PROTECTIVE EFFECTS OF SELECTIN CHIMERAS IN NEUTROPHIL-MEDIATED LUNG INJURY

Recombinant selectin chimeric molecules featuring the joining of the e xtracellular domains of L-, P-, and E-selectin to the CH2 and CH3 doma ins of human IgG1 have been evaluated for their ability to protect aga inst neutrophil-dependent lung injury in rats after systemic activatio n of C caused by vascular infusion of cobra venom factor (CVF) or lung injury that follows intrapulmonary deposition of IgG immune complexes . Previous studies using anti-selectin antibodies have suggested that the former model is P-selectin dependent, whereas the latter is E-sele ctin dependent. Requirements for L-selectin have not been identified b ecause of lack of reagents. For the current studies employing the CVF model of lung injury, infusion of P-selectin-Ig chimera reduced injury (as assessed by changes in permeability and hemorrhage) in a dose-dep endent manner, with parallel reductions in lung myeloperoxidase (MPO) content. Similar results were obtained with the L-selectin-Ig chimera, whereas the E-selectin-Ig chimera was not protective and failed to al ter MPO content. In contrast, in the IgG immune complex model of lung injury, the L- and E-selectin-Ig chimeras both showed dose-related pro tective effects and reductions in MPO content, whereas the P-selectin- Ig chimera failed to protect against injury and did not alter MPO cont ent in this model of lung injury. In all cases of blocking of injury, this was incomplete, suggesting multi-selectin engagement or inadequat e amounts of selectin-Ig chimeras employed. These data indicate that n eutrophil recruitment and attendant lung injury in the CVF model are L - and P-selectin dependent and E-selectin-independent, whereas in the IgG immune complex model, neutrophil recruitment and lung injury are L - and E-selectin-dependent but independent of P-selectin. Thus, differ ing selectin requirements for acute inflammatory lung injury have been identified.