High inspired O2 concentration delivered to an immature respiratory system contributes to the pathogenesis of BPD. Tachykinin peptides such as SP released from sensory nerve endings have been implicated as both inflammatory and neural mediators of lung injury in various adult diseases. In these studies we sought to determine changes in the tachykinin system induced by hyperoxic exposure of the neonatal respiratory tract, and the potential effects on airway contractile responses. Seven day old rat pups were exposed to either room air or hyperoxia (>95% O2) for seven days to assess pulmonary preprotachykinin (β-PPT) gene expression, SP levels, and airway contractile responses to cholinergic stimulation before and after blockade of SP (NK1) receptors. Lung β-PPT mRNA expression, and both lung and tracheal SP levels, were determined in lung extracts after seven days of normoxic and hyperoxic exposure. Electrical field stimulation was used to elicit cholinergically mediated contractile responses in vitro in normoxia and hyperoxia exposed tracheal cylinders. Hyperoxia caused a 1.1 to 2.6-fold increase in steady-state lung β-PPT mRNA, and a 50% and 32% increase in SP of lung and trachea respectively compared to normoxic controls. In response to cholinergic stimulation, maximal contractile force of hyperoxic tracheal muscle was 69% (p<.001) higher than for normoxic controls, even though smooth muscle volume and myosin heavy chain content were comparable between hyperoxic and normoxic tissue. Addition of the SP (NK1) receptor blocker CP99994, 10 μM, decreased sensitivity to electrical field stimulation in both hyperoxic and normoxic trachea without significant decline in maximal contractile response. These data demonstrate: (1) increased SP production in hyperoxia exposed newborn lungs, (2) SP-induced enhancement of cholinergic sensitivity in both normoxic and hyperoxic airways, and (3) increased maximal contractile response of hyperoxia exposed neonatal trachea to cholinergic stimulation which cannot only be attributed to enhanced release of endogenous SP. We therefore speculate that upregulation of SP synthesis during hyperoxia contributes more to the inflammatory than constrictor component of neonatal airway injury.

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