Fetal Meconium Passage Mediated via CRF Pathways

描述（由申请人提供）：在人类中，与许多物种一样，胎粪（MEC）传代是一种发育程序性事件，通常发生在出生后的前24至48小时内。在美国，羊水粪染的患病率为所有出生婴儿的5.6%至24%。5%~12%的MEC染色婴儿在子宫内或出生时吸入，导致胎粪吸入综合征（MAS）; 4%的这些婴儿死亡，占所有围产期死亡的2%。虽然广泛的文献可用于围产期病理MAS，鲜为人知的级联事件，导致MEC通过在新生儿出生后或机制，有助于"早产" MEC通过在子宫内。大量的成年大鼠研究表明，促肾上腺皮质激素释放因子（corticotrophin releasing factor，CRF）作为应激激素家族的第一个成员，在应激过程中对内脏敏感性起着重要的调节作用。外源性CRF以及应激已被充分证明可通过CRF受体I型（CRF-R1）刺激结肠运动和排便。我们假设，压力诱导的子宫内MEC通道在胎儿是类似的压力诱导排便在成年大鼠。我们首次报道了大鼠胎盘表达CRF mRNA和蛋白，提示CRF系统在胎盘-胎儿中起着相互作用。我们已经证明，在子宫内缺氧诱导足月胎鼠MEC通道，与胎儿血浆CRF水平增加，并进一步证明了CRF-R1受体在足月胎鼠结肠的存在。基于我们的初步结果，我们假设，在子宫内MEC通道发生作为胎儿结肠缺氧应激反应，胎盘CRF释放介导的。在本赠款中，我们打算澄清CRF的作用，利用CRF-R1拮抗剂和研究缺氧诱导的MEC通道的机制。我们将检验以下假设：（1）外源性CRF给药将通过CRF-R1受体诱导子宫内MEC通道，（2）急性缺氧应激通过激活足月大鼠外周和/或中枢CRF途径诱导子宫内MEC通道，（3）胎儿MEC通道对缺氧的个体发育依赖于功能性结肠CRF-R1受体的成熟。这些研究结果将为我们关于CRF CRF-R1系统是子宫内MEC通道的介导者的假设提供有力的证据。拟议的研究将提供一个新的方向，了解MEC通道的病理生理机制，并支持进一步调查的治疗方法，以防止MEC吸入综合征的发展。

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.