CONTROL OF INTESTINAL OXYGENATION DURING POSTNATAL LIFE

约4-6%的婴儿出生时孕期为32周或1500克 出生体重每年都会发展为坏死性小肠结肠炎(NEC) (约9000例)；在这些病例中，约25%将死于 这种疾病大约有25%需要广泛的肠道 切除手术。此外，许多托儿所明确推迟了 肠内营养，担心会导致NEC，因为它的发病机制是 如此鲜为人知；这种神秘的做法延长了住院时间和 增加了新生儿保健的成本。NEC的组织病理学研究 清楚地表明，肠道的缺氧缺血性损伤发生在某些 疾病发展过程中的时间。这些实验提出了 试图解释循环事件和 以一种新颖的方式发展NEC。的工作假说 建议如下：新生儿肠道发育调节 在出生后保持非常低的血管阻力，达到了这一目的 部分是由NO和SP引起的，因为松弛血管平滑肌以及 抑制收缩肌刺激的局部产生和血管作用 (例如，A-II和ET)。这种情况在系统运行期间突然改变 低血压。全身A-II和ET-1水平升高，以及 降低灌流压力，大幅增加肠道血管阻力 两种方式：直接，通过它们对肠道内音调的影响 脉管系统，以及间接地通过它们对当地生产和 血管内皮源性扩张剂和缩窄剂的血管效应。 这一假设将在4个实验中得到验证：1)潜在的作用 本地生产的P物质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，并通过 体内、外输注外源性多肽或阻断其作用 (在微血管中)；2)A-I、A-II和ET在导致深静脉血栓形成中的作用 心脏填塞期间的肠道缺血将通过测量 这些多肽的血浆浓度及阻断它们的作用 3)全身性ET水平升高对动脉粥样硬化的影响。 A-I、A-II和去甲肾上腺素的局部产生及血管效应 将通过测量缓冲液灌流中的A-I、A-II产量来确定 并注意到ET输注对剂量的影响。 缓冲灌流小动脉内A-II和NE的反应关系； 4)流速对NO、SP、A-II、NO平衡的影响 ET的产生和血管效应将在体外进行测定 储存(血液灌流)肠环和缓冲灌流的肠系膜 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.