NEUTROPHIL SEQUESTRATION IN THE LUNG FOLLOWING ACUTE AORTIC OCCLUSIONSTARTS DURING ISCHEMIA AND CAN BE ATTENUATED BY TUMOR-NECROSIS-FACTORAND NITRIC-OXIDE BLOCKADE

Objectives: To investigate the role Of lower extremity ischaemia in ac ute lung injury with special emphasis on the role of tumour necrosis f actor (TNF) and nitric oxide (NO) as mediators of neutrophil (PMN) che motaxis in the lung. Design: Prospective randomised study. Materials a nd methods: Sprague-Dawley rats were randomized into four groups: grou p 1 (x-clamp): aorta clamped just above the bifurcation for 3 h; group 2 (AG): 50 mg/kg aminoguanidine, a specific inducible NO synthase (iN OS) inhibitor, was administered prior to aortic occlusion; group 3 (St eroids):1 mg/kg dexamethasone was administered prior to aortic occlusi on; and group 4 (TNFbp): 2 mg/kg TNFbp, a PEGylated dimeric for,rr of the high affinity TNF receptor I (R-1) was administered prior to aorti c occlusion to block TNF action. Groups 2, 3 and 4 were subjected to t he 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 ischaem ia, 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 I increased from 0.9 +/- 0.3 ppb at baseline, to 41.3 +/- 9.2 ppb at the aid of ischaemia. Animals in this group exh ibited significant lung inflammation. Aminoguanidine, dexamethasone an d 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), decreas ed PILIN chemotaxis and sequestration in the lung, and attenuated lung inflammation. Conclusions: Acute lung injury resulting from distal ao rtic occlusion starts during ischaemia. TNF and NO blockade decrease P MN chemotaxis and sequestration and attenuate the lung injury process.