Medical interventions for chronic rhinosinusitis in cystic fibrosis.

BACKGROUND: Chronic rhinosinusitis frequently occurs in people with cystic fibrosis. Several medical interventions are available for treating chronic rhinosinusitis in people with cystic fibrosis; for example, different concentrations of nasal saline irrigations, topical or oral corticosteroids, antibiotics - including nebulized antibiotics - dornase alfa and modulators of the cystic fibrosis transmembrane conductance regulator (CFTR) (such as lumacaftor, ivacaftor or tezacaftor). However, the efficacy of these interventions is unclear. This is an update of a previously published review. OBJECTIVES: The objective of this review is to compare the effects of different medical interventions in people diagnosed with cystic fibrosis and chronic rhinosinusitis. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and hand searching of journals and conference abstract books. Date of last search of trials register: 09 September 2021. We also searched ongoing trials databases, other medical databases and the reference lists of relevant articles and reviews. Date of latest additional searches: 22 November 2021. SELECTION CRITERIA: Randomized and quasi-randomized trials of different medical interventions compared to each other or to no intervention or to placebo. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials identified for potential inclusion in the review. We planned to conduct data collection and analysis in accordance with Cochrane methods and to independently rate the quality of the evidence for each outcome using the GRADE guidelines. MAIN RESULTS: We identified no trials that met the pre-defined inclusion criteria. The most recent searches identified 44 new references, none of which were eligible for inclusion in the current version of this review; 12 studies are listed as excluded and one as ongoing. AUTHORS' CONCLUSIONS: We identified no eligible trials assessing the medical interventions in people with cystic fibrosis and chronic rhinosinusitis. High-quality trials are needed which should assess the efficacy of different treatment options detailed above for managing chronic rhinosinusitis, preventing pulmonary exacerbations and improving quality of life in people with cystic fibrosis.

Phenotypes in Chronic Rhinosinusitis.

PURPOSE OF REVIEW: Chronic rhinosinusitis (CRS) is a heterogenous disease process affecting a significant proportion of the population and impacting quality of life and productivity. Historically, CRS has been classified broadly into CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). Increased understanding regarding unique presentations of CRS subsets and their underlying inflammatory profiles has led to a new system for classifying CRS phenotypes. RECENT FINDINGS: Consideration of CRS phenotypes has traditionally been a key factor in determining treatment paradigms. Under a new phenotype classification system, physical findings will continue to drive treatment decisions, but with more precision. Recent rapidly accumulated knowledge indicates that the broad categorization of CRSwNP or CRSsNP is no longer clinically useful. Reorganization of CRS phenotypes and their underlying endotypes will lead to more targeted and efficacious therapy.

The SARS-CoV-2 pandemic impact on rhinology research: A survey of the American Rhinologic Society.

BACKGROUND: The COVID-19 pandemic has radically shifted healthcare operations within hospitals and universities across the globe. However, the effect of the COVID-19 pandemic on research endeavors and clinical trials is unclear. OBJECTIVE: This study investigates the impact of the COVID-19 pandemic on basic science and clinical research within the rhinology community. METHODS: A cross-sectional study was designed utilizing an 8-question survey to identify changes to rhinology research. Questions evaluated the impact of the COVID-19 pandemic on administrative research support and staffing, basic science research, clinical trials and resident research involvement. RESULTS: Seventy-one participants responded to the survey (8.5% response rate). Most respondents noted changes in IACUC/IRB approval (faster, 33%; slower, 31%). Of those who employed laboratory personnel, 64% were able to continue staff employment with full salary. The majority of animal research and in vitro studies were halted (64% and 56%, respectively), but animal care and cell line maintenance were allowed to continue. Clinical trial enrollment was most commonly limited to COVID derived studies (51%). Forty-seven percent of respondents noted increased resident research participation. CONCLUSION: The rapid spread of the SARS-CoV-2 virus has markedly impacted rhinology-related research. Maintaining safe workplace practices as restrictions are lifted will hopefully mitigate the spread of the virus and allow research productivity to resume.

Medical interventions for chronic rhinosinusitis in cystic fibrosis.

BACKGROUND: Chronic rhinosinusitis frequently occurs in people with cystic fibrosis. Several medical interventions are available for treating chronic rhinosinusitis in people with cystic fibrosis; for example, different concentrations of nasal saline irrigations, topical or oral corticosteroids, antibiotics - including nebulized antibiotics, dornase alfa and modulators of the cystic fibrosis transmembrane conductance regulator (CFTR) (such as lumacaftor, ivacaftor or tezacaftor). However, the efficacy of these interventions is unclear. OBJECTIVES: The objective of this review is to compare the effects of different medical interventions in people diagnosed with cystic fibrosis and chronic rhinosinusitis. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and hand searching of journals and conference abstract books. Date of last search of trials register: 22 May 2019.We also searched ongoing trials databases, other medical databases and the reference lists of relevant articles and reviews. Date of latest additional searches: 20 May 2019. SELECTION CRITERIA: Randomized and quasi-randomized trials of different medical interventions compared to each other or to no intervention or to placebo. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials identified for potential inclusion in the review. We planned to conduct data collection and analysis in accordance with Cochrane methods and to independently rate the quality of the evidence for each outcome using the GRADE guidelines. MAIN RESULTS: We identified no trials that met the pre-defined inclusion criteria. The searches identified 47 trials, none of which were eligible for inclusion in the current version of this review. AUTHORS' CONCLUSIONS: We identified no eligible trials assessing the medical interventions in people with cystic fibrosis and chronic rhinosinusitis. High-quality trials are needed which should assess the efficacy of different treatment options detailed above for managing chronic rhinosinusitis, preventing pulmonary exacerbations and improving quality of life in people with cystic fibrosis.

Influenza virus M2 targets cystic fibrosis transmembrane conductance regulator for lysosomal degradation during viral infection.

We sought to determine the mechanisms by which influenza infection of human epithelial cells decreases cystic fibrosis transmembrane conductance regulator (CFTR) expression and function. We infected human bronchial epithelial (NHBE) cells and murine nasal epithelial (MNE) cells with various strains of influenza A virus. Influenza infection significantly reduced CFTR short circuit currents (Isc) and protein levels at 8 hours postinfection. We then infected CFTR expressing human embryonic kidney (HEK)-293 cells (HEK-293 CFTRwt) with influenza virus encoding a green fluorescent protein (GFP) tag and performed whole-cell and cell-attached patch clamp recordings. Forskolin-stimulated, GlyH-101-sensitive CFTR conductances, and CFTR open probabilities were reduced by 80% in GFP-positive cells; Western blots also showed significant reduction in total and plasma membrane CFTR levels. Knockdown of the influenza matrix protein 2 (M2) with siRNA, or inhibition of its activity by amantadine, prevented the decrease in CFTR expression and function. Lysosome inhibition (bafilomycin-A1), but not proteasome inhibition (lactacystin), prevented the reduction in CFTR levels. Western blots of immunoprecipitated CFTR from influenza-infected cells, treated with BafA1, and probed with antibodies against lysine 63-linked (K-63) or lysine 48-linked (K-48) polyubiquitin chains supported lysosomal targeting. These results highlight CFTR damage, leading to early degradation as an important contributing factor to influenza infection-associated ion transport defects.

Inter-α-inhibitor blocks epithelial sodium channel activation and decreases nasal potential differences in ΔF508 mice.

Increased activity of lung epithelial sodium channels (ENaCs) contributes to the pathophysiology of cystic fibrosis (CF) by increasing the rate of epithelial lining fluid reabsorption. Inter-α-inhibitor (IαI), a serum protease inhibitor, may decrease ENaC activity by preventing its cleavage by serine proteases. High concentrations of IαI were detected in the bronchoalveolar lavage fluid (BALF) of children with CF and lower airway diseases. IαI decreased amiloride-sensitive (IENaC) but not cAMP-activated Cl(-) currents across confluent monolayers of rat ATII, and mouse nasal epithelial cells grew in primary culture by 45 and 25%, respectively. Changes in IENaC by IαI in ATII cells were accompanied by increased levels of uncleaved (immature) surface α-ENaC. IαI increased airway surface liquid depth overlying murine nasal epithelial cells to the same extent as amiloride, consistent with ENaC inhibition. Incubation of lung slices from C57BL/6, those lacking phenylalanine at position 508 (∆F508), or CF transmembrane conductance regulator knockout mice with IαI for 3 hours decreased the open probability of their ENaC channels by 50%. ∆F508 mice had considerably higher levels the amiloride-sensitive fractions of ENaC nasal potential difference (ENaC-NPD) than wild-type littermates and only background levels of IαI in their BALF. A single intranasal instillation of IαI decreased their ENaC-NPD 24 hours later by 25%. In conclusion, we show that IαI is present in the BALF of children with CF, is an effective inhibitor of ENaC proteolysis, and decreases ENaC activity in lung epithelial cells of ∆F508 mice.

Management of the upper airway in cystic fibrosis.

PURPOSE OF REVIEW: Upper airway disease engenders significant morbidity for patients with cystic fibrosis and is increasingly recognized as having a much greater role in pulmonary outcomes and quality of life than originally believed. Widespread disparate therapeutic strategies for cystic fibrosis chronic rhinosinusitis underscore the absence of a standardized treatment paradigm. This review outlines the most recent evidence-based trends in the management of upper airway disease in cystic fibrosis. RECENT FINDINGS: The unified airway theory proposes that the sinuses are a focus of initial bacterial colonization which seeds the lower airway and may play a large role in maintaining lung infections. Mounting evidence suggests more aggressive treatment of the sinuses may confer significant improvement in pulmonary disease and quality of life outcomes in cystic fibrosis patients. However, there is a lack of high-level evidence regarding medical and surgical management of cystic fibrosis chronic rhinosinusitis that makes generalizations difficult. SUMMARY: Well designed clinical trials with long-term follow-up concerning medical and surgical interventions for cystic fibrosis sinus disease are required to establish standardized treatment protocols, but increased interest in the sinuses as a bacterial reservoir for pulmonary infections has generated considerable attention.

Inappropriate image duplications in rhinology research publications.

KEY POINTS: Duplicated images in research articles erode integrity and credibility of biomedical science. Forensic software is necessary to detect figures with inappropriately duplicated images. This analysis reveals a significant issue of inappropriate image duplication in our field.

American Rhinologic Society expert practice statement part 2: Postoperative precautions and management principles following endoscopic skull base surgery.

The goal of this American Rhinologic Society expert practice statement (EPS) is to summarize the best available evidence regarding postoperative precautions for patients following endoscopic skull base surgery for intradural pathology. These topics include the administration of postoperative nasal hygiene; patient mobilization and activity level; the resumption of continuous positive airway pressure in patients with obstructive sleep apnea; and the timing and capacity with which a patient may be subjected to barotrauma, such as air travel postoperatively. This EPS was developed following the recommended methodology and approval process as previously outlined. Given the diverse practices and limited agreement on the accepted principles regarding postoperative precautions for patients following skull base surgery, this EPS seeks to summarize the existing literature and provide clinically relevant guidance to bring clarity to these differing practice patterns. Following a modified Delphi approach, four statements were developed, all of which reached consensus. Because of the paucity of literature on these topics, these statements represent a summation of the limited literature and the experts' opinions. These statements and the accompanying evidence are summarized below, along with an assessment of future needs.

Chitosan-based crosslinking for controlled topical drug release in rhinosinusitis.

KEY POINTS: Chitosan is a promising drug delivery vector for therapeutics owing to its biocompatibility. Once crosslinked with chitosan, prolonged drug release was noted regardless of hydrophilicity. Hydrophilic drugs may require different strategies to obtain a sustained release profile.

American Rhinologic Society expert practice statement part 1: Skull base reconstruction following endoscopic skull base surgery.

The goal of this American Rhinologic Society expert practice statement (EPS) is to summarize the best available evidence for technical factors that optimize outcomes in skull base reconstruction following endoscopic skull base surgery for intradural pathologies. These topics include the use of free mucosal grafts versus vascularized pedicled nasoseptal flaps; the use of autologous versus synthetic grafts; and the roles of lumbar drains, dural sealants, and nasal packing. This EPS was developed following the recommended methodology and approval process as previously outlined. As there are a myriad of techniques and limited agreement on the accepted principles of skull base reconstruction, this EPS aims to summarize the existing evidence and provide clinically meaningful guidance on these divergent practices. Following a modified Delphi approach, five statements were developed, four of which reached consensus and one of which reached near consensus. These statements and the accompanying evidence are summarized along with an assessment of future needs.

Safety and Pharmacokinetics of a Ciprofloxacin and Azithromycin Stent for Chronic Rhinosinusitis.

OBJECTIVES: Previously, we developed a novel double-coated sinus stent containing ciprofloxacin (inner layer) and azithromycin (outer layer) (CASS), but released drug concentrations were found to be insufficient for clinical usage. Our objectives are to improve drug release of CASS and assess safety and pharmacokinetics in rabbits. METHODS: Dip coating was used to create the CASS with 2 mg ciprofloxacin and 5 mg azithromycin. A uniformed double coating was assessed with scanning electron microscopy (SEM), and the release patterns of both drugs and lactate dehydrogenase (LDH) assay were evaluated over 14 days in vitro. Safety, tolerability, and pharmacokinetics of the CASS were tested in rabbits through insertion into the maxillary sinus and evaluated with nasal endoscopy, CT scans, histology, blood counts and chemistries, and in vivo drug release. RESULTS: SEM confirmed the uniformity of the dual coating of ciprofloxacin and azithromycin, and thickness (µm) was found to be 14.7 ± 2.4 and 28.1 ± 4.6, respectively. The inner coated ciprofloxacin showed a sustained release over 14 days (release %) when soaked in saline solution (day 7, 86.2 ± 3.4 vs. day 14,99.2 ± 5.1). In vivo analysis showed that after 12 days, 78.92 ± 7.67% of CP and 84.12 ± 0.45% of AZ were released into the sinus. There were no significant differences in body weight, white blood cell counts, and radiographic changes before and after CASS placement. No significant histological changes were observed compared to the contralateral control side. CONCLUSION: Findings suggest that the CASS is an effective method for delivering therapeutic levels of antibiotics. Further studies are needed to validate efficacy in a preclinical sinusitis model. LEVEL OF EVIDENCE: N/A Laryngoscope, 2024.

Advances in Sinus Surgery for Nasal Polyps.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is comprised of a diverse group of endotypes that cause significant morbidity for afflicted patients. While endoscopic sinus surgery helps ameliorate the disease, polyps frequently recur. Newer strategies are intended to provide access for topical steroid irrigations in attempts to improve the disease process and quality of life, and decrease overall recurrence of polyps. OBJECTIVE: To review the current literature examining the latest surgical approaches for CRSwNP. METHODS: Review article. RESULTS: In dealing with the recalcitrant nature of CRSwNP, surgical techniques have simultaneously become more nuanced and aggressive. Bony resection in anatomically unfavorable areas such as the frontal, maxillary, and sphenoid outflow regions, replacing diseased or denuded mucosa with healthy grafts or flaps at the neo-ostia, and introducing drug-eluting biomaterials to newly opened sinus outflow tracts are highlights in the recent advancements in sinus surgery for CRSwNP. The Draf 3 or modified endoscopic Lothrop procedure has become a standard technique and demonstrated to improve quality of life and decrease polyp recurrence. A number of mucosal grafting or mucosal flap techniques have been described that cover exposed bone of the neo-ostium and evidence shows that this improves healing and diameter of the Draf 3. Partial middle turbinectomy, while controversial, appears to help decrease polyp recurrence in long-term follow-up studies. Modified endoscopic medial maxillectomy improves access to the maxillary sinus mucosa, facilitates debridement and, particularly, in the cystic fibrosis nasal polyp patient, improves overall management of the disease. Sphenoid drill-out procedure provides wider access for topical steroid irrigations and also may improve management of CRSwNP. CONCLUSION: Surgical intervention remains a mainstay of therapy for CRSwNP. Newer techniques revolve around improving access for topical steroid therapy.

Unified Airway-Cystic Fibrosis.

Cystic fibrosis (CF) is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The CFTR channel is responsible for the transport of the anions (chloride and bicarbonate) across airway epithelia. Patients with CF have thick mucus, disrupted mucociliary transport, and chronic bacterial infections in the upper and lower airways. In this article, the pathophysiology of CFTR dysfunction and its impact on the united airway are reviewed as well as the treatment strategies for patients with chronic rhinosinusitis-related CF and acquired CFTR dysfunction.

Long-duration pain block for postoperative anesthesia after endoscopic sinus surgery.

KEY POINTS: A long-duration pain block did not decrease postoperative pain or opioid consumption. Extended sinus procedures do not lead to additional postoperative pain or opioid consumption.

Low molecular weight hyaluronan inhibits lung epithelial ion channels by activating the calcium-sensing receptor.

Herein, we tested the hypothesis that low molecular weight hyaluronan (LMW-HA) inhibits lung epithelial ions transport in-vivo, ex-vivo, and in-vitro by activating the calcium-sensing receptor (CaSR). Twenty-four hours post intranasal instillation of 50-150 µg/ml LMW-HA to C57BL/6 mice, there was a 75% inhibition of alveolar fluid clearance (AFC), a threefold increase in the epithelial lining fluid (ELF) depth, and a 20% increase in lung wet/dry (W/D) ratio. Incubation of human and mouse precision cut lung slices with 150 µg/ml LMW-HA reduced the activity and the open probability (Po) of epithelial sodium channel (ENaC) in alveolar epithelial type 2 (ATII) cells, and in mouse tracheal epithelial cells (MTEC) monolayers as early as 4 h. The Cl- current through cystic fibrosis transmembrane conductance regulator (CFTR) and the activity of Na,K-ATPase were both inhibited by more than 66% at 24 h. The inhibitory effects of LMW-HA on ion channels were reversed by 1 µM NPS-2143, or 150 µg/ml high molecular weight hyaluronan (HMW-HA). In HEK-293 cells expressing the calcium-sensitive Cl- channel TMEM16-A, CaSR was required for the activation of the Cl- current by LMW-HA. This is the first demonstration of lung ions and water transport inhibition by LMW-HA, and its mediation through the activation of CaSR.

Individual SNOT-22 Items Aid in Differentiating Between Spontaneous Cerebrospinal Fluid Rhinorrhea and Chronic Rhinosinusitis Without Nasal Polyps.

OBJECTIVES: Spontaneous cerebrospinal fluid (CSF) rhinorrhea is a diagnostic challenge due to its overlapping symptomatology with other sinonasal diseases. The objective of this study was to investigate whether items on the sinonasal outcome test (SNOT)-22 could suggest a diagnosis of spontaneous CSF rhinorrhea versus chronic rhinosinusitis without nasal polyps (CRSsNP). METHODS: A multi-institutional retrospective chart review of patients with spontaneous CSF rhinorrhea and a control group of CRSsNP patients was performed. Individual SNOT-22 scores and domain scores were compared. RESULTS: One hundred fifteen patients were included in both cohorts. Of the patients in the CSF rhinorrhea group, 48% were misdiagnosed as chronic rhinosinusitis (CRS) prior to the correct identification of a CSF leak. On bivariate analysis, the CSF rhinorrhea group scored significantly higher on the SNOT-22 for runny nose (P < .001) and was more likely to designate this symptom as most important (P < .001). The CRSsNP group scored significantly higher in nasal blockage (P < .001), thick nasal discharge (P < .001), facial pain/pressure (P < .001), and in the ear/facial (P < .001) and rhinologic (P = .003) domains. Multivariable logistic regression revealed that runny nose (P < .001) was most predictive of spontaneous CSF rhinorrhea while nasal blockage (P < .001), thick nasal discharge (P < .001), and facial pain/pressure (P = .001) were predictive of CRSsNP after adjusting for relevant confounders. No significant difference was observed in total SNOT-22 scores between groups (P = .676). CONCLUSIONS: Spontaneous CSF rhinorrhea is commonly misdiagnosed as other sinonasal pathologies. However, individual SNOT-22 items can help aid in suggesting a CSF leak. Spontaneous CSF rhinorrhea should be suspected in patients who have high SNOT-22 scores for runny nose and report this symptom as most important, but have lower scores related to the other cardinal symptoms of CRS.

Optic nerve sheath diameter correlates to intracranial pressure in spontaneous CSF leak patients.

BACKGROUND: Spontaneous cerebrospinal fluid (sCSF) leaks develop from pressure erosion due to idiopathic intracranial hypertension, treatment of which is paramount to preventing recurrence. Direct measurements of intracranial pressure (ICP) for monitoring response to treatment via lumbar drain (LD) or ventriculostomy are invasive and have risks. The objectives of this study are to determine whether ultrasonographic measurements of optic nerve sheath diameter (ONSD) correlate with LD ICP in patients with sCSF leaks undergoing treatment, and whether ONSDs are larger in patients with sCSF leaks than controls. METHODS: Subjects with sCSF leaks and controls were prospectively recruited. ONSD, sex, and body mass index (BMI) were analyzed. For sCSF leak subjects, ultrasonography was performed at the time of LD opening and each pressure check postoperatively, including the acetazolamide response. In control patients, measurements were obtained at the time of surgery. Pearson's correlation between ONSD and ICP was performed. RESULTS: Subjects with sCSF leaks (n = 9, age 52.4 ± 9.5, all female) and controls (n = 8, age 60.1 ± 14.8, two females) had significantly different BMIs, 38.4 ± 8.1 vs. 29.2 ± 4.8, t(15) = 2.793, p = 0.014. ONSD was strongly correlated with ICP measurements (r = 0.583, p = 0.002). However, percentage change in ONSD and ICP measurements were more strongly correlated (r = 0.733, p < 0.001). Patients with sCSF leaks had significantly higher ONSDs than controls, 0.63 cm ± 0.044 vs. 0.56 cm ± 0.074, t(15) = 2.329, p = 0.034. CONCLUSION: ONSD significantly correlated with ICP in sCSF leak patients and was wider in sCSF leak subjects than controls. Ultrasonography has utility in monitoring the ICP response to acetazolamide.

SNOT-22 Quality of Life Scores Improve After Endoscopic Endonasal Repair of Spontaneous Cerebrospinal Fluid Rhinorrhea.

OBJECTIVES: Patients with spontaneous cerebrospinal fluid (CSF) rhinorrhea can experience significant sinonasal symptom burden, leading to poor quality of life (QOL). The objective of this study was to investigate sinonasal outcome test-22 (SNOT-22) scores in patients undergoing endoscopic endonasal surgery for spontaneous CSF rhinorrhea and compare them to patients undergoing endoscopic sinus surgery (ESS) for chronic rhinosinusitis without nasal polyps (CRSsNP). METHODS: A multi-institutional retrospective review of patients with spontaneous CSF rhinorrhea and CRSsNP was performed. Pre-surgery and post-surgery SNOT-22 scores and domains were compared within each group. Improvements in SNOT-22 scores after surgery were compared between the groups. RESULTS: Ninety-one patients were in the CSF rhinorrhea group and 105 patients were in the CRSsNP group. Within each group, surgery significantly improved total SNOT-22 scores, domain scores, and most of the individual symptoms. Comparing the 2 groups revealed similar improvements in total SNOT-22 scores (P = .244). The CSF rhinorrhea group improved more in runny nose (P < .001), postnasal discharge (P < .001), wake up at night (P = .024), and embarrassed (P = .002). The CRSsNP group improved more in sneezing (P = .027), nasal blockage (P < .001), decreased sense of smell/taste (P = .011), thick nasal discharge (P < .001), facial pain/pressure (P = .008), and the ear/facial domain (P = .010). CONCLUSIONS: Patients with spontaneous CSF rhinorrhea experience significant symptom burden. Those who undergo CSF leak repair should experience significant improvement in QOL similar to patients who undergo ESS for CRSsNP as measured by SNOT-22.

Red ginseng aqueous extract improves mucociliary transport dysfunction and histopathology in CF rat airways.

BACKGROUND: We previously discovered that Korean red ginseng aqueous extract (RGAE) potentiates the TMEM16A channel, improved mucociliary transport (MCT) parameters in CF nasal epithelia in vitro, and thus could serve as a therapeutic strategy to rescue the MCT defect in cystic fibrosis (CF) airways. The hypothesis of this study is that RGAE can improve epithelial Cl- secretion, MCT, and histopathology in an in-vivo CF rat model. METHODS: Seventeen 4-month old CFTR-/- rats were randomly assigned to receive daily oral control (saline, n = 9) or RGAE (Ginsenosides 0.4mg/kg/daily, n = 8) for 4 weeks. Outcomes included nasal Cl- secretion measured with the nasal potential difference (NPD), functional microanatomy of the trachea using micro-optical coherence tomography, histopathology, and immunohistochemical staining for TMEM16a. RESULTS: RGAE-treated CF rats had greater mean NPD polarization with UTP (control = -5.48 +/- 2.87 mV, RGAE = -9.49 +/- 2.99 mV, p < 0.05), indicating, at least in part, potentiation of UTP-mediated Cl- secretion through TMEM16A. All measured tracheal MCT parameters (airway surface liquid, periciliary liquid, ciliary beat frequency, MCT) were significantly increased in RGAE-treated CF rats with MCT exhibiting a 3-fold increase (control, 0.45+/-0.31 vs. RGAE, 1.45+/-0.66 mm/min, p < 0.01). Maxillary mucosa histopathology was markedly improved in RGAE-treated cohort (reduced intracellular mucus, goblet cells with no distention, and shorter epithelial height). TMEM16A expression was similar between groups. CONCLUSION: RGAE improves TMEM16A-mediated transepithelial Cl- secretion, functional microanatomy, and histopathology in CF rats. Therapeutic strategies utilizing TMEM16A potentiators to treat CF airway disease are appropriate and provide a new avenue for mutation-independent therapies.