Mucosal IL-12 inhibits airway reactivity to methacholine and respiratory failure in murine asthma

The worldwide incidence, prevalence, and fatality rates from asthma are inc reasing despite currently available therapeutic modalities. Systemic admini stration of interleukin (IL)-12 has been shown to inhibit airway reactivity in murine models of asthma, bat the required dosage is high and may be tox ic. This study tested the hypothesis that IL-12 administered directly into the lungs is more effective in inhibiting airway reactivity than systemical ly administered IL-12, allowing lower doses to be used. A low dose (10 ng) of IL-12 was delivered either intratracheally (mucosal delivery) or intrape ritoneally (systemic delivery) at the time of ragweed (RW) challenge in mic e sensitized to RW. Basal airway resistance and airway reactivity to methac holine were measured 3 days after RW challenge. Compared to phosphate-buffe red saline (PBS) challenge of RW sensitized mice, RW challenge increased ba sal resistance and the slope of the methacholine dose-response curve. Metha choline challenge of RW-challenged mice also induced premature respiratory failure (respiratory rate < 150/min, tidal volume < 0.15 mt) in some animal s. Administration of mucosal or systemic IL-12 at the time of RW challenge decreased basal airway resistance. However, only mucosal IL-12 decreased ai rway reactivity and inhibited respiratory failure during methacholine chall enge. These findings indicate that mucosal delivery of a low dose of IL-12 is more effective than systemic IL-12 in inhibiting airway reactivity and r espiratory failure in a mouse model of asthma.