Neutrophil sequestration in the lung following acute aortic occlusion starts during ischaemia and can be attenuated by tumour necrosis factor and nitric oxide blockade.
OBJECTIVE
To investigate the role of lower extremity ischaemia in acute lung injury with special emphasis on the role of tumour necrosis factor (TNF) and nitric oxide (NO) as mediators of neutrophil (PMN) chemotaxis in the lung.


METHODS
Prospective randomised study.


METHODS
Sprague-Dawley rats were randomized into four groups: group 1 (x-clmap): aorta clamped just above the bifurcation for 3 h; group 2 (AG): 50 mg/kg aminoguanidine, a specific inducible NO synthase (iNOS) inhibitor, was administered prior to aortic occlusion; group 3 (Steroids): 1 mg/kg dexamethasone was administered prior to aortic occlusion; and group 4 (TNFbp): 2 mg/kg TNFbp, a PEGylated dimeric form of the high affinity TNF receptor I (R1) was administered prior to aortic occlusion to block TNF action. Groups 2, 3 and 4 were subjected to the same ischaemia time as group 1. NO concentration in the exhaled gas (ENO) was measured in 30 min intervals. At the end of the 3 h ischaemia, one lung was excised and fixed for routine histological evaluation, and the other underwent bronchoalveolar lavage (BAL). PMN chemotaxis towards the BAL fluid was then measured using the blindwell technique.


RESULTS
ENO in group 1 increased from 0.9 +/- 0.3 ppb at baseline, to 41.3 +/- 9.2 ppb at the end of ischaemia. Animals in this group exhibited significant lung inflammation. Aminoguanidine, dexamethasone and TNFbp blocked NO production (peak ENO values of 7.2 +/- 1.9, 12.6 +/- 1.3 and 8.9 +/- 1.7 ppb for groups 2, 3 and 4 respectively), decreased PMN chemotaxis and sequestration in the lung, and attenuated lung inflammation.


CONCLUSIONS
Acute lung injury resulting from distal aortic occlusion starts during ischaemia. TNF and NO blockade decrease PMN chemotaxis and sequestration and attenuate the lung injury process.
SUNY Health Science Center, Department of Surgery, Syracuse, NY 13210, USA.
A K
AK
Tassiopoulos
T S
TS
Hakim
C M
CM
Finck
A
A
Pedoto
M G
MG
Hodell
S K
SK
Landas
D J
DJ
McGraw
D000704:Analysis of Variance; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001011:Aorta / Q000502:physiology; D002633:Chemotaxis / Q000502:physiology*; D003250:Constriction; D003907:Dexamethasone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D007249:Inflammation; D007511:Ischemia / Q000209:etiology / Q000503:physiopathology*; D008163:Luminescent Measurements; D008168:Lung / Q000473:pathology*; D008297:Male; D009504:Neutrophils / Q000502:physiology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052247:Nitric Oxide Synthase Type II; D011446:Prospective Studies; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology*
D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D006146:Guanidines; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D003907:Dexamethasone; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C004479:pimagedine