The synthesis and release of nitric oxide (NO) by macrophages is a normal part of the non specific immune response to infection, but sustained overproduction of NO by those cells, as in certain chronic inflammations, may present a significant health risk. If at too high a concentration for too long, NO is cytotoxic and mutagenic, making it a potential cause of cancer. What constitutes too high a concentration or too long a time remains unclear, though, because quantitative information on local NO concentrations in the body, or even in cell culture systems, continues to be very limited. This is even more the case for highly reactive compounds such as nitrous anhydride and peroxynitrite, which are derived from NO in biological solutions and which may mediate many of its adverse effects, even if present at extremely low concentrations. It is not feasible to directly measure the concentrations of any of these compounds under most conditions of interest, yet such information is needed to correlate levels of toxicity and rates of mutation measured in cell cultures with actual levels of exposure, and to extrapolate those findings to pathological situations in the body. Accordingly, mathematical models will be developed to predict the concentrations of NO and related compounds in aqueous solutions, cell cultures, and tissues. The models will describe the manner in which rates of reaction compete with rates of diffusion to determine local concentrations. A key element in modeling cellular systems is the net rate of NO production by macrophages, and the influence of NO and oxygen concentrations on NO synthesis will be measured in macrophage cultures. Also needed are diffusion coefficients for NO in dense cellular arrays, which will be inferred from diffusivities to be measured in protein solutions and cell suspensions. This information on the rates of NO synthesis and diffusion will be combined with other kinetic and morphometric data to estimate the concentrations of NO and its products in tissues. Models that simulate specific in vitro situations will help to interpret experiments designed to quantify the toxicity and mutagenicity of NO and its products in various cell types. In vitro models will be used also to derive kinetic parameters from rates of NO-induced damage to proteins and DNA measured in other experiments.
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