LEUKOCYTE INTEGRIN VERY LATE ANTIGEN-4 VASCULAR CELL-ADHESION MOLECULE-1 ADHESION PATHWAY IN SPLANCHNIC ARTERY-OCCLUSION SHOCK/

We investigated the role played by the very late antigen-4 (VLA-4)/vas cular cell adhesion molecule-1 (VCAM-1) interaction in the pathogenesi s of splanchnic artery occlusion shock. Splanchnic artery occlusion sh ock was induced in anaesthetized rats by clamping splanchnic arteries for 45 min. Sham operated animals were used as controls. Survival time , serum tumour necrosis factor (TNF-alpha), monocyte and lymphocyte ce ll count and the responsiveness to acetylcholine of aortic rings were studied. Furthermore we investigated the VCAM-1 expression on vessel e ndothelium and the percentage of VLA-4 positive leukocytes. Splanchnic artery occlusion shocked rats had a decreased survival time (76 +/- 1 0 min, while sham shocked rats survived more than 4 h), increased seru m levels of TNF-alpha (328 +/- 11 U/ml), a decreased number of both mo nocytes and lymphocytes and reduced responsiveness to acetylcholine (1 0 nM-10 mu M) of aortic rings, In addition we found an increased expre ssion of endothelial VCAM-1 on aortic rings and a reduced percentage o f VLA-4 positive lymphocytes and monocytes. Passive immunization with specific antibodies raised against either VCAM-1 or VLA-4 (2 mg/kg, i. v., 3 h before splanchnic artery occlusion shock) increased survival, improved monocyte and lymphocyte count and restored the responsiveness of aortic rings to acetylcholine (P < 0.01). Finally, inhibition of T NF-alpha biosynthesis reversed the increased endothelial expression of VCAM-1 and the reduced percentage of integrin VLA-4 positive leukocyt es. Our findings suggest that (i) VLA-4/VCAM-1 interaction has a role in the pathogenesis of circulatory shock; (ii) this interaction might be a target for new therapeutic approaches to the therapy of low-flow states.