Q000098:blood supply*; D007511:Ischemia / Q000209:etiology / Q000503:physiopathology; D008297:Male; D009504:Neutrophils / Q000502:physiology*; D011446:Prospective Studies; D011652:Pulmonary Circulation / Q000502:physiology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D015427:Reperfusion Injury / Q000150:complications / Q000503:physiopathology*; D012995:Solubility; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism / Q000502:physiology*
chemical_list: D015703:Antigens, CD; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha