Acid-Sensing Ion Channel 1a Contributes to Airway Hyperreactivity in Mice

Abstract

Neurons innervating the airways contribute to airway hyperreactivity (AHR), a hallmark feature of asthma. Several observations suggested that acid-sensing ion channels (ASICs), neuronal cation channels activated by protons, might contribute to AHR. For example, ASICs are found in vagal sensory neurons that innervate airways, and asthmatic airways can become acidic. Moreover, airway acidification activates ASIC currents and depolarizes neurons innervating airways. We found ASIC1a protein in vagal ganglia neurons, but not airway epithelium or smooth muscle. We induced AHR by sensitizing mice to ovalbumin and found that ASIC1a-/- mice failed to exhibit AHR despite a robust inflammatory response. Loss of ASIC1a also decreased bronchoalveolar lavage fluid levels of substance P, a sensory neuropeptide secreted from vagal sensory neurons that contributes to AHR. These findings suggest that ASIC1a is an important mediator of AHR and raise the possibility that inhibiting ASIC channels might be beneficial in asthma.

Solitary Cholinergic Stimulation Induces Airway Hyperreactivity and Transcription of Distinct Pro-inflammatory Pathways

“…Digital images were collected with specialized equipment (BX51 microscope and DP73 digital camera, Olympus) and software (CellSens Pathology Edition, Olympus). Indices of inflammation were assigned as previously described [12]. Histological examination included 3 animals per treatment group that did not undergo flexiVent procedures, in addition to those that did.…”

Early childhood trajectories of separation anxiety: Bearing on mental health, academic achievement, and physical health from mid-childhood to preadolescence

“…In addition to triggering SA behavior in pups(D'Amato et al, 2011), early interference with maternal cares evokes both respiratory hypersensitivity (excessive hyperventilation) to CO 2 , and increased pain sensitivity(Cittaro et al, 2016;D'Amato et al, 2011). These two distinct but interrelated enhancements are underlain by epigenetic enrichment and augmented neural expression of the acid-sensing ion channels ASIC(Cittaro et al, 2016), that are concurrently implicated in detecting transient brain acidification driven by heightened CO 2 (D'Amato et al, 2011), pain(Wemmie, Taugher, & Kreple, 2013) and airway hyperreactivity(Reznikov et al, 2016), a hallmark feature of asthma.Some of the environmental components underlying these dynamics are known: early life adversities interact with genetic factors to enhance reactivity to anxiety-provoking and brain acidifying CO 2 challenges both in man(Spatola et al, 2011) and animals(D'Amato et al, 2011), and disruption of familial ties are risk factors common to heightened SA, SEPAD(Silove et al, 2015), and headache(Lee et al, 2009). Should a diathesis for altered nociception be confirmed by future studies of childhood SA/SEPAD, then manifestations of SEPAD such as headache and abdominal pain might be allowed explanations that are alternative to the routinely assumed roles of "eliciting parental attention" and "maintaining an anxious child safely at home, " that are common place in clinical discussions.…”

“…In addition to triggering SA behavior in pups(D'Amato et al, 2011), early interference with maternal cares evokes both respiratory hypersensitivity (excessive hyperventilation) to CO 2 , and increased pain sensitivity(Cittaro et al, 2016;D'Amato et al, 2011). These two distinct but interrelated enhancements are underlain by epigenetic enrichment and augmented neural expression of the acid-sensing ion channels ASIC(Cittaro et al, 2016), that are concurrently implicated in detecting transient brain acidification driven by heightened CO 2(D'Amato et al, 2011), pain(Wemmie, Taugher, & Kreple, 2013) and airway hyperreactivity(Reznikov et al, 2016), a hallmark feature of asthma.…”

Simple and reproducible approaches for the collection of select porcine ganglia

“…The vagal ganglia, consisting of the jugular and nodose ganglion, send projections to multiple visceral organs, including the respiratory 40 , gastrointestinal 41 , and cardiovascular 42 systems. The vagal ganglia have been implicated in several diseases, including airway hyperreactivity 43,44 , chronic pulmonary disease 45 , inflammatory bowel disease 46 , esophageal motility disorders 47 , and obesity 48 . The DRG are a collection of sensory neurons that convey information from the periphery to the CNS 49 .…”