The newborn human infant is especially susceptible to bacterial infections because of immature host defenses. One of the most consistent defects in the neonate's host defense system is a marked abnormality in polymorphonuclear leukocyte chemotaxis. Unfortunately, very little is known about the pathogenesis of this developmental defect in cell movement. In studies carried out during the first two years of this grant, we have shown that the PMNs from neonates fail to form polymerized, or F actin, from gel actin following stimulation with chemoattractant; a process which is essential in providing the contractile forces required for cell movement. Additional experiments indicate that the PMNs from neonates fail to undergo critical changes in membrane potential following chemotactic factor stimulation and develop lower concentrations of intracellular free calcium. The early cyclic adenosine 3'5' monophosphate (cAMP) response to chemotactic factor stimulation is also blunted in the PMNs from neonates. These results suggest that an abnormality in signal transduction may result in the developmental abnormality in cell motility observed in the human neonate. Based on these rather exciting preliminary results, we wish to attempt to define the exact mechanism(s) of the defect and attempt to correct the abnormality. Specifically, we will 1) determine if the rigid cell membrane of the PMNs from neonates is preventing lateral mobility of receptors and blunting or blocking signal transduction; 2) attempt to define the reasons for, and significance of, the lack of changes in membrane potential and the smaller increases in intracellular in free intracellular calcium in the neonatal PMN; and 3) attempt to develop pharmacologic regimens for correcting the chemotactic responsiveness of PMNs from neonates.
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