CHEMOTATIC MECHANISMS IN NEONATAL BACTERIAL INFECTION

人类的新生儿特别容易受到细菌感染 因为宿主防御系统不成熟 其中一个最一致的缺陷， 新生儿的宿主防御系统明显异常， 多形性白细胞趋化性 不幸的是， 关于这种细胞发育缺陷的发病机制， 运动 在这项赠款的头两年进行的研究中， 我们已经证明，新生儿的中性粒细胞不能形成聚合的，或F 肌动蛋白，在化学引诱物的刺激下从凝胶肌动蛋白中分离出来;一个过程 这是提供细胞所需的收缩力所必需的 运动 另外的实验表明新生儿的中性粒细胞 在趋化后膜电位发生关键变化， 因子刺激并产生较低浓度的细胞内游离 钙 早期环腺苷酸（cAMP）反应 在新生儿的PMN中，趋化因子刺激也减弱。 这些结果表明，信号转导异常可能导致 在人类中观察到的细胞运动发育异常中， 新生儿 基于这些令人兴奋的初步结果，我们希望 尝试定义缺陷的确切机制，并尝试 纠正异常。 具体来说，我们将1）确定刚性 新生儿中性粒细胞的细胞膜阻止了 受体和钝化或阻断信号转导; 2）试图 确定缺乏变化的原因和重要性， 膜电位和细胞内游离 新生儿PMN中的细胞内钙;以及3）试图发展 用于纠正的趋化反应的药理学方案 新生儿的中性粒细胞。

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.