A significant percentage of newborns become intermittently hypoxic secondary to complications during labor and delivery, apnea of prematurity, and respiratory distress syndrome. Although brain injury is suspected in some cases, the potential mechanisms by which episodic hypoxia might cause cerebral dysfunction and neurodevelopmental handicaps are, at present, purely speculative. Thus, no prophylactic treatments are available. In order to develop rational therapeutics to reduce brain injury from intermittent hypoxia, a better understanding of the effects of this stress on the newborn brain needs to be realized by studies in appropriate preclinical models. The general hypothesis is that intermittent hypoxia stimulates the production of interleukin-1B, superoxide radical, and adenosine, and concomitantly inhibits the production of nitric oxide. It is hypothesized that these changes, singly and in combination, activate edothelium, upregulate adhesion molecule expression, and promote an inflammatory response that jeopardizes microcirculatory flow, vascular reactivity, and blood-brain barrier integrity.
The specific aims are: 1) To examine the role of the cytokine interleukin-1B (IL-1B) in mediating leukocyte endothelial adherence secondary to its induction of E-selectin and intercellular adhesion molecule-1 (ICAM); 2) To investigate the participation of superoxide radical in mediating leukocyte-endothelial adherence in response to intermittent hypoxia; 3) To examine how nitric oxide (NO) affects leukocyte-endothelial interactions and their consequences in the setting of intermittent hypoxia; and 4) To elucidate the involvement of adenosine and its receptors in the inflammatory response to intermittent hypoxia.
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