Anti-inflammatory effect of albuterol enantiomers during respiratory syncytial virus infection in rats.

Every year in the United States, respiratory syncytial virus (RSV) infections in infants and young children cause more than 120,000 hospitalizations, often complicated by the need for mechanical ventilation; yet no effective therapy is currently available for this disease. We showed previously that RSV infection is associated with neurogenic inflammation in the lower respiratory tract. In the present study, we sought to determine whether aerosolized beta(2)-receptor agonists inhibit neurogenic-mediated albumin extravasation in the airways of RSV-infected, mechanically ventilated rats, and to compare the anti-inflammatory effects of racemic albuterol ((RS)-albuterol) to its individual enantiomeric components (R)-albuterol and (S)-albuterol. Albumin extravasation evoked by sensorineural stimulation with capsaicin was inhibited only partially by 0.63 mg (RS)-albuterol, and higher doses had minimal incremental effects. In contrast, the anti-inflammatory effect of (R)-albuterol was already larger at the lowest dose of 0.31 mg, and complete inhibition of neurogenic exudation was observed at higher doses. (S)-albuterol had no significant inhibitory effect up to 1.25 mg, and had only partial inhibitory effect at higher doses. The anti-inflammatory effect of (R)-albuterol was independent from the expression of substance P neurokinin 1 receptors, suggesting a direct vascular effect. Our data show that (R)-albuterol has a much stronger inhibitory effect on neurogenic inflammation in RSV-infected airways when aerosolized in enantiomerically pure form, rather than in a racemic mixture with (S)-albuterol. Based on these data, we speculate that (R)-albuterol may be more effective than other adrenergic agents in the management of bronchiolitis.

Nerve growth factor and nerve growth factor receptors in respiratory syncytial virus-infected lungs.

Nerve growth factor (NGF) controls sensorineural development and responsiveness and modulates immunoinflammatory reactions. Respiratory syncytial virus (RSV) potentiates the proinflammatory effects of sensory nerves in rat airways by upregulating the substance P receptor, neurokinin 1 (NK(1)). We investigated whether the expression of NGF and its trkA and p75 receptors in the lungs is age dependent, whether it is upregulated during RSV infection, and whether it affects neurogenic inflammation. Pathogen-free rats were killed at 2 (weanling) to 12 (adult) wk of age; in addition, subgroups of rats were inoculated with RSV or virus-free medium. In pathogen-free rats, expression of NGF and its receptors in the lungs declined with age, but RSV doubled expression of NGF, trkA, and p75 in weanling and adult rats. Exogenous NGF upregulated NK(1) receptor expression in the lungs. Anti-NGF antibody inhibited NK(1) receptor upregulation and neurogenic inflammation in RSV-infected lungs. These data indicate that expression of NGF and its receptors in the lungs declines physiologically with age but is upregulated by RSV and is a major determinant of neurogenic inflammation.

Leukotrienes mediate neurogenic inflammation in lungs of young rats infected with respiratory syncytial virus.

Respiratory syncytial virus (RSV) infection potentiates neurogenic inflammation in rat airways. Because some vascular effects of sensory nerves are mediated by cysteinyl leukotrienes (cysLTs), we studied whether the receptor antagonist montelukast inhibits neurogenic plasma extravasation in RSV-infected rats. Pathogen-free rats were inoculated at 2 wk (weanlings) or 12 wk (adults) of age with RSV or virus-free medium and treated with montelukast or its vehicle starting 1 day before inoculation. Five days postinoculation, we measured the extravasation of Evans blue-labeled albumin in the respiratory tract after stimulation of sensory nerves with capsaicin. Montelukast had no effect in the extrapulmonary airways but abolished albumin extravasation in the intrapulmonary airways of RSV-infected rats, with a larger effect in weanlings than in adults. Increased concentrations of 5-lipoxygenase-encoding mRNA and cysLTs, as well as numerous mast cells, were detected in the lung tissues of RSV-infected weanling rats. These observations suggest that the release of neuropeptides from capsaicin-sensitive sensory nerves and nonneuronal cells in the lungs of RSV-infected young rats increases vascular permeability by promoting the release of leukotrienes from mast cells.