Objective: The goal of this proposal is to study mechanisms of neutrophil-neutrophil communication not involving touch, or diffusive neutrophil crosstalk, that activate neutrophils and produce tissue inflammation. Hypotheses: 1. Active human polymorphonuclear neutrophils (PMN) secrete messengers that act on distant PMN causing their activation independent of other stimuli. 2. The serial activation of multiple PMN depends on transduction, amplification, propagation and prolongation of the original activating signal. 3. Mathematical modeling of this intercellular communication process may improve our understanding of diseases involving generalized acute or chronic inflammation originating from localized and temporary injury. Research Plan: This project will use multi-disciplinary methods to explore the nature of neutrophil-neutrophil interactions leading to cellular activation. The first specific aim is to identify and characterize the agent(s) of diffusive PMN crosstalk. Using techniques derived from patch clamping studies they will activate single PMN resting on non-activating surfaces. Using multiple light microscopy techniques they will describe and measure the process of intercellular activation. By using blockers of known secreted molecules of neutrophils, the investigators will identify the actual intercellular messenger and measure the effects of PMN secreted molecules, such as proteinases and reactive oxygen species. The second specific aim is to describe the serial activation of multiple PMN distant from an initially activated cell. Using intracellular markers and blockade of major intracellular mediators of activation, they will quantify and describe the transduction pathway of a signal and examine the transponding ability of PMN to amplify, prolong and propagate activation signals. The third specific aim is to model activation waves originating from singly activated PMN. Using numerical analytic techniques we will model the diffusion of intercellular activators at the molecular level and compare with experimental observations. By incorporating transduction information and knowledge of microscopic anatomy, the investigators will extend the model to examine the effect of propagating PMN activation waves at cell, tissue and organ levels. Significance: Successful completion of this proposal promises an improved understanding of basic mechanisms that promote inflammatory processes that underlie acute and chronic inflammatory diseases.
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