Mechanisms of loss of human neutrophil chemotaxis following thermal injury.

The increased susceptibility to infection of patients with thermal injury is related to loss of host defense, which is reflected, in part, by the temporal loss of chemotactic function of leukocytic phagocytes. Our studies of patient neutrophils to define the mechanism of this phenomenon involved evaluation of both random and chemotactic migratory functions of patient neutrophils, measurement of receptors for chemotactic ligands, and measurement of receptors mediating substrate adherence of the cells. Measurements of migratory functions were made using the under-agarose technique and measurements of receptor expression were accomplished by flow cytometry using fluorescein-labeled ligand or receptor-specific antibody. We conclude that loss of chemotaxis in response to C5a/C5adesArg is the results of down-regulation of receptors for C5a and of reduced motility, and that loss of chemotaxis in response to the tripeptide FMLP is the result of reduced motility alone. Measurements of changes in the expression of "adherence" (iC3b) receptors revealed that up-regulation occurs early and can be sustained for weeks after injury. These results are taken to suggest that either hyper- or hypo-adherence could explain the loss of random migratory function observed for patient cells. Evidence of auto-oxidative alteration of cytoskeletal elements, to produce loss of random migratory function, also is reviewed. Considering the evidence for activation of the complement cascade after thermal injury C5a and C5adesArg are likely primary factors in effecting the down-regulation of C5a receptors, stimulation of secretion to mobilize iC3b receptors, and stimulation of respiration to auto-oxidize cell components. Such evidence of injury-mediated complement activation included data derived from application of a novel immunoassay for iC3b.