This project investigates the likely first step in the reaction of the respiratory tract to injury by inhalation of toxic smoke. Irritant compounds, as they injure epithelial cells, stimulate the sensory nerves in the trachea and cause release of their transmitters, the neuropeptides. Neuropeptides stimulate an acute inflammatory reaction. Often, in patients with severe bum injury and smoke inhalation injury, inflammation in the trachea and bronchi is followed within days by respiratory failure. The initial step in reaction to airway injury, then, is a natural place to seek targets for therapeutic intervention. The hypothesis behind this work is that inhalation of toxic smoke triggers release of neuropeptides, and that central reflex mechanisms lead to further neuropeptide release and begin a sequence of events that lead to respiratory failure. This problem will be investigated using knockout mice and sheep. The knockout mice provide a means to isolate certain molecular responses in this complex injury and learn their roles. The sheep allow study of a complex disease process similar to the disease of smoke inhalation injury observed in human burn patients. Specifically, this project proposes to: 1: Modify the effects of neuropeptides in the ovine model of combined smoke inhalation and bum injury. We will determine the extent to which endogenous neuropeptides can produce acute inflammation in the sheep trachea. [2: Investigate mechanisms by which CGRP contributes to formation of airway obstructive """"""""casts.""""""""] 3: Use knockout mice and selective inhibitors to study the roles of neuropeptides in smoke and burn injury.
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