The objective of this work was to determine the numbers of stained mast cells (MCs) and substance P (SP) immunoreactivity during the initiation and progression of pulmonary lesions in a model of pneumonic pasteurellosis (PP) in ruminants. The first experiment demonstrated that, at 6 h after intrabronchial deposition of Mannheimia (Pasteurella) haemolytica in neonatal calves, MC numbers decreased in sites of severe lung damage. Prior administration of a sialyl Lewis mimetic (TBC1269) intended to prevent neutrophil infiltration had no effect on MC numbers, suggesting that MC degranulation is unaffected by selectin inhibition. In the second study, a single high dose of dihydrocapsaicin (DHC) administered to neonatal lambs depleted peptidergic nerves of SP. Depletion was measured in nasal septum, the site richest in SP fibers, and was estimated to be 85% of controls. In the upper and lower respiratory tract MCs density increased progressively with age, from 3 to 21 days, but DHC-treated animals had significantly higher numbers of MCs; this suggests a functional association between MCs and SP fibers. Histamine content in the lung was similar to controls. The model is suitable for studies of the inflammatory response in the respiratory tract when the neurogenic contribution is reduced. In the third experiment, diminished numbers of MCs and histamine during the acute phase (1 day) of PP in sheep were associated with SP immunoreactivity in macrophages infiltrating the areas of severe damage, suggesting an extraneural source of SP. At 15 days, MCs were scarce at sites with pyogranulomatous foci, but increased in areas with interstitial pneumonia. Substance P immunoreactivity demonstrated that not only an extrinsic sensory innervation, but also an intrinsic contribution of pulmonary ganglion neurons, sustain the inflammatory response. At 45 days the fibroplastic changes in pleura, interlobular spaces, and interstitium were marked, as was the presence of bronchiolitis obliterans. These changes were associated with an increased number of MCs; however, the elevation in histamine did not correspond with the MCs increment. In areas of severe fibrosis SP immunoreactivity in nerve fibers was mild suggesting that the absence of SP during chronic PP hinders tissue repair.