Chin Melanie P, Schauer David B, Deen William M
Department of Chemical Engineering, Massachusetts Institute of Technology, Room 66-572, Cambridge, MA 02139, USA.
Nitric Oxide. 2008 Nov;19(3):266-75. doi: 10.1016/j.niox.2008.04.025. Epub 2008 May 3.
Nitric oxide production in the colon has been linked to inflammatory bowel disease (IBD) and increased risk for colon cancer. However, measurements of NO concentration in the inflamed colon have not been available and it is not known what NO levels are pathophysiological. A computational model, based on anatomical length scales and rates of NO production measured in cell cultures, was used to predict spatially varying NO concentrations within a colonic crypt under inflammatory conditions. A variety of scenarios were considered, including different spatial distributions of macrophages and a range of possible macrophage and epithelial synthesis rates for NO. Activated macrophages arranged as a monolayer at the base of the crypt elicited maximum NO concentrations of approximately 0.3 microM. The epithelial contribution to NO synthesis was calculated to be negligible. Assuming a uniform macrophage layer, NO synthesis rates greater than 20 microM/s, or more than three times that measured in vitro, would be necessary to achieve maximum NO concentrations of 1 microM in the crypt. Thus, unless NO synthesis rates in macrophages and/or epithelial cells greatly exceed those measured in cell cultures, NO concentrations will remain submicromolar in the crypt during inflammation. Additionally, the results were used to predict the range of NO concentrations (<0.3 microM) and cumulative NO dose (560 microM min) experienced by a given epithelial cell migrating from the base to the top of the crypt. These estimates of NO concentrations in inflamed crypts should facilitate efforts to elucidate the molecular biological linkage between NO exposure and carcinogenesis in IBD.
结肠中一氧化氮的产生与炎症性肠病（IBD）以及结肠癌风险增加有关。然而，目前尚无法测量发炎结肠中的一氧化氮浓度，也不清楚何种一氧化氮水平具有病理生理学意义。基于细胞培养中测量的解剖长度尺度和一氧化氮产生速率构建的计算模型，被用于预测炎症条件下结肠隐窝内一氧化氮浓度的空间变化。研究考虑了多种情况，包括巨噬细胞的不同空间分布以及一系列可能的巨噬细胞和上皮细胞一氧化氮合成速率。在隐窝底部排列成单层的活化巨噬细胞引发的最大一氧化氮浓度约为0.3微摩尔/升。计算得出上皮细胞对一氧化氮合成的贡献可忽略不计。假设巨噬细胞层均匀，要在隐窝中实现1微摩尔/升的最大一氧化氮浓度，一氧化氮合成速率需大于20微摩尔/秒，即比体外测量值高出三倍以上。因此，除非巨噬细胞和/或上皮细胞中的一氧化氮合成速率大幅超过细胞培养中的测量值，否则在炎症期间隐窝中的一氧化氮浓度将保持在亚微摩尔水平。此外，研究结果还被用于预测从隐窝底部迁移至顶部的特定上皮细胞所经历的一氧化氮浓度范围（<0.3微摩尔/升）和一氧化氮累积剂量（560微摩尔·分钟）。这些对发炎隐窝中一氧化氮浓度的估计应有助于阐明一氧化氮暴露与IBD致癌作用之间的分子生物学联系。
