Postlethwait E M, Langford S D, Bidani A
Department of Internal Medicine, University of Texas Medical Branch, Galveston 77550.
Toxicol Appl Pharmacol. 1991 Jul;109(3):464-71. doi: 10.1016/0041-008x(91)90009-4.
Absorption of inhaled NO2 across the pulmonary gas/tissue interface is principally governed by chemical reaction(s) rather than by physical solubility. While the kinetics of NO2 transfer into reactant-containing aqueous solutions appear to be bulk phase independent, it is unclear whether unreacted NO2 diffuses appreciably through the epithelial lining fluid (ELF) to cellular compartments. We avoided the difficulties associated with directly quantifying NO2 dissolved in biological fluids by indirectly determining the potential for NO2 penetration to underlying tissues. An in vitro system was developed which horizontally suspended a wettable, gas permeable, fibrous material between two gas chambers. Aqueous substrates were applied to the sieve material and NO2 (10.9 ppm) was introduced into one chamber and sampled for in the other. O2 served as a tracer gas. We determined the influence of ELF, a model biochemical (reduced glutathione; GSH), and PO4 buffer (control) on NO2 transfer as evaluated by "breakthrough time." (A) Both O2 and NO2 rapidly diffused through the sieve material when dry. Under PO4 wetted conditions, O2 continued to penetrate rapidly but NO2 transfer was slightly inhibited relative to O2. (B) Addition of GSH (1 mM) significantly prolonged NO2 breakthrough time. Increasing initial [GSH] resulted in concomitant prolongation of NO2 breakthrough time. (C) We observed a direct correlation between oxidation of sieve GSH and NO2 breakthrough. (D) Freshly harvested rat ELF inhibited NO2 transfer in a concentration-dependent manner similar to GSH. These data suggest that in the presence of reactant solutes, unreacted NO2 does not penetrate through the ELF layer. Reactive absorption must, therefore, occur primarily within the ELF compartment so that reaction products which induce subsequent toxicity are generated as a result of the initial uptake interactions.
吸入的二氧化氮穿过肺气体/组织界面的吸收主要由化学反应而非物理溶解度决定。虽然二氧化氮转移到含反应物的水溶液中的动力学似乎与体相无关，但尚不清楚未反应的二氧化氮是否能显著地通过上皮衬液（ELF）扩散到细胞区室。我们通过间接测定二氧化氮渗透到下层组织的可能性，避免了直接定量生物流体中溶解的二氧化氮所带来的困难。开发了一种体外系统，该系统在两个气室之间水平悬挂一种可湿润、透气的纤维材料。将水性底物施加到筛网材料上，将二氧化氮（10.9 ppm）引入一个气室并在另一个气室中取样。氧气用作示踪气体。我们通过“穿透时间”评估了ELF、一种模型生化物质（还原型谷胱甘肽；GSH）和磷酸缓冲液（对照）对二氧化氮转移的影响。（A）当干燥时，氧气和二氧化氮都能迅速扩散通过筛网材料。在磷酸湿润条件下，氧气继续迅速渗透，但二氧化氮的转移相对于氧气略有抑制。（B）添加GSH（1 mM）显著延长了二氧化氮的穿透时间。增加初始[GSH]会导致二氧化氮穿透时间相应延长。（C）我们观察到筛网GSH的氧化与二氧化氮穿透之间存在直接相关性。（D）新鲜采集的大鼠ELF以类似于GSH的浓度依赖性方式抑制二氧化氮转移。这些数据表明，在存在反应物溶质的情况下，未反应的二氧化氮不会穿透ELF层。因此，反应性吸收必须主要发生在ELF区室内，以便由于初始摄取相互作用而产生诱导后续毒性的反应产物。
