Sudden infant death syndrome (SIDS) is a leading cause of infant mortality. Cigarette smoke (nicotinic exposure) is the key risk factor and hypoxemia is an acute precursor for SIDS. Although the pathogenic mechanisms of SIDS are poorly understood, a depressed hypoxic ventilatory response (dHVR) has been assumed to be a major player. An existing SIDS animal model induced by traditional prenatal nicotinic exposure (tPNE) has shown an excessive mortality (15%) during 60 min severe hypoxia in rat pups.
Aim 1 of this project is to improve this model by using a more realistic """"""""full-term"""""""" PNE (fPNE) that consists of the period before pregnancy and during pregnancy and lactation to maximize adverse impacts of PNE on cardiorespiratory functions. In addition, the causal role of the dHVR in the mortality and the central origin of the dHVR will be further defined. Recently, we found that inactivation of bronchopulmonary C-firers (PCFs) uniquely eliminated the dHVR observed in rats with pulmonary inflammation, suggesting a critical role of PCFs in blunting the HVR under pathological condition. PCFs are reportedly sensitized by cigarette smoke (nicotine) and stimulated by the hypoxic product adenosine (AD) mainly via acting on A1 receptor (A1R). These findings, along with increased vagal C-fibers in SIDS victims, lead to Aim 2, in which we will determine if fPNE-induced dHVR and death depend on AD stimulating PCFs and if fPNE amplifies the PCF response to hypoxia (AD) mainly via increasing PCFs'population and A1Rs in our model. It is generally accepted that activation of PCFs inhibits ventilation via releasing glutamate that stimulates PCF-driven neurons in the caudal and middle nucleus tractus solitarius (mNTS) via acting on AMPA receptor (AMPAR). This inhibition is amplified by local substance P (SP) acting on neurokinin 1 receptor (NK1R). Most importantly, local SP release is mediated by hypoxic stimulation of the carotid body and is greatly elevated in SIDS victims. Because fPNE upregulates mNTS NK1R expression in our pilot data, studies in Aim 3 will define if fPNE promotes NK1R and SP synthesis and the hypoxia-induced SP release in the mNTS to centrally augment PCF-driven neuronal activity via SP facilitating AMPAR-mediated neuronal activity, leading to the dHVR. The proposed studies will be performed in rat pups by using electrophysiological, pharmacological, immunocytochemical, and molecular approaches. Our predicted results as described in the aims will: 1) generate a new concept of PCFs'plasticity and PCFs'role in control of breathing during postnatal development and under pathological condition;2) gain new insight into the mechanisms underlying the pathogenesis of respiratory disorders inherent in the diseases involving cigarette smoking (PNE) and hypoxemia, such as SIDS;and 3) help us to develop new preventive strategies and pharmacological therapies for these patients.
We will establish the key role a depressed ventilatory response to hypoxia (dHVR) plays in the mortality observed in a new SIDS animal model and further elucidate the peripheral and central mechanisms underlying this dVHR. These studies will broaden our knowledge of respiratory pathophysiology, yield a new concept of SIDS genesis and, most importantly, may highlight new targets for preventing and therapeutically intervening in the respiratory failure in SIDS victims.
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