Hypoxia/hypoxemia (H) which occurs in a wide spectrum of cardiopulmonary and vascular disorders has especially severe consequences in the perinatal period. Endothelial cells (ECs), most immediately subject to environmental perturbation, rapidly respond with alterations in hemostatic functions important in vascular homeostasis, and by setting in motion compensatory mechanisms facilitating adaptation to oxygen deprivation.
The first aim of this proposal is to elucidate mechanisms through which H rapidly modulates the character of the EC surface to one which ultimately favors procoagulant events leading ultimately to the development of thrombosis. This proposal is based on pilot studies showing the H induces release of prothrombotic von Willebrand fat or from ECs, decreases EC surface expression of the anticoagulant cofactor thrombomodulin, and induces translocation of the neutrophil adherence molecule P-selectin to the EC surface (bound/activated leukocytes damage the endothelium and initiate clotting in the subendothelium). This hypothesis will be examined in cell culture and animal models. Because our previous work has shown that augmentation of EC cGMP suppresses H-induced binding of leukocytes, the ability of maneuvers which elevate intracellular cGMP levels to block P-selectin expression will be studied as a potentially protective therapeutic intervention.
The second aim i s to study H-mediated induction of Interleukin 6 (IL-6) a cytokine with anti-inflammatory and neuroprotective properties, which may promote cellular survival during oxygen deprivation. These experiments will examine molecular mechanisms underlying enhanced expression of Il-6 in H at the promoter level, based on our recent finding that the NF-IL-6 promoter has a central role in gene expression under H. We will also address the potential protective effects of il-6 in models of pulmonary and cerebral ischemia using wild-type and deletionally mutant Il-6 transgenic mice. Work in project V will be carried out closely with studies proposed in other parts of the PERC: (i) we will assist in experiments to determine mechanisms underlying the H-induced increase in corticotropin-releasing hormone expression in the placenta (Goland); and (ii) we will participate int he sheep (Dr. Daniel) and baboon models (Dr. Stark) of placental ischemia to determine if mechanisms identified in our studies are operative in these settings relevant to perinatology. Through a combination of in vitro and in vivo studies, involving Project V and its interactions with the other projects in the PERC, we seek to accomplish the long-term objective of understanding how the response to H perturbs cellular functions and brings about adaptations critical to survival during oxygen deprivation.
| Ammari, Amer; Schulze, Karl F; Ohira-Kist, Kiyoko et al. (2009) Effects of body position on thermal, cardiorespiratory and metabolic activity in low birth weight infants. Early Hum Dev 85:497-501 |
| Tropper, P J; Goland, R S; Wardlaw, S L et al. (1987) Effects of betamethasone on maternal plasma corticotropin releasing factor, ACTH and cortisol during pregnancy. J Perinat Med 15:221-5 |
