Allergic Asthma and Serotonin 5‐HT 2 Receptor Activation: New Therapeutic Directions

Asthma affects ~235 million people worldwide, leading to over 250,000 deaths from the disease each year. It is a chronic inflammatory disease of the lungs characterized by acute bronchoconstriction, increased mucus production, and pulmonary inflammation. The current therapies available for asthma include short acting beta agonists for relief of bronchoconstriction, and glucocorticoids to control pulmonary remodeling. Short acting beta agonists only provide relief of acute symptoms and do not control chronic disease progression. Glucocorticoids can control overall disease progression but carry significant side effects and do not relieve acute airways hyperresponsivness. Serotonin, a small molecule hormone and neurotransmitter has long been known to be involved in inflammatory processes. Its exact role in asthma, however, is unknown. Here, we show that activation of serotonin receptors in the lung with the selective 5‐HT 2 receptor agonist ( R )‐2,5‐dimethoxy‐4‐iodoamphetamine (( R )‐DOI) blocks the development of allergic asthma in a mouse model. At inhaled doses as low as 0.01 mg/kg, ( R )‐DOI alleviates airways hyperresponsiveness, mucus overproduction, and lung eosinophilia commonly seen in asthmatic animals. Molecular data examining cytokine and chemokine mRNA levels in the lung as well as IgE levels in serum provide evidence that activated T‐cells and/or innate immune cells in the lung are the therapeutic target. For the first time, our results define a role for serotonin 5‐HT 2 receptors in allergic airways disease and suggest that activation of these receptors provides a novel therapeutic strategy against asthma.