ERJ Open Res. 2022 Dec 12;8(4):00060-2022. doi: 10.1183/23120541.00060-2022. eCollection 2022 Oct.

ABSTRACT

BACKGROUND: Although interest in nontuberculous mycobacteria (NTM) infection has increased in the last decades, published data vary according to different geographical areas, diagnostic facilities and quality of study design. This study aims at assessing both prevalence and incidence of NTM infection and NTM pulmonary disease (NTM-PD) among adults with bronchiectasis, to describe patients' characteristics, therapeutic options and clinical outcomes.

METHODS: Bronchiectasis adults who had been tested for NTM were enrolled at the Bronchiectasis Program of the Policlinico Hospital in Milan, Italy, from 2016 to 2018.

RESULTS: Among the 373 patients enrolled, 26.1% had at least one respiratory sample positive for NTM and 12.6% reached a diagnosis of NTM-PD. Incidence rates for NTM infection and NTM-PD were 13 (95% CI 10-16) and 4 (95% CI 2-6) per 100 person-years, respectively. The most prevalent NTM species causing NTM-PD were M. intracellulare (38.3%), M. avium (34.0%), M. abscessus (8.5%) and M. kansasii (8.5%). Once treatment for NTM-PD was initiated, a favourable outcome was documented in 52.2% of the patients, while a negative outcome was recorded in 32.6%, including recurrence (17.4%), treatment failure (10.9%), re-infection (2.2%) and relapse (2.2%). Treatment halted was experienced in 11 (23.9%) patients.

CONCLUSIONS: NTM infection is frequent in bronchiectasis patients and the presence of NTM-PD is relevant. The low success rate of NTM-PD treatment in bronchiectasis patients requires a call to action to identify new treatment modalities and new drugs to improve patients' outcomes.

PMID:36655224 | PMC:PMC9835995 | DOI:10.1183/23120541.00060-2022

ERJ Open Res. 2022 Dec 12;8(4):00382-2022. doi: 10.1183/23120541.00382-2022. eCollection 2022 Oct.

ABSTRACT

BACKGROUND: Human nasal epithelial (HNE) cells can be sampled noninvasively and cultured to provide a model of the airway epithelium that reflects cystic fibrosis (CF) pathophysiology. We hypothesised that in vitro measures of HNE cell physiology would correlate directly with in vivo measures of lung physiology and therapeutic response, providing a framework for using HNE cells for therapeutic development and precision medicine.

METHODS: We sampled nasal cells from participants with CF (CF group, n=26), healthy controls (HC group, n=14) and single CF transmembrane conductance regulator (CFTR) mutation carrier parents of the CF group (CR group, n=16). Participants underwent lung physiology and sweat chloride testing, and nuclear imaging-based measurement of mucociliary clearance (MCC) and small-molecule absorption (ABS). CF participants completed a second imaging day that included hypertonic saline (HS) inhalation to assess therapeutic response in terms of MCC. HNE measurements included Ussing chamber electrophysiology, small-molecule and liquid absorption rates, and particle diffusion rates through the HNE airway surface liquid (ASL) measured using fluorescence recovery after photobleaching (FRAP).

RESULTS: Long FRAP diffusion times were associated with increased MCC response to HS in CF. This implies a strong relationship between inherent factors affecting ASL mucin concentration and therapeutic response to a hydrating therapy. MCC decreased with age in the CR group, which had a larger range of ages than the other two groups. Likely this indicates a general age-related effect that may be accentuated in this group. Measures of lung ABS correlated with sweat chloride in both the HC and CF groups, indicating that CFTR function drives this measure of paracellular small-molecule probe absorption.

CONCLUSIONS: Our results demonstrate the utility of HNE cultures for assessing therapeutic response for hydrating therapies. In vitro measurements of FRAP were particularly useful for predicting response and for characterising important properties of ASL mucus that were ultimately reflected in lung physiology.

PMID:36655223 | PMC:PMC9835985 | DOI:10.1183/23120541.00382-2022

ERJ Open Res. 2022 Dec 12;8(4):00227-2022. doi: 10.1183/23120541.00227-2022. eCollection 2022 Oct.

ABSTRACT

BACKGROUND: Increasing awareness of milder presentations of cystic fibrosis (CF) and greater interest in non-CF bronchiectasis are likely to lead to more CF screening by respiratory clinicians. As a result, adults who may not strictly fulfil CF diagnostic criteria yet display evidence of abnormal CF transmembrane conductance regulator (CFTR) function are being identified. The degree of agreement on diagnosis and care needs in these cases between CF clinicians remains unknown, and has implications for patient care, including access to CFTR modulator therapies.

METHODS: We surveyed adult CF physicians in Canada, the USA, the UK and Ireland, and presented them with anonymised vignettes of adult patients referred for assessment of possible CF. Diagnostic inter-rater agreement over diagnosis, ease of classifying cases and appropriate follow-up was assessed using Krippendorff's reliability coefficient (α).

RESULTS: Agreement over diagnosis (α=0.282), ease of classification (α= -0.01) and recommended follow-up (α=0.054) was weak. Clinician experience (>10 and 5-10 years versus <5 years) and location (UK and Ireland versus Canada) were associated with higher odds of recommending further testing compared with selecting a formal diagnosis (respectively, OR 2.87; p=0.022, OR 3.74; p=0.013 and OR 3.16; p=0.007). A modified standard of care was recommended in 28.7% of cases labelled as CF. 70% of respondents agreed with the statement that "Accurate distinction between CF and CFTR-related disorder has become significantly more pertinent with the advent of highly effective CFTR modulators".

CONCLUSIONS: Our results demonstrate low diagnostic concordance among CF specialists assessing cases of possible adult CF and highlight an area in need of improvement.

PMID:36655218 | PMC:PMC9835972 | DOI:10.1183/23120541.00227-2022

J Endocr Soc. 2022 Dec 12;7(3):bvac182. doi: 10.1210/jendso/bvac182. eCollection 2023 Jan 6.

ABSTRACT

Given the close anatomical and physiological links between the exocrine and endocrine pancreas, diseases of 1 compartment often affect the other through mechanisms that remain poorly understood. Pancreatitis has been associated with both type 1 and type 2 diabetes, but its association with monogenic diabetes is unknown. Patients heterozygous for pathogenic CFTR variants are cystic fibrosis carriers and have been reported to have an increased risk of acute pancreatitis. We describe a 12-year-old patient with monogenic neonatal diabetes due to a pathogenic heterozygous paternally inherited mutation of the insulin gene (INS), c.94 G > A (p.Gly32Ser), who experienced 3 recurrent episodes of acute pancreatitis over 7 months in conjunction with poor glycemic control, despite extensive efforts to improve glycemic control in the past 4 years. Intriguingly, the maternal side of the family has an extensive history of adult-onset pancreatitis consistent with autosomal dominant inheritance and the proband is heterozygous for a maternally inherited, CFTR variant c.3909C > G (p.Asn1303Lys). Paternally inherited monogenic neonatal diabetes may have promoted earlier age-of-onset of pancreatitis in this pediatric patient compared to maternal relatives with adult-onset acute pancreatitis. Further study is needed to clarify how separate pathophysiologies associated with INS and CFTR mutations influence interactions between the endocrine and exocrine pancreas.

PMID:36655002 | PMC:PMC9836200 | DOI:10.1210/jendso/bvac182

AAPS PharmSciTech. 2023 Jan 18;24(1):39. doi: 10.1208/s12249-023-02502-1.

ABSTRACT

Pulmonary administration of biodegradable polymeric formulation is beneficial in the treatment of various respiratory diseases. For respiratory delivery, the polymer must be non-toxic, biodegradable, biocompatible, and stable. Poly D, L-lactic-co-glycolic acid (PLGA) is a widely used polymer for inhalable formulations because of its attractive mechanical and processing characteristics which give great opportunities to pharmaceutical industries to formulate novel inhalable products. PLGA has many pharmaceutical applications and its biocompatible nature produces non-toxic degradation products. The degradation of PLGA takes place through the non-enzymatic hydrolytic breakdown of ester bonds to produce free lactic acid and glycolic acid. The biodegradation products of PLGA are eliminated in the form of carbon dioxide (CO2) and water (H2O) by the Krebs cycle. The biocompatible properties of PLGA are investigated in various in vivo and in vitro studies. The high structural integrity of PLGA particles provides better stability, excellent drug loading, and sustained drug release. This review provides detailed information about PLGA as an inhalable grade polymer, its synthesis, advantages, physicochemical properties, biodegradability, and biocompatible characteristics. The important formulation aspects that must be considered during the manufacturing of inhalable PLGA formulations and the toxicity of PLGA in the lungs are also discussed in this paper. Additionally, a thorough overview is given on the application of PLGA as a particulate carrier in the treatment of major respiratory diseases, such as cystic fibrosis, lung cancer, tuberculosis, asthma, and pulmonary hypertension.

PMID:36653547 | DOI:10.1208/s12249-023-02502-1

J Pediatr. 2023 Jan 16:S0022-3476(22)01135-0. doi: 10.1016/j.jpeds.2022.12.017. Online ahead of print.

NO ABSTRACT

PMID:36653281 | DOI:10.1016/j.jpeds.2022.12.017

J Cyst Fibros. 2023 Jan 16:S1569-1993(23)00004-8. doi: 10.1016/j.jcf.2023.01.005. Online ahead of print.

ABSTRACT

The combination of CFTR modulators ivacaftor, tezacaftor and elexacaftor (Trikafta®, Kaftrio®) significantly improve outcomes, including survival in a broad range of cystic fibrosis patients. These drugs have complicated metabolic profiles that make the potential for drug interactions an important consideration for prescribers, care providers and patients. Prolonged survival also increases risk of age-related disease and their associated pharmacotherapy, further increasing the risk of drug interactions and the need for increased vigilance amongst care providers. We systematically searched the literature for studies identifying and evaluating pharmacokinetic and pharmacodynamic drug interactions involving the components of Trikafta®/Kaftrio®. We also searched electronic databases of drugs for possible drug interactions based on metabolic profiles. We identified 86 potential drug interactions of which 13 were supported by 14 studies. There is a significant need for research to describe the likelihood, magnitude and clinical impact of the drug interactions proposed here.

PMID:36653239 | DOI:10.1016/j.jcf.2023.01.005

Tuberculosis (Edinb). 2023 Jan 10;138:102303. doi: 10.1016/j.tube.2023.102303. Online ahead of print.

ABSTRACT

Mycobacterium abscessus complex is a group of environmental pathogens that recently have been isolated more from patients with underlying lung diseases, such and COPD, bronchiectasis, and cystic fibrosis. The mechanisms involved in the pathogenesis of these diseases have only recently been investigated. Infection is associated with biofilm formation on the airway mucosa, invasion of the mucosal epithelial cells and a time-dependent impairment of the integrity of the monolayer. Using electron microscopy, it was shown that Mycobacterium abscessus induced lesions of the cell surface structures. Tight junction proteins claudin-1 and occludin-1 have increased transcription in cells exposed to Mycobacterium abscessus, in contrast to cells exposed to Mycobacterium avium. Infection of A549 alveolar epithelial cells by Mycobacterium abscessus reduced the oxidative metabolism of the cell, without inducing necrosis. A transposon library screen identified mutants that do not alter the metabolism of the A549 cells.Once the bacterium crosses the epithelial barrier, it may encounter sub-epithelial macrophages. Select mutants were used for infection assays to determine their effects on membrane integrity. Translocated select mutants were attenuated in macrophages compared to wild type Mycobacterium abscessus. In summary, the dynamics of Mycobacterium abscessus infection appears to be different from other non-tuberculous mycobacteria (NTMs). Future studies will attempt to address the mechanism involved in airway membrane lesions.

PMID:36652813 | DOI:10.1016/j.tube.2023.102303

Microbiol Spectr. 2023 Jan 18:e0327922. doi: 10.1128/spectrum.03279-22. Online ahead of print.

ABSTRACT

Nontuberculous mycobacteria (NTM), including Mycobacterium avium, are clinically important pathogens in cystic fibrosis (CF). The innate immune response to M. avium remains incompletely understood. We evaluated the role of complement opsonization in neutrophil-mediated killing of M. avium. Killing assays were performed using neutrophils from healthy donors (HDs) and persons with CF (pwCF). Clinical isolates of M. avium were opsonized with plasma from HDs or pwCF, which was intact or heat-treated to inactivate complement. HD neutrophils had killing activity against M. avium opsonized with intact HD plasma and killing was significantly reduced when M. avium was opsonized with heat-inactivated HD plasma. When opsonized with HD plasma, CF neutrophils had killing activity against M. avium that was not different than HD neutrophils. When opsonized with intact plasma from pwCF, HD neutrophil killing of M. avium was significantly reduced. Opsonization of M. avium with C3-depleted serum or IgM-depleted plasma resulted in significantly reduced killing. Plasma C3 levels were elevated in pwCF with NTM infection compared to pwCF without NTM infection. These studies demonstrate that human neutrophils efficiently kill M. avium when opsonized in the presence of plasma factors from HD that include C3 and IgM. Killing efficiency is significantly lower when the bacteria are opsonized with plasma from pwCF. This indicates a novel role for opsonization in neutrophil killing of M. avium and a deficiency in complement opsonization as a mechanism of impaired M. avium killing in CF. IMPORTANCE Mycobacterium avium is a member of a group of bacterial species termed nontuberculous mycobacteria (NTM) that cause lung disease in certain populations, including persons with cystic fibrosis (CF). NTM infections are challenging to diagnose and can be even more difficult to treat. This study investigated how the immune system responds to M. avium infection in CF. We found that neutrophils, the most abundant immune cell in the lungs in CF, can effectively kill M. avium in individuals both with and without CF. Another component of the immune response called the complement system is also required for this process. Levels of complement proteins are altered in persons with CF who have a history of NTM compared to those without a history of NTM infection. These results add to our understanding of how the immune system responds to M. avium, which can help pave the way toward better diagnostic and treatment strategies.

PMID:36651756 | DOI:10.1128/spectrum.03279-22

J Bras Pneumol. 2023 Jan 13;48(6):e20220445. doi: 10.36416/1806-3756/e20220445.

NO ABSTRACT

PMID:36651443 | DOI:10.36416/1806-3756/e20220445

Pediatr Pulmonol. 2023 Jan 18. doi: 10.1002/ppul.26319. Online ahead of print.

ABSTRACT

INTRODUCTION: There are no precise data about the effect of Aspergillus infection on lung function other than allergic bronchopulmonary aspergillosis (ABPA) in patients with cystic fibrosis (pwCF). Here, we aimed to determine clinical phenotypes caused by Aspergillus spp. using laboratory and immunologic parameters and to compare Aspergillus phenotypes in terms of pulmonary function tests (PFT) prospectively.

METHODS: Twenty-three pwCF who had Aspergillus isolation from respiratory cultures in the last year (case group) and 20 pwCF without Aspergillus isolation in sputum (control group) were included. Aspergillus IgG, Aspergillus IgE, Aspergillus PCR, galactomannan, total IgE from blood samples, and Aspergillus PCR and galactomannan from sputum, and skin prick test reactivity to Aspergillus antigen were used to distinguish different Aspergillus phenotypes. Pulmonary functions and frequency of pulmonary exacerbations were evaluated during a one-year follow-up.

RESULTS: Of 23 pwCF, 11 (47.8%) had Aspergillus colonization, nine (39.1%) had Aspergillus bronchitis, and three (13%) had ABPA. Aspergillus infection was not associated with worse z-scores of forced expiratory volume in the first second (FEV1) (p = 0.612), forced vital capacity (FVC) (p = 0.939), and the median FEV1% decline (0.0%/year vs -4.7%/year, p = 0.626). The frequency of pulmonary exacerbations in the Aspergillus infected and noninfected groups was similar.

CONCLUSION: Although Aspergillus spp. Isolation in pwCF was not associated with decreased lung function, a further decline was seen in the ABPA subgroup, and frequent pulmonary exacerbations during the one-year follow-up. This article is protected by copyright. All rights reserved.

PMID:36651101 | DOI:10.1002/ppul.26319

J Biomol Struct Dyn. 2023 Jan 18:1-10. doi: 10.1080/07391102.2023.2167118. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa is one of the leading opportunistic pathogens that causes nosocomial pneumonia and mostly in people with cystic fibrosis. In the present study, an in-silicoapproach was adopted to identify the novel drug target against Pseudomonas aeruginosa by employing subtractive genomics and molecular docking studies. Each step in the subtractive genomics scrutinized the bacterial proteome and determined a potential drug target against Pseudomonas aeruginosa. 71 essential proteins were obtained from the subcellular localization method that resides in the extracellular region. Metabolic pathways were studied to elucidate the unique pathways where the involvement of proteins present in the pathogen was predicted and a total of 6 unique pathways were determined. By, Genome mining of the source organism Paenibacillusehimensis, 9 ligands were obtained. The molecular docking analysis between the binding site of target protein NDK and ligands was carried out by employing the AutoDock Vina tool. Based on the highest binding affinity, Paenibactin, AnabaenopeptinNZ857 and Nostamide A complex with NDK protein with a lower binding energy of -7.5 kcal/mol, -7.4and -7.2 kcal/molrespectively were considered for the simulation studies. Molecular dynamics simulation studies showed the ligand in complex with protein was highly stable and rigid for a duration of 150 ns. For Paenibactin, AnabaenopeptinNZ857 and Nostamide Acomplex with protein, RMSD plot showed a deviation of ∼0.2-0.3 nm till ∼30ns/50 ns-110ns and further stabilized. The radius of the gyration plot clearly showed that the values stayed at ∼1.45 nm- 1.55 nm showing compactness and stability. The SASA stayed at the range ∼80nm2 and at least one total number of hydrogen bonds was shown throughout the 150 ns simulation for all three possible ligand-protein complexes. In the RMSF plot, the maximum fluctuation was ranged from ∼0.4-0.42 nm at the range between ∼57ns-60ns.The Paenibactin, AnabaenopeptinNZ857 and Nostamide A complex with NDK protein showed a stable, rigid and compact interaction throughout the simulation of duration 150 ns.Communicated by Ramaswamy H. Sarma.

PMID:36651083 | DOI:10.1080/07391102.2023.2167118

Pediatr Pulmonol. 2023 Jan 17. doi: 10.1002/ppul.26323. Online ahead of print.

ABSTRACT

To date few data are available on the long-term outcome of subjects with 5T;TG12 in trans with another VVCC and here we report the clinical course of an Italian cohort This article is protected by copyright. All rights reserved.

PMID:36650664 | DOI:10.1002/ppul.26323

Pediatr Pulmonol. 2023 Jan 17. doi: 10.1002/ppul.26318. Online ahead of print.

ABSTRACT

RATIONALE: Limited published research is available on the impact of elexacaftor/tezacaftor/ivacaftor (ETI) beyond the initial few months post-drug initiation, especially for those who initiated therapy via individual investigational new drug application. The experiences of patients with cystic fibrosis (CF) experiencing severe lung disease were reviewed for significant improvements in clinical symptoms and quality of life.

OBJECTIVES: To examine clinical outcomes two years post- ETI in patients with CF and advanced lung disease.

METHODS: This single center IRB-approved, retrospective chart review assessed clinical markers (ppFEV1 , weight, sweat chloride), quality of life and CT scans in patients with advanced lung disease who met criteria for compassionate use/expanded access program due to high risk of death or transplant need within two years.

RESULTS: Eighteen identified patients (ages 15 - 49 years) initiated drug between July and September 2019. Clinical markers indicated that therapy was well tolerated, not discontinued by any participant, and lab values did not indicate medical concern or discontinuation. Monitoring results indicated the safety of modulator therapy as there were no adverse clinical occurrences and all patients presented universal stabilization. There were no deaths and no transplants to date.

CONCLUSIONS: This study focused on patients with CF eligible for modulator therapy and were initiated due to advanced lung disease. Initiation of modulator therapy was deemed safe and resulted in objective positive changes in nutrition, cough, FEV1 , subjective reports of clinical status, level of activity, and a reduction in burden of treatment. This article is protected by copyright. All rights reserved.

PMID:36650567 | DOI:10.1002/ppul.26318

Semin Respir Crit Care Med. 2023 Jan 17. doi: 10.1055/s-0042-1759883. Online ahead of print.

ABSTRACT

Nontuberculous mycobacteria (NTM) are a group of mycobacteria which represent opportunistic pathogens that are of increasing concern in people with cystic fibrosis (pwCF). The acquisition has been traditionally though to be from environmental sources, though recent work has suggested clustered clonal infections do occur and transmission potential demonstrated among pwCF attending CF specialist centers. Guidelines for the screening, diagnosis, and identification of NTM and management of pwCF have been published. The emergence of CF-specific therapies, in particular cystic fibrosis transmembrane regulator (CFTR) modulator drugs, have led to significant improvement in the health and well-being of pwCF and may lead to challenges in sampling the lower respiratory tract including to screen for NTM. This review highlights the epidemiology, modes of acquisition, screening and diagnosis, therapeutic approaches in the context of improved clinical status for pwCF, and the clinical application of CFTR modulator therapies.

PMID:36649736 | DOI:10.1055/s-0042-1759883

Int J Technol Assess Health Care. 2023 Jan 17;39(1):e6. doi: 10.1017/S0266462322003373.

ABSTRACT

BACKGROUND: Adherence to preventative inhaled therapies in people with cystic fibrosis (CF) is low, resulting in potentially avoidable health losses and the need for costly rescue therapies.

OBJECTIVES: To estimate the cost-effectiveness of the CFHealthHub (CFHH) intervention to support adherence to inhaled medications.

METHODS: A state transition model was developed to assess the cost-effectiveness of the CFHH intervention versus usual care from the perspective of the UK National Health Service and Personal Social Services over a lifetime horizon. Costs and health outcomes were discounted at a rate of 3.5 percent per annum. Costs were valued at 2021/22 prices. The model structure includes health states defined by survival status, level of lung function, and transplant history. Treatment effects were modeled by changing the probabilities of transitioning between lung function states and reducing exacerbation rates. Model parameters were informed by the CFHH trial, CF Registry data, routine cost databases, literature, and expert opinion. Deterministic and probabilistic sensitivity analyses were undertaken to assess uncertainty.

RESULTS: The CFHH intervention is expected to generate additional health gains and cost savings compared with usual care. Assuming that it is delivered for 10 years, the CFHH intervention is expected to generate 0.17 additional quality-adjusted life years and cost savings of GBP 1,600 (EUR 1,662) per patient.

CONCLUSIONS: The CFHH intervention is expected to dominate usual care, irrespective of the duration over which the intervention is delivered. The modeled benefits and cost savings are smaller than initially expected and are sensitive to relative treatment effects on lung function.

PMID:36647697 | DOI:10.1017/S0266462322003373

Lancet Respir Med. 2023 Jan 13:S2213-2600(23)00002-4. doi: 10.1016/S2213-2600(23)00002-4. Online ahead of print.

NO ABSTRACT

PMID:36646100 | DOI:10.1016/S2213-2600(23)00002-4

J Eur Acad Dermatol Venereol. 2023 Jan 16. doi: 10.1111/jdv.18869. Online ahead of print.

NO ABSTRACT

PMID:36645858 | DOI:10.1111/jdv.18869

FASEB Bioadv. 2022 Oct 31;5(1):13-26. doi: 10.1096/fba.2022-00085. eCollection 2023 Jan.

ABSTRACT

Highly effective modulator therapies for cystic fibrosis (CF) make it a treatable condition for many people. However, although CF respiratory illness occurs after birth, other organ systems particularly in the digestive tract are damaged before birth. We use an ovine model of CF to investigate the in utero origins of CF disease since the sheep closely mirrors critical aspects of human development. Wildtype (WT) and CFTR -/- sheep tissues were collected at 50, 65, 80, 100, and 120 days of gestation and term (147 days) and used for histological, electrophysiological, and molecular analysis. Histological abnormalities are evident in CFTR-/- -/- animals by 80 days of gestation, equivalent to 21 weeks in humans. Acinar and ductal dilation, mucus obstruction, and fibrosis are observed in the pancreas; biliary fibrosis, cholestasis, and gallbladder hypoplasia in the liver; and intestinal meconium obstruction, as seen at birth in all large animal models of CF. Concurrently, cystic fibrosis transmembrane conductance regulator (CFTR)-dependent short circuit current is present in WT tracheal epithelium by 80 days gestation and is absent from CFTR -/- tissues. Transcriptomic profiles of tracheal tissues confirm the early expression of CFTR and suggest that its loss does not globally impair tracheal differentiation.

PMID:36643895 | PMC:PMC9832529 | DOI:10.1096/fba.2022-00085

ACS Omega. 2022 Dec 28;8(1):846-856. doi: 10.1021/acsomega.2c06212. eCollection 2023 Jan 10.

ABSTRACT

Patients with chronic rhinosinusitis (CRS) often show persistent colonization by bacteria in the form of biofilms which are resistant to antibiotic treatment. One of the most commonly isolated bacteria in CRS is Staphylococcus aureus (S. aureus). Nitric oxide (NO) is a potent antimicrobial agent and disperses biofilms efficiently. We hypothesized that S-nitrosoglutathione (GSNO), an endogenous NO carrier/donor, synergizes with gentamicin to disperse and reduce the bacterial biofilm density. We prepared GSNO formulations which are stable up to 12 months at room temperature and show the maximum amount of NO release within 1 h. We examined the effects of this GSNO formulation on the S. aureus biofilm established on the apical surface of the mucociliary-differentiated airway epithelial cell cultures regenerated from airway basal (stem) cells from cystic fibrosis (CF) and CRS patients. We demonstrate that for CF cells, which are defective in producing NO, treatment with GSNO at 100 μM increased the NO levels on the apical surface and reduced the biofilm bacterial density by 2 log units without stimulating pro-inflammatory effects or inducing epithelial cell death. In combination with gentamicin, GSNO further enhanced the killing of biofilm bacteria. Compared to placebo, GSNO significantly increased the ciliary beat frequency (CBF) in both infected and uninfected CF cell cultures. The combination of GSNO and gentamicin also reduced the bacterial density of biofilms grown on sinonasal epithelial cells from CRS patients and improved the CBF. These findings demonstrate that GSNO in combination with gentamicin may effectively reduce the density of biofilm bacteria in CRS patients. GSNO treatment may also enhance the mucociliary clearance by improving the CBF.

PMID:36643497 | PMC:PMC9835527 | DOI:10.1021/acsomega.2c06212