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. ? ? ?
|Lakshmanan, J; Magee, T R; Richard, J D et al. (2008) Localization and gestation-dependent pattern of corticotrophin-releasing factor receptor subtypes in ovine fetal distal colon. Neurogastroenterol Motil 20:1328-39|
|Lakshmanan, J; Ross, M G (2008) Mechanism(s) of in utero meconium passage. J Perinatol 28 Suppl 3:S8-13|