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Isolating the function of these two nerve populations in vivo, to distinguish how each is affected by inflammatory processes and contributes to hyperreactivity in asthma, has been challenging. In this study, we used optogenetic activation of airway nerves in vivo to study parasympathetic contributions to airway hyperreactivity in two mouse models of asthma: 1) acute challenge with house dust mite antigen; and 2) chronic airway hypereosinophilia due to genetic IL-5 overexpression in airways. Overall airway hyperreactivity, as measured by bronchoconstriction to an inhaled agonist, was increased in both models. In contrast, optogenetic stimulation of isolated efferent parasympathetic nerves induced bronchoconstriction only in the acute house dust mite antigen challenge group. Using whole-mount tissue immunofluorescence and modeling software, we then measured, in three dimensions, the interactions between eosinophils and parasympathetic nerves in both models and found that eosinophils were more numerous and more proximal to airway parasympathetic nerves in antigen-challenged and IL-5\u2013transgenic mice than in their respective controls but were not significantly different between the two asthma models. Thus, even though eosinophils were increased around nerves in both models, parasympathetic nerves only mediated airway hyperreactivity in the antigen-challenged mice. This study demonstrates divergent effects of acute versus chronic eosinophilia on parasympathetic airway nerve activity and points to eosinophil\u2013nerve interactions as a key regulator of airway hyperreactivity in antigen challenged mice.<\/jats:p>","DOI":"10.1165\/rcmb.2024-0360oc","type":"journal-article","created":{"date-parts":[[2024,12,3]],"date-time":"2024-12-03T16:52:16Z","timestamp":1733244736000},"page":"698-707","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":3,"title":["Parasympathetic Airway Hyperreactivity Is Enhanced in Acute but Not Chronic Eosinophilic Asthma Mouse Models"],"prefix":"10.1093","volume":"72","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4373-0543","authenticated-orcid":false,"given":"Alexandra B.","family":"Pincus","sequence":"first","affiliation":[{"name":"Department of Pediatrics, University of California San Francisco, San Francisco, California; 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