Human Nasal Epithelium Research Articles

β-Cyclodextrins as affordable antivirals to treat coronavirus infection

The SARS-CoV-2 pandemic made evident that there are only a few drugs against coronavirus. Here we aimed to identify a cost-effective antiviral with broad spectrum activity and high safety profile. Starting from a list of 116 drug candidates, we used molecular modelling tools to rank the 44 most promising inhibitors. Next, we tested their efficacy as antivirals against α and β coronaviruses, such as the HCoV-229E and SARS-CoV-2 variants. Four drugs, OSW-1, U18666A, hydroxypropyl-β-cyclodextrin (HβCD) and phytol, showed in vitro antiviral activity against HCoV-229E and SARS-CoV-2. The mechanism of action of these compounds was studied by transmission electron microscopy and by fusion assays measuring SARS-CoV-2 pseudoviral entry into target cells. Entry was inhibited by HβCD and U18666A, yet only HβCD inhibited SARS-CoV-2 replication in the pulmonary Calu-3 cells. Compared to the other cyclodextrins, β-cyclodextrins were the most potent inhibitors, which interfered with viral fusion via cholesterol depletion. β-cyclodextrins also prevented infection in a human nasal epithelium model ex vivo and had a prophylactic effect in the nasal epithelium of hamsters in vivo. All accumulated data point to β-cyclodextrins as promising broad-spectrum antivirals against different SARS-CoV-2 variants and distant alphacoronaviruses. Given the wide use of β-cyclodextrins for drug encapsulation and their high safety profile in humans, our results support their clinical testing as prophylactic antivirals.

Comparing Cytology Brushes for Optimal Human Nasal Epithelial Cell Collection: Implications for Airway Disease Diagnosis and Research.

Primary nasal epithelial cells and culture models are used as important diagnostic, research and drug development tools for several airway diseases. Various instruments have been used for the collection of human nasal epithelial (HNE) cells but no global consensus yet exists regarding the optimal tool. This study compares the efficiency of two cytology brushes (Olympus (2 mm diameter) and Endoscan (8 mm diameter)) in collecting HNE cells. The study involved two phases, with phase one comparing the yield, morphology and cilia beat frequency (CBF) of cells collected from paediatric participants using each of the two brushes. Phase two compared nasal brushing under general anaesthetic and in the awake state, across a wide age range, via the retrospective audit of the use of the Endoscan brush in 145 participants. Results indicated no significant difference in CBF measurements between the two brushes, suggesting that the choice of brush does not compromise diagnostic accuracy. However, the Endoscan brush collected significantly more total and live cells than the Olympus brush, making it a more efficient option. Importantly, the Endoscan brush is more cost-effective, with a notable price difference between the two brushes.

Validating organoid-derived human intestinal monolayers for personalized therapy in cystic fibrosis.

Highly effective drugs modulating the defective protein encoded by the CFTR gene have revolutionized cystic fibrosis (CF) therapy. Preclinical drug-testing on human nasal epithelial (HNE) cell cultures and 3-dimensional human intestinal organoids (3D HIO) are used to address patient-specific variation in drug response and to optimize individual treatment for people with CF. This study is the first to report comparable CFTR functional responses to CFTR modulator treatment among patients with different classes of CFTR gene variants using the three methods of 2D HIO, 3D HIO, and HNE. Furthermore, 2D HIO showed good correlation to clinical outcome markers. A larger measurable CFTR functional range and access to the apical membrane were identified as advantages of 2D HIO over HNE and 3D HIO, respectively. Our study thus expands the utility of 2D intestinal monolayers as a preclinical drug testing tool for CF.

IL-4 drastically decreases deuterosomal and multiciliated cells via alteration in progenitor cell differentiation.

Allergic inflammation affects the epithelial cell populations resulting in goblet cell hyperplasia and decreased ciliated cells. Recent advances in single-cell RNA sequencing (scRNAseq) have enabled the identification of new cell subtypes and genomic features of single cells. In this study, we aimed to investigate the effect of allergic inflammation in nasal epithelial cell transcriptomes at the single-cell level. We performed scRNAseq in cultured primary human nasal epithelial (HNE) cells and in vivo nasal epithelium. The transcriptomic features and epithelial cell subtypes were determined under IL-4 stimulation, and cell-specific marker genes and proteins were identified. We confirmed that cultured HNE cells were similar to in vivo epithelial cells through scRNAseq. Cell-specific marker genes were utilized to cluster the cell subtypes, and FOXJ1+ -ciliated cells were sub-classified into multiciliated and deuterosomal cells. PLK4 and CDC20B were specific for deuterosomal cells, and SNTN, CPASL, and GSTA2 were specific for multiciliated cells. IL-4 altered the proportions of cell subtypes, resulting in a decrease of multiciliated cells and loss of deuterosomal cells. The trajectory analysis revealed deuterosomal cells as precursor cells of multiciliated cells and deuterosomal cells function as a bridge between club and multiciliated cells. A decrease in deuterosomal cell marker genes was observed in nasal tissue samples with type 2 inflammation. The effects of IL-4 appear to be mediated through the loss of the deuterosomal population, resulting in the reduction of multiciliated cells. This study also newly suggests cell-specific markers that might be pivotal for investigating respiratory inflammatory diseases.

Human Nasal Epithelium Damage as the Probable Mechanism Involved in the Development of Post-COVID-19 Parosmia.

Since the beginning of the COVID-19 pandemic, understanding the physiopathological mechanisms of its manifestations has been crucial to understand the disease and its implications. As the disease evolved, post-infection complications have arisen such as olfactory dysfunctions including parosmia in which odourants are perceived in a distorted or an unpleasant way. In this article, we attempt to clarify these mechanisms and the role of human nasal epithelium in the development of post-COVID-19 parosmia. The mechanisms by which SARS-CoV-2 generates olfactory dysfunction have not been elucidated, and multiple theories have been proposed pointing to the sustentacular cells of the olfactory epithelium as the main probable target of the virus. Establishing the main physiopathological mechanism of post-COVID-19 parosmia will set a path for further investigations and determine treatment and preventive options for patients who have been reported to be extensively affected in multiple aspects of their lives such as eating habits and mental health.

IL-4 decreases multiciliated cell numbers via the loss of deuterosomal cells in human nasal epithelium

IL-4 decreases multiciliated cell numbers via the loss of deuterosomal cells in human nasal epithelium

In vitro interactions of aerosol formulations with human nasal epithelium using real-time monitoring of drug transport in a nasal mucosa-on-a-chip

The current organ-on-chip platforms used for studying respiratory drug delivery are limited to the administration of drug solutions and suspensions, lacking the in vivo aerosol drug administration and aerosol interaction with the respiratory tract barrier. Moreover, they mostly rely on conventional assays that require sample collection and ‘off the chip’ analyses, which can be labor-intensive and costly. In this study, a human nasal epithelial mucosa (NEM)-on-a-chip is developed that enables the deposition of aerosolized nasal formulations while emulating realistic shear stresses (0.23 and 0.78 Pa), exerted to the inferior and middle turbinate of the human nasal cavity. Under these different dynamic conditions in the donor channel of the NEM-on-a-chip, the deposited dose of aerosols and particle size distributions varied. In addition, the increase in the shear stress to 0.78 Pa adversely affected the cells' viability, reflected by a 36.9 ± 5.4% reduction in the transepithelial electrical resistance. The epithelial transport profiles of aerosolized ibuprofen formulations under 0.23 Pa shear stress were successfully monitored in real-time by an electrochemical sensor embedded in the acceptor channel, where the NEM-on-a-chip was able to monitor the effect of permeation enhancer in the test formulation on the rate of drug transport. The novel NEM-on-a-chip can potentially be a promising physiologically relevant tool for reliable nasal aerosol testing in vitro.

Impairment mechanism of nasal mucosa after radiotherapy for nasopharyngeal carcinoma.

The nasal mucosa, which performs the crucial functions of filtering, humidifying and temperature regulation, is one of the most vulnerable areas of nasopharyngeal carcinoma (NPC) patients after radiotherapy (RT). Following RT, NPC patients experience a series of pathological changes in the nasal mucosa, ultimately leading to physiological dysfunction of the nasal epithelium. This article systematically reviews the clinical and pathological manifestations of RT-related nasal damage in NPC patients and summarizes the potential mechanism of damage to the human nasal epithelium by RT. Finally, we outline the current mechanistic models of nasal epithelial alterations after RT in NPC patients and provide additional information to extend the in-depth study on the impairment mechanisms of the nasal mucosa resulting from RT. We also describe the relationship between structural and functional alterations in the nasal mucosa after RT to help mitigate and treat this damage and provide insights informing future clinical and fundamental investigations.

Efficacy and toxicity of Anatolian propolis on healthy nasal epithelial cells.

In our study we aimed to evaluate the effects of applying propolis topically to epithelial cells of the nasal cells, to discover whether this causes any toxic effect upon the cells. Samples of healthy human primary nasal epithelium harvested during septoplasty from volunteers were incubated in cell culture. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays may be utilized when assessing cellular damage (toxicity), as evidenced by DNA fragmentation, nuclear condensation, alteration in the outer plasma membrane and cytoskeletal alteration. This was the method used in the study. Cultured epithelial cells were incubated with propolis (Bee&You) for 24 hours at 37°C. The MTT assay was then performed, and the cell morphology was examined by confocal microscopy. In addition, via wound healing assay, cellular proliferation was assessed by the artificial scratch method followed by light microscopy. MTT assay results showed that the primary nasal cells were not affected by the topical application of propolis for 24 hours. All of the applied doses not changed significantly the viability of the cells. The agent was not found to be cytotoxic to the primary nasal cells in the application time of 24 hours. Our confocal microscopy findings supported the MTT findings. According to the confocal images, control cells that were not treated with test agent were with compact morphology and undamaged fusiform cell shape and nucleus. In test group of nasal cells, Propolis was found not to be cytotoxic on the cellular morphology and not changed the cells. When evaluating the results from the wound healing assay, the clear area of scratch obtained at the start of incubation (0th) was closed totally with the proliferated primary nasal cells after incubation of 24 hours with propolis. These findings are supported by our MTT findings that imply to the slight induce of proliferation of the primary cells by Propolis. Topically applied propolis did not have a cytotoxic effect on nasal epithelium cells. Considering its antibacterial and antioxidant effects, it has been concluded that topical application in sinonasal inflammatory diseases (e.g., acute and chronic rhinosinusitis) may have an auxiliary effect in treatment. Moreover, there is a slight induce of proliferation of the primary cells by propolis which may help wound healing in septal surgeries and epistaxis.

A safety investigation into topical effects of naproxen sodium on nasal epithelial cells and potential toxicity in local application

ObjectivesWe examined how topically-applied naproxen sodium affects human nasal epitheliocytes in culture. MethodsSamples of healthy human primary nasal epithelium (NE) harvested during septoplasty from volunteers without rhinosinusitis were incubated in cell culture. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays may be utilised when assessing cellular damage (toxicity), as evidenced by DNA fragmentation, nuclear condensation, alteration in the outer plasma membrane and cytoskeletal alteration. This was the method used in the study. Cultured epitheliocytes were incubated with naproxen sodium for 24 h at 37 °C. The MTT assay was then performed and the cells' morphology was examined by confocal microscopy. Additionally, cellular proliferation was assessed by the artificial scratch method followed by light microscopy. ResultsThe results indicated that naproxen sodium does not cause any cytotoxic effects upon nasal epithelial cells when applied topically. There was no evidence indicating cytotoxicity on the nasal epitheliocytes in culture for the 24 h period over which the drug was applied. In particular, there was no alteration in cellular morphology, damage to the intracellular organelles structure or the cytoskeleton secondary to naproxen sodium. Furthermore, cellular proliferation occurred normally in these conditions, as on scratch test. ConclusionTopical naproxen sodium may be used on nasal epithelial cells without inducing toxicity. This agent is therefore suitable, given its known anti-inflammatory effects, for use in patients suffering from diseases involving nasal and paranasal sinusal inflammation, including rhinosinusitis (both chronic and acute) and nasal polyposis which should be investigated. In the future, topical medication forms for nasal usage should be developed.

Interactions Between Severe Acute Respiratory Syndrome Coronavirus 2 Replication and Major Respiratory Viruses in Human Nasal Epithelium.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), along with extensive non-pharmacological interventions, have profoundly altered the epidemiology of major respiratory viruses. Some studies have described virus-virus interactions, particularly manifested by viral interference mechanisms at different scales. Still, our knowledge of the mutual interactions between SARS-CoV-2 and other respiratory viruses remains incomplete.Here, we studied the interactions between SARS-CoV-2 and several respiratory viruses (influenza, RSV, hMPV, and hRV) in a reconstituted human epithelial airway model, exploring different scenarios affecting the sequence and timing of co-infections. We show that the virus type and the sequence of infections are key parameters of virus-virus interactions, having the impact of primary infections on the regulation of the immune response a determinant role in the outcome of secondary infections.

27-Hydroxycholesterol inhibits rhinovirus replication in vitro and on human nasal and bronchial histocultures without selecting viral resistant variants

The genetic plasiticity of viruses is one of the main obstacles to the development of antivirals. The aim of this study has been to assess the ability of two physiologic oxysterols and host-targeting antivirals - namely 25- and 27-hydroxycholesterol (25OHC and 27OHC) - to select resistant strains, using human rhinovirus (HRV) as a challenging model of a viral quasispecies. Moreover, we selected 27OHC for further studies aimed at exploring its potential for the development of antiviral drugs. The results obtained with clonal or serial passage approaches show that 25OHC and 27OHC do not select HRV oxysterol-resistant variants. Moreover, we demonstrate the ability of 27OHC to inhibit the yield of HRV in 3D in vitro fully reconstituted human nasal and bronchial epithelia from cystic fibrosis patients and prevent virus-induced cilia damage. The promising antiviral activity of 27OHC and its competitive advantages over direct-acting antivirals, make this molecule a suitable candidate for further studies to explore its clinical potential.

Temporal Whole-Transcriptomic Analysis of Characterized In Vitro and Ex Vivo Primary Nasal Epithelia.

Air-liquid interface (ALI) cell culture of primary airway progenitors enables the differentiation and recapitulation of a pseudostratified epithelium in vitro, providing a highly useful tool for researching respiratory health and disease. Previous studies into gene expression in ALI-cultures compared to ex vivo nasal brushings have been limited in the number of time-points and/or the number of genes studied. In this study physiological and global transcriptomic changes were assessed in an extended in vitro 63-day human healthy nasal epithelium ALI-culture period and compared to ex vivo nasal brushing samples. Ex vivo nasal brushing samples formed distinct transcriptome clusters to in vitro ALI-cultured nasal epithelia, with from day 14 onwards ALI samples best matching the ex vivo samples. Immune response regulation genes were not expressed in the in vitro ALI-culture compared to the ex vivo nasal brushing samples, likely because the in vitro cultures lack an airway microbiome, lack airborne particles stimulation, or did not host an immune cell component. This highlights the need for more advanced co-cultures with immune cell representation to better reflect the physiological state. During the first week of ALI-culture genes related to metabolism and proliferation were increased. By the end of week 1 epithelial cell barrier function plateaued and multiciliated cell differentiation started, although widespread ciliation was not complete until day 28. These results highlight that time-points at which ALI-cultures are harvested for research studies needs to be carefully considered to suit the purpose of investigation (transcriptomic and/or functional analysis).

Cell-Type-Specific Expression of Hyaluronan Synthases HAS2 and HAS3 Promotes Goblet Cell Hyperplasia in Allergic Airway Inflammation.

Allergic rhinitis (AR) is a multifactorial airway disease characterized by basal and goblet cell hyperplasia. Hyaluronic acid (HA) is a major component of extracellular matrix and a critical contributor to tissue repair and remodeling after injury. We previously demonstrated that the intermediate progenitor cell (IPC) surface marker CD44v3 is upregulated in the basal and suprabasal layers of well-differentiated primary human nasal epithelial (HNE) cells after stimulation with the Th2 (T-helper cell type 2) cytokine IL-4, and an antibody blocking the CD44v3-HA interaction suppressed IL-4-induced goblet cell hyperplasia. We now show that the expression of HA and two HA synthases, HAS2 and HAS3, was upregulated in both the nasal surface epithelium of subjects with AR and IL-4-stimulated HNE cells. Inhibition of HA synthesis by 4-methylumbelliferone suppressed IL-4-induced goblet cell hyperplasia. Moreover, HAS2 and HAS3 were expressed in IPCs depending on the differentiation events, as follows: the rapid, transient upregulation of HAS2 induced basal IPC proliferation and basal-to-suprabasal transition, whereas the delayed upregulation of HAS3 promoted the transition of suprabasal IPCs to a goblet cell fate. 4-methylumbelliferone treatment in a house dust mite-induced murine AR model attenuated goblet cell metaplasia. Last, HA concentrations in nasal epithelial lining fluids from patients with AR positively correlated with the concentrations of mediators causing allergic inflammation. These data suggest that HA produced after the sequential upregulation of HAS2 and HAS3 contributes to goblet cell hyperplasia in allergic airway inflammation and modulates disease progression.

Supporting Cells of the Human Olfactory Epithelium Co-Express the Lipid Scramblase TMEM16F and ACE2 and May Cause Smell Loss by SARS-CoV-2 Spike-Induced Syncytia.

Quantitative and qualitative alterations in the sense of smell are well established symptoms of COVID-19. Some reports have shown that non-neuronal supporting (also named sustentacular) cells of the human olfactory epithelium co-express ACE2 and TMPRSS2 necessary for SARS-CoV-2 infection. In COVID-19, syncytia were found in many tissues but were not investigated in the olfactory epithelium. Some studies have shown that syncytia in some tissues are formed when SARS-CoV-2 Spike expressed at the surface of an infected cell binds to ACE2 on another cell, followed by activation of the scramblase TMEM16F (also named ANO6) which exposes phosphatidylserine to the external side of the membrane. Furthermore, niclosamide, an approved antihelminthic drug, inhibits Spike-induced syncytia by blocking TMEM16F activity. The aim of this study was to investigate if proteins involved in Spike-induced syncytia formation, i.e., ACE2 and TMEM16F, are expressed in the human olfactory epithelium. We analysed a publicly available single-cell RNA-seq dataset from human nasal epithelium and performed immunohistochemistry in human nasal tissues from biopsies. We found that ACE2 and TMEM16F are co-expressed both at RNA and protein levels in non-neuronal supporting cells of the human olfactory epithelium. Our results provide the first evidence that TMEM16F is expressed in human olfactory supporting cells and indicate that syncytia formation, that could be blocked by niclosamide, is one of the pathogenic mechanisms worth investigating in COVID-19 smell loss.

Molnupiravir combined with different repurposed drugs further inhibits SARS-CoV-2 infection in human nasal epithelium in vitro.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a worldwide pandemic with unprecedented economic and societal impact. Currently, several vaccines are available and multitudes of antiviral treatments have been proposed and tested. Although many of the vaccines show clinical efficacy, they are not equally accessible worldwide. Additionally, due to the continuous emergence of new variants and generally short duration of immunity, the development of effective antiviral treatments remains of the utmost importance. Since the emergence of SARS-CoV-2, substantial efforts have been undertaken to repurpose existing drugs for accelerated clinical testing and emergency use authorizations. However, drug-repurposing studies using cellular assays often identify hits that later prove ineffective clinically, highlighting the need for more complex screening models. To this end, we evaluated the activity of single compounds that have either been tested clinically or already undergone extensive preclinical profiling, using a standardized in vitro model of human nasal epithelium. Furthermore, we also evaluated drug combinations based on a sub-maximal concentration of molnupiravir. We report the antiviral activity of 95 single compounds and 30 combinations. We show that only a few single agents are highly effective in inhibiting SARS-CoV-2 replication while selected drug combinations containing 10 µM molnupiravir boosted antiviral activity compared to single compound treatment. These data indicate that molnupiravir-based combinations are worthy of further consideration as potential treatment strategies against coronavirus disease 2019 (COVID-19).

Cell function and identity revealed by comparative scRNA-seq analysis in human nasal, bronchial and epididymis epithelia

The evolutionary relationship of cells within tissues having a similar function but located in different anatomical sites is of considerable biological interest. The development of single-cell RNA sequencing (scRNA-seq) protocols has greatly enhanced opportunities to address this topic. Here we focus on cells in the epithelium which lines two regions of the human respiratory tract and the male genital ducts to delineate the shared, differentiated functions of the different cell populations. Transcriptomic data were used to assess the gene expression profiles of human bronchial, nasal, and epididymal epithelium (HBE, HNE, and HEE). Bulk RNA-seq showed many shared genes expressed in cells from the nasal and bronchial epithelium and highlighted their divergence from the epididymal epithelium. ScRNA-seq in HBE and HNE cells demonstrated overlapping gene expression patterns within basal and secretory cell populations. Moreover, the distribution of cell types was altered in HNE cells derived from donors with cystic fibrosis (CF) when compared to cells from healthy donors. Next, the HBE and HNE datasets were merged and confirmed intersection of cell type gene expression profiles from the two sites. However, secretory and ciliated cells were the most abundant types in the HBE samples, while more basal cells were seen in the HNE populations. We then merged single-cell data from the epididymis to determine if overlapping functions of these cells corresponded to those in the airway. Of note, only the pulmonary ionocytes/epididymis clear cells showed a strongly conserved identity, which was confirmed by imputation in bulk RNA-seq datasets from the same cells.

Primary Human Nasal Epithelial Cells: Biobanking in the Context of Precision Medicine.

Human nasal epithelial (HNE) cells are easy to collect by simple, non-invasive nasal brushing. Patient-derived primary HNE cells can be amplified and differentiated into a pseudo-stratified epithelium in air-liquid interface conditions to quantify cyclic AMP-mediated Chloride (Cl-) transport as an index of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) function. If critical steps such as quality of nasal brushing and cell density upon cryopreservation are performed efficiently, HNE cells can be successfully biobanked. Moreover, short-circuit current studies demonstrate that freeze-thawing does not significantly modify HNE cells' electrophysiological properties and response to CFTR modulators. In the culture conditions used in this study, when less than 2 x 106 cells are frozen per cryovial, the failure rate is very high. We recommend freezing at least 3 x 106 cells per cryovial. We show that dual therapies combining a CFTR corrector with a CFTR potentiator have a comparable correction efficacy for CFTR activity in F508del-homozygous HNE cells. Triple therapy VX-445 + VX-661 + VX-770 significantly increased correction of CFTR activity compared to dual therapy VX-809 + VX-770. The measure of CFTR activity in HNE cells is a promising pre-clinical biomarker useful to guide CFTR modulator therapy.

Nasal symbiont Staphylococcus epidermidis restricts the cellular entry of influenza virus into the nasal epithelium

Our recent study presented that human nasal commensal Staphylococcus epidermidis could potentiate antiviral immunity in the nasal mucosa through interferon-related innate responses. Here, we found that human nasal commensal S. epidermidis promoted protease–protease inhibitor balance in favor of the host and prevented influenza A virus (IAV) replication in the nasal mucosa and lungs. A relatively higher induction of Serpine1 exhibited in S. epidermidis-inoculated nasal epithelium and S. epidermidis-induced Serpine1 significantly decreased the expression of serine proteases. Furthermore, the transcription of urokinase plasminogen activator (uPA) and Serpine1 was biologically relevant in S. epidermidis-inoculated nasal epithelium, and the induction of uPA might be related to the sequential increase of Serpine1 in human nasal epithelium. Our findings reveal that human nasal commensal S. epidermidis manipulates the cellular environment lacking serine proteases in the nasal epithelium through Serpine1 induction and disturbs IAV spread to the lungs at the level of the nasal mucosa.

Genetic evidence supports the development of SLC26A9 targeting therapies for the treatment of lung disease

Over 400 variants in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) are CF-causing. CFTR modulators target variants to improve lung function, but marked variability in response exists and current therapies do not address all CF-causing variants highlighting unmet needs. Alternative epithelial ion channel/transporters such as SLC26A9 could compensate for CFTR dysfunction, providing therapeutic targets that may benefit all individuals with CF. We investigate the relationship between rs7512462, a marker of SLC26A9 activity, and lung function pre- and post-treatment with CFTR modulators in Canadian and US CF cohorts, in the general population, and in those with chronic obstructive pulmonary disease (COPD). Rs7512462 CC genotype is associated with greater lung function in CF individuals with minimal function variants (for which there are currently no approved therapies; p = 0.008); and for gating (p = 0.033) and p.Phe508del/ p.Phe508del (p = 0.006) genotypes upon treatment with CFTR modulators. In parallel, human nasal epithelia with CC and p.Phe508del/p.Phe508del after Ussing chamber analysis of a combination of approved and experimental modulator treatments show greater CFTR function (p = 0.0022). Beyond CF, rs7512462 is associated with peak expiratory flow in a meta-analysis of the UK Biobank and Spirometa Consortium (p = 2.74 × 10−44) and provides p = 0.0891 in an analysis of COPD case-control status in the UK Biobank defined by spirometry. These findings support SLC26A9 as a therapeutic target to improve lung function for all people with CF and in individuals with other obstructive lung diseases.