REACTION AND DIFFUSION OF NITRIC OXIDE IN BIOLOGICAL SYSTEMS

它已被证明，一氧化氮（NO）被广泛合成，并作为信使分子在体内使用，但它也有细胞毒性和致突变作用，是一个潜在的癌症原因。尽管NO的生物学重要性，但关于体内或细胞培养系统中NO浓度的空间或时间变化的信息仍然非常有限。对于活性中间体如亚硝酸酐和过氧亚硝酸盐来说，这是双重真实的，它们可能是由于NO局部过量产生而对健康产生不利影响的介质。在大多数感兴趣的条件下测量这些化合物的浓度在技术上是不可行的，但是需要这样的信息来将细胞培养物中测量的毒性水平和突变率与实际暴露水平相关联，并将这些发现外推到体内的病理情况。因此，将开发数学模型来预测水溶液、细胞培养物和组织中NO和相关化合物的浓度。由于各种浓度是由反应速率和扩散速率之间的竞争决定的，因此模型将基于反应动力学和控制通过水、穿过细胞膜和在细胞内扩散的物理性质。NO和相关化合物的扩散和反应将在细胞或细胞样颗粒的悬浮液中进行检查，重点是细胞膜的脂质双层组分的渗透性和/或反应性。反应扩散模型的预测将在细胞培养系统中进行测试。特别令人感兴趣的是产生大量NO的细胞与作为其毒性或致突变作用靶的细胞之间的相互作用。将开发用于在细胞培养物中控制递送过氧亚硝酸盐的方法。其目的是通过化学和物理手段（即，而不需要“发生器”单元）。

It has been shown that nitric oxide (NO) is widely synthesized and used as a messenger molecule in the body, but that it also has cytotoxic and mutagenic effects and is a potential cause of cancer. The biological importance of NO notwithstanding, information on the spatial or temporal variations in NO concentrations in the body or in cell culture systems continues to be very limited. This is doubly true for reactive intermediates such as nitrous anhydride and peroxynitrite, which may be mediators of adverse health effects due to the local overproduction of NO. It is not technically feasible to measure the concentrations 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. Because the various concentrations are determined by a competition between rates of reaction and diffusion, the models will be based on reaction kinetics and on the physical properties governing diffusion through water, across cell membranes, and within cells. The diffusion and reaction of NO and related compounds will be examined in suspensions of cells or cell-like particles, with an emphasis on the permeability and/or reactivity of the lipid bilayer component of cell membranes. The predictions of the reaction-diffusion models will be tested in cell culture systems. Of particular interest are the interactions between cells which generate large amounts of NO and cells which act as targets for its toxic or mutagenic effects. Methods will be developed for the controlled delivery of peroxynitrite in cell cultures. The objective there is to provide known, near-physiological doses of peroxynitrite for "target" cells by chemical and physical means (i.e., without the need for "generator" cells).