CONTROL OF INTESTINAL OXYGENATION DURING POSTNATAL LIFE

大约4-6%的婴儿出生时妊娠期小于32周或体重小于1500克 出生体重每年都会发生坏死性小肠结肠炎（NEC） （约9000例）;其中约25%将死于 而大约25%的疾病将需要广泛的肠道 切除术此外，许多托儿所专门推迟发病， 肠内营养担心“引起”NEC，因为其发病机制是 如此鲜为人知;这种《双城之战》的做法使病人住院， 增加了新生儿保健的费用。NEC的组织病理学 清楚地表明，缺氧缺血性损伤的肠道发生在一些 在疾病发展的过程中。这些实验旨在 试图解释循环系统事件与 以一种新颖的方式发展NEC。的工作假设 建议如下：新生儿肠道受到发育调节， 在出生后保持非常低的血管阻力， NO和SP部分通过舒张血管平滑肌以及 抑制收缩肌刺激的局部产生和血管作用 (eg., A-II和ET）。这种情况在系统性期间突然发生变化 低血压A-II和ET-1的全身水平增加，以及 降低灌注压，急剧增加肠道血管阻力， 两种方法：直接，通过它们对肠道内的张力的影响 通过对当地生产的影响， 内皮源性扩张剂和收缩剂的血管效应。 这一假设将在4个实验中进行检验：1）潜在的作用 作为新生儿肠道的关键决定因素 血管张力将通过测量肽组织水平来确定， 外源肽的体内外输注或阻断其作用 (in 2）A-I、A-II和ET在引起深静脉血栓形成中的作用 心脏填塞期间的肠缺血将通过测量 这些肽的血浆浓度和通过阻断它们的作用 在填塞期间; 3）增加全身ET水平对 A-I、A-II和去甲肾上腺素（NE）的局部产生和血管效应 将通过测量缓冲液灌注中的A-I、A-II产量来确定 肠系膜，并注意到ET输注对剂量的影响， 缓冲液灌注的小动脉内A-II和NE的反应关系; 流速对NO、SP、A-II、 ET的产生和血管效应将在体外确定 储血肠袢和缓冲液灌注肠系膜 小动脉

Approximately 4-6% of infants born <32 weeks gestation or <1500 gm birthweight will develop necrotizing enterocolitis (NEC) each year (approximately 9000 cases); of these, approximately 25% will succumb to the disease while approximately 25% will require extensive bowel resection. Additionally, many nurseries specifically delay the onset of enteral nutrition for fear of "causing" NEC because its pathogenesis is so poorly understood; this arcane practice prolongs hospitalization and increases the cost of neonatal health care. The histopathology of NEC clearly indicates that hypoxic-ischemic injury to the gut occurs at some time during the development of the disease. The experiments proposed to seek to explain the putative link between circulatory events and the development of NEC in a novel fashion. The working hypothesis of the proposal is as follows: newborn gut is developmentally regulated to maintain a very low vascular resistance after birth, an end achieved, in part, by NO and SP, because the relax vascular smooth muscle as well as suppress the local production and vascular action of constrictor stimuli (eg., A-II and ET). This circumstance changes abruptly during systemic hypotension. Increased systemic levels of A-II and ET-1, as well as reduced perfusion pressure, sharply increase gut vascular resistance by two means: directly, by their effect on the tone within the gut vasculature, and indirectly, by their effect on local production and vascular effect of endothelium-derived dilator and constrictor agents. This hypothesis will be tested in 4 experiments: 1) the potential role of locally-produced substance P as a key determinant of newborn gut vascular tone will determined by measuring peptide tissue levels, and by infusing exogenous peptide or blocking its action in vivo and in vitro (in microvessels); 2) the roles of A-I, A-II and ET in causing profound gut ischemia during cardiac tamponade will be determined by measuring the plasma concentration of these peptides and by blocking their effects during tamponade; 3) the effect of increased systemic levels of ET on the local production and vascular effect of A-I, A-II and norepinephrine (NE) will be determined by measuring A-I, A-II production in buffer-perfused mesentery and also by noting the effects of ET infusion on the dose- response relationships for A-II and NE within buffer-perfused arterioles; and 4) the effect of flow rate on the balance between NO, SP, A-II and ET production and vascular effect will be determined within in vitro reservoir (blood-perfused) gut loops and buffer-perfused mesenteric arterioles.