Role of neutrophil adherence receptors (CD 18) in lung permeability following lower torso ischemia

Ischemia and reperfusion of the lower torso lead to leukotriene- and neutrophil (PMN)-dependent lung injury characterized by lung PMN sequestration, increased permeability, and noncardiogenic edema. It is thought that PMNs require adhesion to endothelium to alter barrier function. This study tests the role of CD 18, the PMN adherence receptor, in mediating lung permeability after lower torso ischemia and reperfusion. Anesthetized rabbits (n=9) underwent 3 hours of bilateral hind limb ischemia. Ten minutes after the release of the tourniquets, plasma leukotriene B₄ levels increased to 395±85 pg/ml, higher than 129±35 pg/ml in controls (n=9,p<0.01). At this time there was a reduction in circulating white blood cells (×10³), 3.56±0.49/mm³ relative to 6.07±0.61/mm³ in controls (p<0.01). PMNs were sequestered in the hind limbs, indicated by increased myeloperoxidase activity of 1.06±0.19 units/g compared with 0.56±0.09 units/g in controls (p<0.05). Four hours after tourniquet release, PMNs were sequestered in the lungs, 52±4 PMNs per 10 high-power fields, a value higher than 31.5±3 PMNs per 10 high-power fields in controls; bronchoalveolar lavage fluid protein content increased to 554±90 Mg/ml relative to 277±46 μg/ml in controls; and there was lung edema, measured by increased wet weight-to-dry weight ratios of 5.19±0.10, higher than 4.29±0.21 in controls (all p<0.01). The wet/dry ratios of the heart, liver, and kidney were unchanged. Pretreatment of other rabbits (n=8) with a purified anti-CD 18 monoclonal antibody (R 15.7, 1 mg/kg) 10 minutes before tourniquet release did not affect the rise in leukotriene B₄ but was effective in preventing leukopenia (7.29± 1.05/mm³, p<0.01) and sequestration of PMNs in the hind limbs (myeloperoxidase activity, 0.46±0.12 units/g, p<0.05). Further, the anti-CD 18 monoclonal antibody prevented lung sequestration of PMNs (34±3 PMNs per 10 high-power fields, p<0.01) and reduced permeability, shown by a fall in bronchoalveolar lavage fluid protein to 324±41 μg/ml and a fall in wet/dry weight ratio to 4.61±0.10 (both p<0.05). These data suggest that CD 18 is important in PMN-dependent lung injury after remote ischemia.