Neutrophil sequestration in the lung following acute aortic occlusion starts during ischaemia and can be attenuated by tumour necrosis factor and nitric oxide blockade

Objectives: 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. Design: Prospective randomised study. Materials and Methods: Sprague-Dawley rats were randomised into four groups: group 1 (x-clamp): aorta clamped just above the bifurcation for 3 h; group 2 (AG): 50 mg/kg aminogaunidine, 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, a PEGylated dimeric form of the high affinity TNF receptor I (R(I)) was administered prior to aortis occlusion to block TNF action. Groups 2, 3 and 4 were subject 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 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 from Group 1 increased from 0.9 ± 0.3 ppb at baseline, to 41.3 ± 9.2 pb at the end of ischaemia. Animals in this gorup 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 PMA 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.