Protective effects of selectin chimeras in neutrophil-mediated lung injury.
Recombinant selectin chimeric molecules featuring the joining of the extracellular domains of L-, P-, and E-selectin to the CH2 and CH3 domains of human IgG1 have been evaluated for their ability to protect against neutrophil-dependent lung injury in rats after systemic activation 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-selectin dependent. Requirements for L-selectin have not been identified because 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-dependent 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 alter MPO content. In contrast, in the IgG immune complex model of lung injury, the L- and E-selectin-Ig chimeras both showed dose-related protective effects and reductions in MPO content, whereas the P-selectin-Ig chimera failed to protect against injury and did not alter MPO content in this model of lung injury. In all cases of blocking of injury, this was incomplete, suggesting multi-selectin engagement or inadequate amounts of selectin-Ig chimeras employed. These data indicate that neutrophil 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, differing selectin requirements for acute inflammatory lung injury have been identified.
Mulligan
M S
MS
Department of Pathology, University of Michigan Medical School, Ann Arbor 48109-0602.
Watson
S R
SR
Fennie
C
C
Ward
P A
PA
D000818:Animals; D000936:Antigen-Antibody Complex / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000494:pharmacology*; D019040:E-Selectin; D004546:Elapid Venoms / Q000633:toxicity; D007074:Immunoglobulin G / Q000276:immunology; D019041:L-Selectin; D007958:Leukocyte Count / Q000187:drug effects; D008168:Lung / Q000473:pathology*; D008297:Male; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D019007:P-Selectin; D009195:Peroxidase / Q000032:analysis; D010980:Platelet Membrane Glycoproteins / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*
D000936:Antigen-Antibody Complex; D015815:Cell Adhesion Molecules; D019040:E-Selectin; D004546:Elapid Venoms; D007074:Immunoglobulin G; D019007:P-Selectin; D010980:Platelet Membrane Glycoproteins; D011993:Recombinant Fusion Proteins; C016310:cobra venom factor; D019041:L-Selectin; D009195:Peroxidase