Airway sympathectomy attenuates inflammation, transcriptional ratios of Muc5ac and Muc5b, and airway mechanic deficits in mice delivered intranasal IL-13.

Abstract

Excessive mucus in the airways is an underlying pathological feature of many airway diseases, including asthma. Therapeutic options to reduce mucus production in the airways remain limited. One possible therapeutic target is the airway sympathetic nerves. Although lung sympathetic innervation has been considered sparse, sympathetic nerves secrete neurotransmitters that act on adrenergic receptors, including β₂-adrenergic receptor (β₂AR). Interestingly, in experimental models, chronic use β₂AR agonists can augment mucus secretion. Thus, in the present study, we tested the hypothesis that airway sympathetic nerves regulate mucus production in the airway in response to the type 2 cytokine interleukin 13 (IL-13). We performed airway sympathectomy using intranasal instillation of the synthetic neurotoxin 6-hydroxydopamine (6-OHDA). Airway sympathectomy attenuated multiple IL-13-mediated airway deficits, including density of goblet cells containing neutral mucins, transcriptional ratio of mucin 5ac (Muc5ac) to mucin 5b (Muc5b) and airway elastance and tissue damping. Although total Muc5ac and Muc5b transcript levels and Muc5ac and Muc5b protein levels in bronchoalveolar lavage were not significantly altered, these changes suggest that airway sympathectomy modifies goblet cell phenotype and mucin composition. Airway sympathectomy also dampened IL-13 mediated increases in total lung transcripts important for regulating allergic responses, including interleukin 6, complement component 3, and colony stimulating factor. This study reveals that airway sympathetic nerves regulate physiologic, molecular, and inflammatory responses to type 2 (IL-13-mediated) airway inflammation and raises the possibility that they may serve as potential targets for therapeutic intervention.