Neuropeptides released from sensory nerve endings are potential mediators of airway
inflammation in
asthma and
lung injury induced by inhalation of respiratory irritants. To develop an in vivo model for assessing the contribution of
neurogenic inflammation in these processes, we have generated transgenic mice with altered innervation of the lung. To generate mice with an increased innervation of the airways, we placed the gene that encodes
nerve growth factor (
NGF) under control of the lung-specific
Clara-cell secretory protein (CCSP) promoter. Two lineages of CCSP-
NGF transgenic mice overexpressed
NGF in the lung and developed a hyperinnervation of the airways. Immunohistochemistry for
substance P, a
substance P enzyme immunoassay, and
catecholamine histofluorescence indicated that both
tachykinin-containing sensory fibers and sympathetic fibers were increased around the airways of CCSP-
NGF mice. Treatment of CCSP-
NGF mice with the sympathetic-specific
neurotoxin 6-hydroxydopamine (6-OHDA) eliminated the sympathetic component of the airway innervation, leaving a specific hyperinnervation by
tachykinin-containing sensory fibers. CCSP-
NGF mice were more sensitive than normal mice to
capsaicin-induced increases in respiratory system resistance, demonstrating that the increased sensory innervation led to a change in airway function. We conclude that
NGF overexpression from a lung-specific promoter produces anatomic and functional changes in lung innervation, and that CCSP-
NGF mice will be useful for studying the role of
neurogenic inflammation in airway disease.