ERJ Open Res. 2023 Nov 20;9(6):00240-2023. doi: 10.1183/23120541.00240-2023. eCollection 2023 Nov.

ABSTRACT

BACKGROUND: Interstitial lung disease associated with genetic disorders of the surfactant system is a rare entity in adults that can lead to lung transplantation. Our objective was to describe the outcome of these patients after lung transplantation.

METHODS: We conducted a retrospective, multicentre study, on adults who underwent lung transplantation for such disease in the French lung transplant centres network, from 1997 to 2018.

RESULTS: 20 patients carrying mutations in SFTPA1 (n=5), SFTPA2 (n=7) or SFTPC (n=8) were included. Median interquartile range (IQR) age at diagnosis was 45 (40-48) years, and median (IQR) age at lung transplantation was 51 (45-54) years. Median overall survival after transplantation was 8.6 years. Two patients had a pre-transplant history of lung cancer, and two developed post-transplant lung cancer. Female gender and a body mass index <25 kg·m-2 were significantly associated with a better prognosis, whereas transplantation in high emergency was associated with a worst prognosis.

CONCLUSIONS: Lung transplantation in adults with interstitial lung disease associated with genetic disorders of surfactant system may be a valid therapeutic option. Our data suggest that these patients may have a good prognosis. Immunosuppressive protocol was not changed for these patients, and close lung cancer screening is needed before and after transplantation.

PMID:38020562 | PMC:PMC10658627 | DOI:10.1183/23120541.00240-2023

Breathe (Sheff). 2023 Sep;19(3):230169. doi: 10.1183/20734735.0169-2023. Epub 2023 Nov 14.

ABSTRACT

This article provides an overview of some of the highlights of the Lung Science Conference 2023 https://bit.ly/46oWCEX.

PMID:38020340 | PMC:PMC10644106 | DOI:10.1183/20734735.0169-2023

Front Med (Lausanne). 2023 Nov 8;10:1289948. doi: 10.3389/fmed.2023.1289948. eCollection 2023.

ABSTRACT

Birt-Hogg-Dubé syndrome (BHDS) is a genetic disorder characterized by fibrofolliculomas, renal cell cancer and lung cysts. Patients are at risk to develop pneumothorax but the magnitude of this risk during pregnancy is unknown. Information was obtained from 46 women with BHDS that had at least one pregnancy (BHDS-with preg), 18 female BHDS relatives without pregnancies (BHDS-no preg) and 25 non-BHDS female relatives with at least one pregnancy (noBHDS-with preg). In total, 77 pneumothoraces occurred in the BHDS-with preg group (mean 1.7/patient) and 11 in the BHDS-no preg group. Comparison of patient years for the first two groups showed pneumothorax incidence rates of 0.054 and 0.016, respectively. The incidence rate difference was significant [0.038 (CI 0.02-0.057), value of p-value 0.0001]. This difference is not caused by an increased number of patients with pneumothorax but by an increased number of pneumothoraces per patient. Pregnancy in BHDS therefore might be a risk factor for multiple pneumothoraces.

PMID:38020174 | PMC:PMC10663224 | DOI:10.3389/fmed.2023.1289948

PLoS One. 2023 Nov 29;18(11):e0295009. doi: 10.1371/journal.pone.0295009. eCollection 2023.

ABSTRACT

A major unmet need in the cystic fibrosis (CF) therapeutic landscape is the lack of effective treatments for nonsense CFTR mutations, which affect approximately 10% of CF patients. Correction of nonsense CFTR mutations via genomic editing represents a promising therapeutic approach. In this study, we tested whether prime editing, a novel CRISPR-based genomic editing method, can be a potential therapeutic modality to correct nonsense CFTR mutations. We generated iPSCs from a CF patient homozygous for the CFTR W1282X mutation. We demonstrated that prime editing corrected one mutant allele in iPSCs, which effectively restored CFTR function in iPSC-derived airway epithelial cells and organoids. We further demonstrated that prime editing may directly repair mutations in iPSC-derived airway epithelial cells when the prime editing machinery is efficiently delivered by helper-dependent adenovirus (HDAd). Together, our data demonstrated that prime editing may potentially be applied to correct CFTR mutations such as W1282X.

PMID:38019847 | DOI:10.1371/journal.pone.0295009

Mol Biol Cell. 2023 Nov 29:mbcE23080336. doi: 10.1091/mbc.E23-08-0336. Online ahead of print.

ABSTRACT

Over 80% of people with cystic fibrosis (CF) carry the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride ion channel at the apical plasma membrane (PM) of epithelial cells. F508del impairs CFTR folding causing it to be destroyed by endoplasmic reticulum associated degradation (ERAD). Small molecule correctors, which act as pharmacological chaperones to divert CFTR-F508del from ERAD, are the primary strategy for treating CF, yet corrector development continues with only a rudimentary understanding of how ERAD targets CFTR-F508del. We conducted genome-wide CRISPR/Cas9 knockout screens to systematically identify the molecular machinery that underlies CFTR-F508del ERAD. Although the ER-resident ubiquitin ligase, RNF5 was the top E3 hit, knocking out RNF5 only modestly reduced CFTR-F508del degradation. Sublibrary screens in an RNF5 knockout background identified RNF185 as a redundant ligase and demonstrated that CFTR-F508del ERAD is robust. Gene-drug interaction experiments illustrated that correctors tezacaftor (VX-661) and elexacaftor (VX-445) stabilize sequential, RNF5-resistant folding states. We propose that binding of correctors to nascent CFTR-F508del alters its folding landscape by stabilizing folding states that are not substrates for RNF5-mediated ubiquitylation.

PMID:38019608 | DOI:10.1091/mbc.E23-08-0336

Ann Am Thorac Soc. 2023 Nov 29. doi: 10.1513/AnnalsATS.202308-735RL. Online ahead of print.

NO ABSTRACT

PMID:38019099 | DOI:10.1513/AnnalsATS.202308-735RL

Pediatr Pulmonol. 2023 Nov 29. doi: 10.1002/ppul.26774. Online ahead of print.

ABSTRACT

INTRODUCTION: Cystic fibrosis (CF) is a genetic disorder that creates a multisystem pathology resulting in complex treatment regimens. In 2014, 43% of people with CF at an academic medical center experienced medication acquisition barriers. The creation of an integrated specialty pharmacy with an embedded CF team pharmacist was launched in 2016. In addition to filling specialty medications, this specialty pharmacy filled all patient medications through a service called total care pharmacy (TCP). This service was hypothesized to positively impact medication adherence.

METHODS: Adherence analysis was performed by utilizing the proportion of days covered (PDC). PDC was analyzed during years 1, 2, and 3 of therapy. PDC was calculated for medications with at least three fills during each year. Patients with PDC less than 80% were considered nonadherent and underwent manual chart review to identify a documented reason for nonadherence.

RESULTS: Patients in the first year of dornase alfa therapy had significantly higher adherence in the TCP cohort compared to non-TCP (81.3% PDC vs. 66.0%; p = .006), which was largely driven by adult patients (73.3% vs. 56.5% for pediatric). Analysis of other medications and groups did not yield statistically significant differences. Many patients who had been classified as nonadherent had valid clinical reasons that explained gaps in therapy.

CONCLUSIONS: When filling medications at a specialty pharmacy integrated within the academic medication center, dornase alfa adherence was higher in the TCP group. Further studies comparing TCP with services offered by pharmacies external to the health system would better characterize the impact of TCP services.

PMID:38018665 | DOI:10.1002/ppul.26774

Pediatr Pulmonol. 2023 Nov 29. doi: 10.1002/ppul.26778. Online ahead of print.

NO ABSTRACT

PMID:38018663 | DOI:10.1002/ppul.26778

Recent Adv Drug Deliv Formul. 2023 Nov 24. doi: 10.2174/0126673878245506231031124020. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis is the predominant autosomal recessive disorder known to reduce life expectancy. Research findings indicate that around 60 to 70% of adult individuals with this condition carry infections of Pseudomonas aeruginosa.

OBJECTIVE: The ongoing research investigates the potential synergy of merging ivacaftor and ciprofloxacin to address bacterial infections.

METHODS: The two drugs were spray-dried into microparticles, which were then coated with Lsalbutamol and were to be delivered by a dry powder inhaler. Microparticles were generated by applying the spray drying method, utilizing bovine serum albumin and L-leucine in their preparation. Additionally, L-salbutamol was mixed and adsorbed onto the surface of the spray-dried microparticles, and it acted as a bronchodilator.

RESULTS: The microparticles produced via spray drying exhibited a particle size measuring 1.6 ± 0.04 μm, along with a polydispersity ratio of 0.33. Their zeta potential measured -27.3 ± 1.1 mV, while the mass median aerodynamic diameter of these microparticles was 3.74 ± 0.08 μm. SEM, XRD, and FTIR studies confirmed the entrapment of ivacaftor and ciprofloxacin. The morphology was observed by SEM and TEM scans. Antibacterial synergy was confirmed through the agar broth and dilution method, and the formulation's safety was established based on the outcomes of the MTT assay.

CONCLUSION: Using spray-dried microparticles containing ciprofloxacin, ivacaftor, and L-salbutamol presents a novel approach to the treatment of cystic fibrosis.

PMID:38018213 | DOI:10.2174/0126673878245506231031124020

ChemMedChem. 2023 Nov 28:e202300544. doi: 10.1002/cmdc.202300544. Online ahead of print.

ABSTRACT

Antimicrobial resistance (AMR) is a rapidly spreading global health problem, and approximately five million deaths associated with AMR pathogens were identified prior to the COVID-19 pandemic. Pseudomonas aeruginosa has developed increasing AMR, and in patients with cystic fibrosis (CF) colonized by this bacterium, rare phenotypes have emerged that complicate the diagnosis and treatment of the hosts, in addition to multiple associated "epidemic strains" with high morbidities and mortalities. The conjugation of aptamers with fluorochromes or nanostructures has allowed the design of new identification strategies for Pseudomonas aeruginosa with detection limits of up to 1 cell·mL-1, and the synergy of aptamers with antibiotics, antimicrobial peptides and nanostructures has exhibited promising therapeutic qualities. Some selected aptamers against this bacterium have shown intrinsic antimicrobial activity. However, these aptamers have been poorly evaluated in clinical isolates and have shown decreased interactions for CF isolates, demonstrating, in these cases, uncommon phenotypes resulting from the selective qualities of this disease as well as the great adaptive capacity of the pathogen. Therefore, finding an aptamer or set of aptamers that have the ability to recognize strange phenotypes of this bacillus is crucial in the battle against AMR.

PMID:38016927 | DOI:10.1002/cmdc.202300544

Zhonghua Gan Zang Bing Za Zhi. 2023 Oct 20;31(10):1087-1089. doi: 10.3760/cma.j.cn501113-20230202-00030.

ABSTRACT

患者为青少年不明原因肝硬化，肝功能异常，胆红素高，相关血清学检查阴性，肝穿刺病理提示汇管区间质水肿，较多量炎细胞浸润，以淋巴细胞为主，纤维组织轻度增生，全外显子基因测序提示CFTR基因c.106G>A（p.Asp36Asn）杂合突变，诊断为囊性纤维化。患者肝损害病因在我国人群中极为罕见，缺乏常规可行的诊断方法及有效的基因治疗方案，可供临床医师借鉴，提高对囊性纤维化的认识。.

PMID:38016775 | DOI:10.3760/cma.j.cn501113-20230202-00030

Am J Audiol. 2023 Nov 28:1-9. doi: 10.1044/2023_AJA-22-00237. Online ahead of print.

ABSTRACT

PURPOSE: Persons with cystic fibrosis (PwCF) are at high risk for ototoxicity due to the routine use of intravenous aminoglycoside (IV-AG) antibiotics in respiratory infection management. Additionally, factors that contribute to ototoxicity-related symptom development and severity in PwCF are unknown. Given the increased risk of ototoxicity in people with diabetes, we explored the association between cystic fibrosis-related diabetes (CFRD) and self-reported ototoxicity symptoms (tinnitus and vestibular problems) in PwCF treated with aminoglycosides.

METHOD: PwCF (N = 39; 25 females, 14 males; Mage = 30.1 years, SD = 10.3) were recruited from the Cystic Fibrosis Care Center at Oregon Health & Science University. Patients completed the validated questionnaires to ascertain their experiences with ototoxicity-related symptoms of tinnitus and balance function. The diagnosis of CFRD, including oral glucose tolerance testing (OGTT), insulin treatment, hemoglobin A1c, and cumulative IV-AG treatment history, was obtained through a medical chart review. Participants were classified into three groups based on their medical diagnoses via OGTT: normal glucose tolerance (NGT; control; n = 16), abnormal glucose tolerance (AGT; n = 9), and CFRD (n = 14). Participants in each group were further classified based on survey outcomes for ototoxicity-related symptoms.

RESULTS: There was a trend toward a higher proportion of patients with CFRD reporting tinnitus compared to the AGT and NGT groups, but did not meet statistical significance (X2 = 2.24, p = .13). Approximately, 43% of patients with CFRD reported experiencing clinically significant tinnitus lasting > 3 min compared to 11% in the AGT group and 13% in the NGT group (X2 = 3.751, p = .05). Cumulative IV-AG exposure tended to be higher in CFRD compared to other groups. High balance function was generally reported in all groups.

CONCLUSIONS: Patients with CFRD have greater ototoxicity-related symptoms. Further investigation of the relationship between CF-related comorbidities and the risk of developing ototoxicity-related symptoms is warranted to improve the detection and management of ototoxicity in PwCF.

PMID:38016170 | DOI:10.1044/2023_AJA-22-00237

Am J Respir Crit Care Med. 2023 Nov 28. doi: 10.1164/rccm.202306-1093OC. Online ahead of print.

ABSTRACT

Rationale: Non-cystic fibrosis bronchiectasis (NCFB) may originate in bronchiolar regions of the lung. Accordingly, there is a need to characterize the morphology and molecular characteristics of NCFB bronchioles. Objective: Test the hypothesis that NCFB exhibits a major component of bronchiolar disease manifest by mucus plugging and ectasia. Methods: Morphologic criteria and region-specific epithelial gene expression, measured histologically and by RNA in situ hybridization (RNA-ISH) and immunohistochemistry (IHC), identified proximal and distal bronchioles in excised NCFB lungs. RNA-ISH and IHC assessed bronchiolar mucus accumulation and mucin gene expression. CRISPR-Cas9-mediated IL-1R1 knockout in human bronchial epithelial (HBE) cultures tested IL-1α/β contributions to mucin production. Spatial transcriptional profiling characterized NCFB distal bronchiolar gene expression. Measurements and Main Results: Bronchiolar perimeters and lumen areas/section area were increased in proximal, but not distal, bronchioles in NCFB vs control lungs, suggesting proximal bronchiolectasis. In NCFB, mucus plugging was observed in ectatic proximal bronchioles and associated non-ectatic distal bronchioles in sections with disease. MUC5AC and MUC5B mucins were upregulated in NCFB proximal bronchioles, whereas MUC5B was selectively upregulated in distal bronchioles. Bronchiolar mucus plugs were populated by IL-1β-expressing macrophages. NCFB sterile sputum supernatants induced HBE MUC5B/MUC5AC expression that was >80% blocked by IL-1R1 ablation. Spatial transcriptional profiling identified upregulation of genes associated with secretory cells, hypoxia, interleukin pathways, IL-1β-producing macrophages in mucus plugs, and downregulation of epithelial ciliogenesis genes. Conclusions: NCFB exhibits distinctive proximal and distal bronchiolar disease. Both bronchiolar regions exhibit bronchiolar secretory cell features and mucus plugging but differ in mucin gene regulation and ectasia.

PMID:38016030 | DOI:10.1164/rccm.202306-1093OC

Minerva Pediatr (Torino). 2023 Nov 28. doi: 10.23736/S2724-5276.23.07221-X. Online ahead of print.

ABSTRACT

BACKGROUND: Pulmonary exacerbations in cystic fibrosis (CF) significantly impact morbidity and mortality. This study aimed to assess treatment response rates and identify contributing factors towards treatment response.

METHODS: In this single-center, retrospective, longitudinal study spanning four years, we analyzed all pulmonary exacerbation admissions. We compared lung function at baseline, admission, end of treatment, and 6-week follow-up. Treatment response was defined as ≥95% recovery of baseline FEV<inf>1</inf>%.

RESULTS: There were 78 children who required a total of 184 admissions. The mean duration of treatment was 14.9±2.9 days. FEV<inf>1</inf>% returned to 95% of baseline in 59% following treatment. The magnitude of the decline in lung function on admission in children who did not respond to treatment was 21.7±15.2% while the decline in children who responded to treatment was 8.3±9.4%, P<0.001. Children who experienced a decline in FEV<inf>1</inf>% greater than 40% exhibited an 80% reduced likelihood of returning to their baseline values (OR -0.8, 95% CI -0.988; -0.612). Similarly, those with FEV<inf>1</inf>% reductions in the ranges of 30-39% (OR -0.63, 95% CI -0.821; -0.439), 20-29% (OR -0.52, 95% CI -0.657; -0.383), and 10-19% (OR -0.239, 95% CI -0.33; -0.148) showed progressively lower odds of returning to baseline. Fourty-eight children required readmission within 7.7±5.4 months, children who responded to treatment had a longer time taken to readmission (8.9±6.4 months) versus children who did not respond to treatment (6.4±3.5 months), (OR: -0.20, 95% CI -0.355; -0.048).

CONCLUSIONS: A greater decline in lung function on admission and readmission within 6 months of the initial admission predicts non-response to treatment. This highlights the importance of re-evaluating follow-up strategies following discharge.

PMID:38015431 | DOI:10.23736/S2724-5276.23.07221-X

Pediatr Pulmonol. 2023 Nov 28. doi: 10.1002/ppul.26781. Online ahead of print.

ABSTRACT

BACKGROUND: Pulmonary exacerbations (PEx) are strong predictors of respiratory disease progression in children with cystic fibrosis (CwCF) and may be associated with persistent decreased lung function after acute management. Telemonitoring devices can be used for early detection and monitoring of PEx, but its utility is debated.

RESEARCH QUESTION: Which symptoms and telemonitoring spirometry characterics are related to outcome dynamics following initial PEx management?

METHODS: This retrospective study included CwCF followed at Bordeaux University Hospital, France. All severe PEx episodes treated with intravenous (IV) antibiotics (ATB) between 1 January 2017 and 31 December 2021 in CwCF using home telemonitoring were analyzed. Symptoms and home spirometry data were collected 45 days before and up to 60 days after each IV ATB course. We defined three response profiles based on terciles of baseline forced expiratory volume in 1 s (FEV1 ) recovery.

RESULTS: A total of 346 IV ATB courses for PEx were administered to 65 CwCF during the study period. The drop in FEV1 became significant 8 days before IV ATB initiation. Forty-one percent of IV ATB courses failed to restore baseline FEV1 . The magnitude of FEV1 drop and a greater delay in the initiation of treatment correlated with a low response level. On the 14th day of the IV treatment, a FEV1 recovery less than 94% of baseline was associated with a nonresponder profile.

INTERPRETATION: Home spirometry may facilitate the early recognition of PEx to implement earlier interventions. This study also provides an outcome lung function threshold which identifies low responders to IV ATB.

PMID:38014613 | DOI:10.1002/ppul.26781

Pediatr Pulmonol. 2023 Nov 28. doi: 10.1002/ppul.26772. Online ahead of print.

ABSTRACT

BACKGROUND: Caregivers have crucial role in the care of the children with Cystic Fibrosis (CF), but there is limited knowledge about their knowledge, attitude, and practices (KAP) regarding chronic disease. This pilot study aimed to validate a self-developed KAP questionnaire for caregivers of young children with CF in India and determine factors associated with KAP.

MATERIALS AND METHODS: A cross-sectional study was conducted among 95 caregivers of children with CF attending the specialty clinic of the pediatric outpatient department (OPD) in Northern India. Participants possessing certain characteristics such as willingness to participate and ability to understand Hindi or English language were enrolled in the study. Caregivers of children reported to the OPD with acute exacerbation requiring immediate hospitalization were excluded from the study.

RESULTS: The self-developed KAP questionnaire had good content validity (CVI- 0.87-1.0) and internal consistency (Cronbach's α coefficient = 0.70, 0.71, 0.75 respectively). The majority of participants belonged to the Good KAP group (85.3%), while the remaining were in the Poor KAP group (14.7%). A χ2 test showed that KAP clusters vary significantly with sociodemographic variables like gender, marital status, educational status and monthly family income (p < .05). A weak negative correlation was found between knowledge and attitude scores in the Good KAP group (p < .001). Multiple linear regression analysis showed that the KAP of the caregivers was significantly influenced by knowledge related to clinical manifestation and complications, and attitude.

CONCLUSION: All three sections of the KAP tool demonstrated good content validity and internal consistency. Caregivers had good knowledge, a positive attitude, and appropriate practices related to CF. However, targeted interventions are necessary to address specific areas for improvement, particularly for male caregivers with lower educational levels belonging to poor socioeconomic strata.

PMID:38014609 | DOI:10.1002/ppul.26772

Pediatr Pulmonol. 2023 Nov 28. doi: 10.1002/ppul.26787. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is a genetic disease that causes progressive lung disease with major impact on the quality of life. Lung ultrasound (LUS) allows to assess the lung involvement through the artefacts analysis and is increasingly used in children but is not yet used to monitor people with CF(pwCF). The main aim of this study was to describe the LUS pattern of pwCF during their routinary check-up visit. The secondary objective was to correlate the LUS findings with pulmonary function indices.

METHODS: We performed a cross-sectional observational study, enrolling adolescents and young adults with CF. Each patient underwent clinical assessment, measurement of SpO2, assessment of lung function by spirometry and LUS.

RESULTS: Twenty-nine subjects with CF were included. The most frequent alterations were consolidations (72.4%) located in the left apical anterior and right apical posterior regions followed by interstitial syndrome (65.5%). The 41.4% of cases presented the lingula involvement, characterized by a consolidation with static air bronchogram, and 55.2% showed pleural irregularity mainly in the posterior apical regions. A significant correlation was found between the LUS total score and spirometric indices: FEV1 (p = .003), FVC (p = .002), Tiffenau Index <80% (p = .014), and FEF 25-75 (p = .004).

CONCLUSIONS: Our study describes LUS findings in pwCF. It also showed a correlation between LUS score and the patients' lung function measured by spirometric indices. We conclude that LUS may be useful in routine monitoring of pwCF in combination with clinical and spirometric assessment.

PMID:38014586 | DOI:10.1002/ppul.26787

Eur J Pharm Sci. 2023 Nov 25:106654. doi: 10.1016/j.ejps.2023.106654. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is an inherited lung disease characterised by the accumulation of thick layers of dried mucus in the lungs which serve as a nidus for chronic infection. Pseudomonas aeruginosa is the predominant cause of chronic lung infection in cystic fibrosis. The dense mucus coupled with biofilm formation hinder antibiotic penetration and prevent them from reaching their target. Mucoactive agents are recommended in the treatment of CF in combination with antibiotics. In spite of the extensive research in developing novel drug combinations for the treatment of lung infection in CF, to our knowledge, there is no study that combines antibiotic, antibiofilm and mucoactive agent in a single inhaled dry powder formulation. In the present study, we investigate the possibility of adding a mucoactive agent to our previously developed ciprofloxacinquercetin (antibiotic-antibiofilm) dry powder for inhalation. Three mucoactive agents, namely mannitol (MAN), N-acetyl-L-cysteine (NAC) and ambroxol hydrochloride (AMB), were investigated for this purpose. The ternary combinations were prepared via spray drying without the addition of excipients. All ternary combinations conserved or improved the antibacterial and biofilm inhibition activities of ciprofloxacin against P. aeruginosa (ATCC 10145). The addition of AMB resulted in an amorphous ternary combination (SD-CQA) with superior physical stability as indicated by DSC and nonambient XRPD. Furthermore, SD-CQA displayed better in vitro aerosolization performance (ED ∼ 71%; FPF ∼ 49%) compared to formulations containing MAN and NAC (ED ∼ 64% and 44%; FPF ∼ 44% and 29%, respectively). In conclusion, a ternary drug combination powder with suitable aerosolization, physical stability and antibacterial/antibiofilm properties was prepared by a single spray drying step.

PMID:38013123 | DOI:10.1016/j.ejps.2023.106654

J Exp Zool A Ecol Integr Physiol. 2023 Nov 27. doi: 10.1002/jez.2766. Online ahead of print.

ABSTRACT

In marine habitats, Atlantic salmon (Salmo salar) imbibe seawater (SW) to replace body water that is passively lost to the ambient environment. By desalinating consumed SW, the esophagus enables solute-linked water absorption across the intestinal epithelium. The processes underlying esophageal desalination in salmon and their hormonal regulation during smoltification and following SW exposure are unresolved. To address this, we considered whether two Na+ /H+ exchangers (Nhe2 and -3) expressed in the esophagus contribute to the uptake of Na+ from lumenal SW. There were no seasonal changes in esophageal nhe2 or -3 expression during smoltification; however, nhe3 increased following 48 h of SW exposure in May. Esophageal nhe2, -3, and growth hormone receptor b1 were elevated in smolts acclimated to SW for 2.5 weeks. Treatment with cortisol stimulated branchial Na+ /K+ -ATPase (Nka) activity, and Na+ /K+ /2Cl- cotransporter 1 (nkcc1), cystic fibrosis transmembrane regulator 1 (cftr1), and nka-α1b expression. Esophageal nhe2, but not nhe3 expression, was stimulated by cortisol. In anterior intestine, cortisol stimulated nkcc2, cftr2, and nka-α1b. Our findings indicate that salinity stimulates esophageal nhe2 and -3, and that cortisol coordinates the expression of esophageal, intestinal, and branchial solute transporters to support the SW adaptability of Atlantic salmon.

PMID:38010889 | DOI:10.1002/jez.2766

J Cyst Fibros. 2023 Nov 25:S1569-1993(23)01678-8. doi: 10.1016/j.jcf.2023.11.008. Online ahead of print.

ABSTRACT

People with CF (PwCF), particularly those with advanced lung disease (ALD), experience frequent respiratory symptoms. A major CF breakthrough was the approval of elexacaftor/tezacaftor/ivacaftor (ETI) in 2019, which has been shown to improve symptoms and lung function in the CF population, and decrease pulmonary exacerbations. The purpose of this study was to analyze longitudinal changes in respiratory symptoms over 24 months in ETI-treated and untreated PwCF with ALD Symptoms were measured among CF adults with ppFEV1 < 40% (N = 48, 24 ETI-treated, 24 untreated) using the CFRSD-CRISS and the CFQ-R [respiratory]. Two multilevel growth models assessed the rate of change in symptoms overall and within the ETI-treated and untreated groups. PwCF on ETI had significantly lower symptom severity over 24 months than those not on ETI as measured by the CRISS and CFQ-R. The ETI-treated group maintained an -11.7 and +19.3 point difference(p<0.01) in CRISS and CFQ-R scores over the study compared to the non-ETI group, achieving minimal clinically important differences on average between groups on both instruments. No change in the symptom burden trajectory between groups was observed (p = 0.58). Even with ALD, ETI-treated PwCF have a lower respiratory burden than those not on ETI. This may be confounded by survivorship bias in the non-ETI group. Of note, in this ALD cohort, neither instrument demonstrated ceiling effects. Our results suggest that, while ETI has significantly improved the lived experience, PwCF with ALD are still plagued by respiratory symptoms.

PMID:38008684 | DOI:10.1016/j.jcf.2023.11.008