BACKGROUND Neural mechanisms have been suggested to contribute to the pathogenesis of chronic asthma. The expression of neuropeptides such as substance P may be regulated by infectious pathogens, including Mycoplasma species. In contrast to substance P, the substance P receptor neurokinin 1 has not been examined at the protein level in asthmatic airways. OBJECTIVE This study evaluated substance P and neurokinin 1 protein expression and mucus content in endobronchial biopsy specimens from normal control subjects and asthmatic subjects. Detection of Mycoplasma pneumoniae was performed in both biopsy and bronchoalveolar lavage specimens. METHODS Biopsy specimens were collected from 10 normal control subjects and 18 asthmatic subjects before and after a 6-week treatment with a macrolide antibiotic (n = 11) or placebo (n = 7) and were stained for substance P, neurokinin 1, and mucus. M pneumoniae was evaluated by PCR. RESULTS At baseline, compared with normal control subjects, asthmatic subjects demonstrated increased expression of substance P and neurokinin 1 and mucus content in the airway epithelium. Epithelial mucus content correlated with epithelial substance P expression (r (s) = 0.45, P =.04) and FEV(1) percent predicted (r (s) = -0.51, P =.019). After antibiotic treatment, both epithelial substance P and neurokinin 1 expression were significantly reduced in asthmatic subjects. M pneumoniae was found in 8 of 18 asthmatic subjects. Asthmatic subjects with M pneumoniae, compared with those without M pneumoniae, showed higher baseline epithelial neurokinin 1 expression, which was significantly reduced after antibiotic treatment (P =.02). CONCLUSIONS Our data suggest that abnormalities in neural mechanisms may exist in the epithelium of asthmatic airways, and M pneumoniae is possibly involved in this process. Antibiotic intervention may be effective in the treatment of asthma partly through the downregulation of the neurogenic process.