Pulmonary Ionocytes Regulate Airway Surface Liquid pH in Primary Human Bronchial Epithelial Cells.

Rationale: Pulmonary ionocytes are a newly discovered airway epithelial cell type proposed to be a major contributor to cystic fibrosis (CF) lung disease based on observations they express the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel at a higher level than any other cell type in the airway epithelia. Moreover, genetically manipulated experimental models that lack ionocytes develop NaCl transport abnormalities and airway surface liquid (ASL) dehydration consistent with CF. However, no direct evidence indicates ionocytes engage in NaCl transport or contribute to ASL formation, questioning the relevance of ionocytes to CF lung disease. Objectives: To determine the ion transport properties of pulmonary ionocytes and club cells in genetically intact healthy and CF airway epithelia. Methods: We measured ion transport at the single-cell level using a self-referencing ion-selective microelectrode technique in primary human bronchial epithelial cell culture. Measurements and Main Results: cAMP-stimulated non-CF ionocytes do not secrete Na+ or Cl- into the ASL, but rather modulate its pH by secreting bicarbonate via CFTR-linked Cl-/bicarbonate exchange. Non-CF club cells secrete Na+ and Cl- to the lumen side after cAMP stimulation. CF ionocytes and club cells do not transport ions in response to cAMP stimulation, but incubation with CFTR modulators elexacaftor/tezacaftor/ivacaftor restores transport properties. Conclusions: We conclude that ionocytes do not contribute to ASL formation but regulate ASL pH. Club cells secrete the bulk of airway fluid. In CF, abnormal ionocyte and club cell function results in acidic and dehydrated ASL, causing reduced antimicrobial properties and mucociliary clearance.

A comparison of self-triage tools to nurse driven triage in the emergency department.

INTRODUCTION: Canadian patients presenting to the emergency department (ED) typically undergo a triage process where they are assessed by a specially trained nurse and assigned a Canadian Triage and Acuity Scale (CTAS) score, indicating their level of acuity and urgency of assessment. We sought to assess the ability of patients to self-triage themselves through use of one of two of our proprietary self-triage tools, and how this would compare with the standard nurse-driven triage process. METHODS: We enrolled a convenience sample of ambulatory ED patients aged 17 years or older who presented with chief complaints of chest pain, abdominal pain, breathing problems, or musculoskeletal pain. Participants completed one, or both, of an algorithm generated self-triage (AGST) survey, or visual acuity scale (VAS) based self-triage tool which subsequently generated a CTAS score. Our primary outcome was to assess the accuracy of these tools to the CTAS score generated through the nurse-driven triage process. RESULTS: A total of 223 patients were included in our analysis. Of these, 32 (14.3%) presented with chest pain, 25 (11.2%) with shortness of breath, 75 (33.6%) with abdominal pain, and 91 (40.8%) with musculoskeletal pain. Of the total number of patients, 142 (47.2%) completed the AGST tool, 159 (52.8%) completed the VAS tool and 78 (25.9%) completed both tools. When compared to the nurse-driven triage standard, both the AGST and VAS tools had poor levels of agreement for each of the four presenting complaints. CONCLUSIONS: Self-triage through use of an AGST or VAS tool is inaccurate compared to the established standard of nurse-driven triage. Although existing literature exists which suggests that self-triage tools developed for specific subsets of complaints may be feasible, our results would suggest that adopting the self-triage approach on a broader scale for all-comers to the ED does not appear to be a viable option to enhance the current triage process. Further study is required to show if self-triage can be used in the ED to optimize the triage process.

Lipopolysaccharides induce a RAGE-mediated sensitization of sensory neurons and fluid hypersecretion in the upper airways.

Thoracic dorsal root ganglia (tDRG) contribute to fluid secretion in the upper airways. Inflammation potentiates DRG responses, but the mechanisms remain under investigation. The receptor for advanced glycation end-products (RAGE) underlies potentiation of DRG responses in pain pathologies; however, its role in other sensory modalities is less understood. We hypothesize that RAGE contributes to electrophysiological and biochemical changes in tDRGs during inflammation. We used tDRGs and tracheas from wild types (WT), RAGE knock-out (RAGE-KO), and with the RAGE antagonist FPS-ZM1, and exposed them to lipopolysaccharides (LPS). We studied: capsaicin (CAP)-evoked currents and action potentials (AP), tracheal submucosal gland secretion, RAGE expression and downstream pathways. In WT neurons, LPS increased CAP-evoked currents and AP generation, and it caused submucosal gland hypersecretion in tracheas from WT mice exposed to LPS. In contrast, LPS had no effect on tDRG excitability or gland secretion in RAGE-KO mice or mice treated with FPS-ZM1. LPS upregulated full-length RAGE (encoded by Tv1-RAGE) and downregulated a soluble (sRAGE) splice variant (encoded by MmusRAGEv4) in tDRG neurons. These data suggest that sensitization of tDRG neurons contributes to hypersecretion in the upper airways during inflammation. And at least two RAGE variants may be involved in these effects of LPS.