REACTION AND DIFFUSION OF NITRIC OXIDE IN BIOLOGICAL SYSTEMS

研究表明，一氧化氮（NO）作为信使分子在体内被广泛合成和使用，但它也具有细胞毒性和诱变作用，是癌症的潜在原因。尽管一氧化氮具有重要的生物学意义，但关于体内或细胞培养系统中一氧化氮浓度的时空变化的信息仍然非常有限。对于活性中间体，如酸酐亚氮和过氧亚硝酸盐，情况更是如此，它们可能是由于局部NO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，但需要这些信息来将细胞培养中测量的毒性水平和突变率与实际暴露水平相关联，并将这些发现推断为体内的病理情况。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在水中、跨细胞膜和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，重点是细胞膜脂质双分子层成分的渗透性和/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的细胞和作为其毒性或诱变作用靶点的细胞之间的相互作用。在细胞培养物中控制过氧亚硝酸盐递送的方法将被开发出来。其目的是通过化学和物理手段（即不需要“产生器”细胞）为“目标”细胞提供已知的、接近生理剂量的过氧亚硝酸盐。

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).