Fetal Meconium Passage Mediated via CRF Pathways

描述(申请人提供)：在人类中，就像在许多物种中一样，胎粪(MEC)的通过通常是在出生后24至48小时内的一种发育程序性事件。在美国，羊水胎粪污染的患病率从所有新生儿的5.6%到24%不等。5%至12%的MEC染色婴儿在宫内或出生时吸入，导致胎粪吸入综合征(MAS)；这些婴儿中有4%死亡，占围产儿死亡总数的2%。尽管有大量关于MAS围产期病理的文献，但对于导致新生儿出生后MEC通过的一连串事件或导致MEC在子宫内“过早”通过的机制，我们知之甚少。在成年大鼠身上的大量证据表明，促肾上腺皮质激素释放因子(CRF)是应激激素家族的第一个成员，是应激过程中内脏敏感性的重要调节因子。外源性CRF和应激通过CRF受体I型(CRF-R1)刺激结肠运动和排便。我们假设，应激诱导的胎儿子宫微血管内皮细胞传代类似于应激诱导的成年大鼠排便。我们首次报道了大鼠胎盘表达CRF基因和蛋白，提示CRF系统在胎盘和胎儿之间起着交互作用。我们已证实宫内缺氧可诱导足月胎鼠MEC传代，并伴随着胎儿血浆CRF水平的升高，并进一步证明足月胎鼠结肠中存在CRF-R1受体。根据我们的初步结果，我们假设在子宫内MEC的传递是胎儿对低氧应激的结肠反应，由胎盘CRF的释放介导。在本研究中，我们打算利用CRF-R1拮抗剂来阐明CRF的作用，并研究低氧诱导MEC传递的机制。我们将验证以下假设：(1)外源性CRF将通过CRF-R1受体在子宫内诱导MEC通过；(2)急性低氧应激通过激活外周和/或中枢CRF通路在足月大鼠子宫内诱导MEC通过；(3)胎儿MEC对低氧的响应依赖于结肠CRF-R1受体的成熟。这些研究结果将为我们的假设提供令人信服的证据，即CRF CRF-R1系统是宫内MEC传递的中介。这些研究将为理解MEC传递的病理生理机制提供新的方向，并为进一步研究预防MEC吸入综合征的治疗方法提供支持。

DESCRIPTION (provided by applicant): In humans, as in many species, meconium (MEC) passage is a developmental^ programmed event normally within the first 24 to 48 hrs after birth. The prevalence of meconium-stained amniotic fluid ranges from 5.6 to 24% of all births in the US. Five to twelve percent of infants with MEC staining aspirate either in utero or during birth resulting in meconium aspiration syndrome (MAS); 4% of these infants die, accounting for 2% of all perinatal deaths. Although extensive literature is available on perinatal pathology of MAS, little is known of the cascade of events that leads to MEC passage in the newborn following birth or to the mechanisms contributing to "premature" MEC passage in utero. Overwhelming evidence in adult rats indicates that the corticotrophin releasing factor (CRF), the first member of stress hormone family is an important regulator of visceral sensitivity during the time of stress. Exogenous CRF, as well as stress, have been well documented to stimulate colonic motility and defecation via CRF-receptor type I (CRF-R1). We hypothesize that stress-induced in utero MEC passage in the fetus is analogous to stress-induced defecation in adult rats. We report for the first time that rat placenta expresses CRF mRNA and protein suggesting that the CRF system plays an interactive placental-fetal role. We have demonstrated that in utero hypoxia induces term fetal rat MEC passage, in association with increased fetal plasma CRF levels, and have further demonstrated the presence of CRF-R1 receptor in term fetal rat colon. Based on our preliminary results we hypothesize that in utero MEC passage occurs as a fetal colonic response to hypoxic stress, mediated by placental CRF release In the present grant we intend to clarify the role of CRF utilizing a CRF-R1 antagonist and examine the mechanism underlying hypoxia-induced MEC passage. We will test the following hypotheses: (1) Exogenous CRF administration will induce in utero MEC passage via CRF-R1 receptor, (2) Acute hypoxic stress induces in utero MEC passage by activation of peripheral and/or central CRF pathways in term rats, and (3) The ontogeny of fetal MEC passage in response to hypoxia is dependent upon maturation of functional colonic CRF-R1 receptors. The results of these studies will provide convincing evidence in support of our hypothesis that CRF CRF-R1 system is the mediator of in utero MEC passage. The proposed studies will provide a new direction in understanding the pathophysiological mechanisms of MEC passage and support further investigation for the development of therapeutic approaches to prevent MEC aspiration syndrome.