Phagocytic cells are essential for host defense against infection. The function of these cells is controlled by a complicated interplay of responses to surface signals followed by appropriate effector functions which results in migration to the infected site, engulfment and subsequent killing of microbes. In order to better understand phagocytic function and to modulate this in favor of the host, we plan to study the interrelationships of surface signals and effector function in human polymorphonuclear neutrophils, monocytes and monocyte-derived macrophages. External calcium concentrations are about ten thousand-fold greater than internal concentrations and entrance or mobilization of calcium into the cytoplasm has been closely associated with the triggering of effector functions. Thus, we will pay special attention to the role of calcium as a putative second messenger. We will utilize sophisticated computer-enhanced microscopic techniques in order to visualize and quantitate subcellular calcium concentrations. These calcium concentrations will be monitored in living phagocytes subjected to various environments and stimuli. The intracellular patterns of calcium distribution will be determined. Probes of calcium concentration, including quin-2, aequorin, and chlortetracycline will be utilized. The latter will detect membrane associated calcium. The ion microscope will be used to detect total subcellular elemental calcium. We will be able to measure the effect on calcium pools of various pharmacologicagents that have been shown to enhance, and those that have been shown to depress phagocyte function and thus relate microenvironmental changes in calcium to phagocyte function. Effectot functions such as chemotaxis, motility, phagocytosis, membrane receptor topography and mobility, bactericidal activity, and oxidative activity will be axamined. Enhanced understanding of control of phagocytic cells should allow is to modulate the function of these cells to enable patients to better combat, or avoid infection.
| Vollmer, K L; Alberts, J S; Carper, H T et al. (1992) Tumor necrosis factor-alpha decreases neutrophil chemotaxis to N-formyl-1-methionyl-1-leucyl-1-phenylalanine: analysis of single cell movement. J Leukoc Biol 52:630-6 |
| Sawyer, D W; Donowitz, G R; Mandell, G L (1989) Polymorphonuclear neutrophils: an effective antimicrobial force. Rev Infect Dis 11 Suppl 7:S1532-44 |
