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KINETICS OF PULMONARY MICROCIRCULATION DURING PERMISSIVE HYPERCAPNIA

允许性高碳酸血症期间肺微循环的动力学

基本信息

批准号：
09670628
负责人：
YAMAGUCHI Kazuhiro
金额：
$ 2.24万
依托单位：
Keio University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1999
项目状态：
已结题

项目摘要

Impairment of the acinar microvessel response to profound acidosis in injured lungs has not been vigorously analyzed despite the importance of knowledge about it when treating patients with lung injury by permissive hypercapnia. Real-time confocal luminescence microscopy was used to measure changes in the diameter of arterioles, venules, and capillaries in response to stimulation with hypercapnic and isocapnic acidosis in isolated rat lungs injured by 90% OィイD22ィエD2 exposure for 48 hours. Observations were made with and without inhibition of constitutive isoforms of endothelial nitric oxide (NO) synthase (ecNOS) and cyclooxygenase (COX-1), and of inducible isoforms of NOS (iNOS) and COX (COX-2). The effect of excessive NO generated by nitroprusside on acidosis-elicited microvessel diameter changes was also investigated. Upregulation of NOS was estimated by measuring the enzyme protein content of lung homogenates by Western blot analysis, and enhancement of COX-related pathway was judged from perfusate concentrations of 6-keto-prostaglandin FィイD21ィエD2α. We found that ecNOS and COX-1, but not iNOS and COX-2, are upregulated in hyperoxia-injured lungs. The NO produced by ecNOS negatively modulates COX-1 activity in injured arterioles and venules, but COィイD22ィエD2 positively modulates it, leading to paradoxical dilatation of these microvessels under hypercapnic conditions with ecNOS inhibition. The NO-dependent COX-1 inhibition is confined to acinar microvessels, while NO excites COX-1 in other lung regions. High concentrations of COィイD22ィエD2, but not HィイD1+ィエD1, appear to be indispensable for excitation of COX-1. COX-1 inhibition enhances venule constriction in response to HィイD1+ィエD1. In conclusion, NOS inhibition may be useful in the clinical management of patients with permissive hypercapnic, but COX inhibition may not.

尽管在使用容许性高碳酸血症治疗肺损伤患者时，对损伤肺的腺泡微血管对深度酸中毒反应的损害的了解很重要，但尚未对其进行强有力的分析。实时共焦荧光显微镜是用来测量直径的变化小动脉、小静脉和毛细血管反应刺激hypercapnic和isocapnic酸中毒隔离大鼠肺部受伤90% OィイD22摊位ィエD2曝光48小时。观察内皮型一氧化氮（NO）合成酶（ecNOS）和环加氧酶（COX-1）的组成型异构体以及一氧化氮（NOS）和COX （COX-2）的诱导型异构体是否受到抑制。研究了硝普苷产生的过量NO对酸中毒引起的微血管直径变化的影响。Western blot检测肺匀浆酶蛋白含量，检测NOS表达上调；灌注液中6-酮-前列腺素F γ γ γ - D21 γ γ - D2α浓度，检测cox相关通路增强。我们发现，在高氧损伤的肺中，ecNOS和COX-1上调，而iNOS和COX-2不上调。ecNOS产生的NO负向调节损伤小动脉和小静脉中的COX-1活性，但CO γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ。NO依赖的COX-1抑制仅限于腺泡微血管，而NO刺激其他肺区域的COX-1。高浓度的CO γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ。COX-1抑制可增强小静脉对H + l的收缩。综上所述，NOS抑制可能对允许性高碳酸血症患者的临床治疗有用，但COX抑制可能无效。