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- W4378675270 abstract "Airway hyperreactivity (AHR) is a hallmark of allergic asthma, and the major cause of exacerbations. Although acute bronchospasm can be mitigated by bronchodilators and corticosteroids, no therapeutics effectively target AHR. Recent studies have shown that airway afferent/sensory nerves play a critical role in AHR, but the mechanisms are not well understood. Here we show employing two-photon ex vivo imaging of the vagal ganglia of Pirt Cre ;R26 ‐ GCaMP6s mice, HDM extract caused a robust activation of the majority of naïve airway-specific C-fibers. Importantly, diphtheria toxin-mediated ablation of C-fibers using Nav1.8 Cre , caused a significant reduction in HDM induced AHR in mice. HDM extract is made up of proteases and can activate PARs, the G-protein coupled receptors (GPCR). We analyzed PAR receptor expression in airway specific C-fibers using single neuron RT-PCR and found that all airway C-fibers expressed PAR1 and only 5% expressed PAR2 receptors. Ex vivo imaging of the vagal ganglia of Pirt Cre ;R26 ‐ GCaMP6s mice we observed that pretreatment (10mins) with an antagonist (FR171113, 15μM) to PAR1 but not PAR2 receptors, significantly blocked the stimulatory effect of HDM on C-fibers. We created sensory neuronal conditional knockout of PAR1 and PAR2 using the Pirt Cre mice crossed with PAR1 and PAR2 floxed mice to generate experimental Pirt Cre /PAR1 fl/fl and Pirt Cre /PAR2 fl/fl CKO mice. We found that Pirt Cre /PAR1 fl/fl (CKO) mice exposed to HDM over a period of 12 days had significantly reduced HDM-induced AHR. Our data suggests that direct activation of airway vagal C-fiber afferent PAR1 receptors by HDM allergens leads to HDM-induced airway hyperreactivity. Supported by AHA predoctoral grant 14PRE18490009 and Warren Alpert Foundation grant This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process." @default.
- W4378675270 created "2023-05-30" @default.
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- W4378675270 date "2023-05-01" @default.
- W4378675270 modified "2023-10-17" @default.
- W4378675270 title "Vagal C-fibers mediate HDM induced airway hyperreactivity via PAR1 receptors" @default.
- W4378675270 doi "https://doi.org/10.1152/physiol.2023.38.s1.5734190" @default.
- W4378675270 hasPublicationYear "2023" @default.
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