Expression Of Corticotropin-Releasing Hormone And Its Receptor Type-1 In Intrahepatic Cholestatic Placental Tissue

Intrahepatic cholestasis of pregnancy (ICP) is a common pregnancy-related disease emerging during the second half of pregnancy associated with a high rate of premature delivery, meconium stained amniotic fluid, antepartum fetal death, and fetal anoxia and stillbirth. There is unknown etiology and pathogenesis. Stress may be involved in the pathophysiology of fetal unwell outcom in obstetric cholestasis as well as reduced intervillous space. It is well established that labor and delivery are associated with a major stressful condition and with an important complex neuroendocrine and behavioral adaptation. Corticotropin-releasing hormone (CRH) is among the major stress-related neuropeptide. The human placenta and other gestational intrauterine tissues largely produce and secrete immunoreactive CRH. CRH derived from the human placenta that represents the main source of this stress-related neuropeptide during gestation is secreted into both the maternal and fetal circulation in large amounts, and results in an important increase of CRH levels in maternal and fetal plasma, amniotic fluid, and local tissues and may have endocrine effects on mother and fetus, and has important paracrine / autocrine effects within placenta and decidua. Placentally derived CRH is linked to a placental clock controlling the length of human pregnancy and may betaken into account the species specificity of the mechanisms regulating parturition. CRH stimulates placental trophoblast and maternal decidua to express Fas ligand (FasL), a proapoptotic cytokine, that binds to a cell-surface receptor termed Fas and triggers apoptosis of activated T lymphocytes at maternal-fetal interfaces. These' presented evidence suggests that CRH promotes blastocyst implantation and maternal immune tolerance induced by FasL. CRH is a potent concentration-dependent vasodilator of the human utero-placental-fetal circulation, acting at concentrations comparable to plasma CRH levels in maternal and fetal circulations. Placental CRH has a significant physiological role in control of paracrine / autocrine regulation of utero-placental-fetal blood flow.This study has used IHC and ISH methods to investigate the expression patterns of CRH and its receptor CRH-R1 in human placentas at term from women who have undergone uncomplicated pregnancies (n=8) and patients who have been diagnosed as having ICP (n=9). Placental tissues were collected after cesarian section before threatened labor. Results showed that the human placental tissues produced CRH and its receptor CRH-R1. Novel findings are also presented on that CRH derived from endothelial cells and even smooth muscle cells of the lobule vessel may represent the main source of CRH levels in fetal plasma. There is the ability of mobilizing compensation mechanism quickly to adapt to the acute stress by CRH ultra-short positive feedback loop in human fetal-placental unit. The reduction in the size of the intervillous space was observed in pregnancies complicated by ICP. We demonstrated the presence of translation block of placental CRH mRNA and CRH-R1 mRNA investigated by IHC and ISH resulting in reduced protein levels in ICP subjects, in which CRH-R1 was particularly severe.The following results may be caused by expression block of CRH and its receptortype-1 in intrahepatic cholestatic placental tissue. ?Lower CRH levels in maternal and fetal plasma, amniotic fluid, and local gestational intrauterine tissues. ? Stress dysfunction and block of CRH ultra-short positive feedback loop of utero-placental-fetal unit. In ICP subjects, these findings might suggest that: ?Happening to be acute hypoxia stress, the block of CRH ultra-short positive feedback loop and positive feedback loop of fetal acute hypoxia-HPAA-placental CRH induces dysfunctional compensation mechanism to adapt to the acute hypoxia stress of human utero-placental-fetal unit, and finally might lead to a death of fetus on a background of 30% insufficiency of placental oxygen reserve. ?The block of CRH positive feedback loop stimulating placental trophoblast and maternal decidua to express FasL results in decrease of triggering apoptosis of activated T lymphocytes and dysfunctional immune tolerance at maternal-fetal interfaces.