title: Role of nitric oxide and tumor necrosis factor on lung injury caused by ischemia/reperfusion of the lower extremities.
abstract: OBJECTIVE
  Acute aortic occlusion with subsequent ischemia/reperfusion (I/R) of the lower extremities is known to predispose to lung injury. The pathophysiologic mechanisms of this injury are not clear. In the present study, we studied the role of tumor necrosis factor (TNF) and nitric oxide (NO) in lung injury caused by lower extremity I/R.
  
  
  METHODS
  A rat model in which the infrarenal aorta was cross-clamped for 3 hours followed by 1 hour of reperfusion was used. The rats were randomized into five groups: group 1, aorta exposed but not clamped; group 2, aorta clamped for 3 hours, followed by 1 hour of reperfusion; group 3, 1 mg/kg dexamethasone administered before the aorta was clamped; group 4, 25 mg aminoguanidine, a specific inducible NO synthase (iNOS) inhibitor, administered before the aorta was clamped; and group 5, 2 mg/kg TNFbp, a PEG-ylated dimeric form of the high-affinity p55 TNF receptor I (RI), administered before the aorta was clamped. NO concentration in the exhaled gas (ENO) was measured, as an index of NO production by the lung, in 30 minute intervals during I/R. Serial arterial blood samples for TNF assay were obtained during the course of the experiment. At the end of the experiment, the lungs were removed and histologically examined for evidence of injury.
  
  
  RESULTS
  ENO in group 2 increased from 0.7 +/- 0.3 ppb at baseline to 54.3 +/- 7.5 ppb at the end of ischemia and remained stable during reperfusion (54.6 +/- 8.5 ppb at the end of reperfusion). ENO production was blocked by aminoguanidine, by dexamethasone, and by TNFbp given before aortic occlusion. Serum TNF in groups 2, 3 and 4 increased rapidly during early ischemia, reaching its peak value 60 minutes after occlusion of the aorta, then gradually declined to baseline levels at the end of ischemia, and remained low during reperfusion. TNFbp decreased serum TNF concentration significantly when it was given before aortic occlusion. Histologic examination of the lungs at the end of the experiment revealed that aminoguanidine, dexamethasone, and TNFbp had a protective effect on the lungs.
  
  
  CONCLUSIONS
  Serum TNF increases rapidly during lower extremity ischemia and causes increased production of NO from the lung by upregulating iNOS. Increased NO is associated with more severe lung injury, and iNOS blockade has beneficial effects on the lung. TNF blockade before ischemia decreases NO production by the lung and attenuates lung injury. ENO can be used as an early marker of lung injury caused by lower extremity I/R.
authors.affiliation: Department of Surgery, State University of New York Health Science Center, Syracuse 13210, USA.
authors.forename: A K
authors.initials: AK
authors.lastname: Tassiopoulos
authors.forename: R E
authors.initials: RE
authors.lastname: Carlin
authors.forename: Y
authors.initials: Y
authors.lastname: Gao
authors.forename: A
authors.initials: A
authors.lastname: Pedoto
authors.forename: C M
authors.initials: CM
authors.lastname: Finck
authors.forename: S K
authors.initials: SK
authors.lastname: Landas
authors.forename: D G
authors.initials: DG
authors.lastname: Tice
authors.forename: W
authors.initials: W
authors.lastname: Marx
authors.forename: T S
authors.initials: TS
authors.lastname: Hakim
authors.forename: D J
authors.initials: DJ
authors.lastname: McGraw
mesh_terms: D000818:Animals; D001012:Aorta, Abdominal; D003250:Constriction; D003907:Dexamethasone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D006614:Hindlimb / Q000098:blood supply*; D008168:Lung / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000502:physiology*
chemical_list: D004791:Enzyme Inhibitors; D006146:Guanidines; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D003907:Dexamethasone; D019001:Nitric Oxide Synthase; C004479:pimagedine