Proc Natl Acad Sci U S A. 2023 May 9;120(19):e2221542120. doi: 10.1073/pnas.2221542120. Epub 2023 May 1.

ABSTRACT

Laboratory models are critical to basic and translational microbiology research. Models serve multiple purposes, from providing tractable systems to study cell biology to allowing the investigation of inaccessible clinical and environmental ecosystems. Although there is a recognized need for improved model systems, there is a gap in rational approaches to accomplish this goal. We recently developed a framework for assessing the accuracy of microbial models by quantifying how closely each gene is expressed in the natural environment and in various models. The accuracy of the model is defined as the percentage of genes that are similarly expressed in the natural environment and the model. Here, we leverage this framework to develop and validate two generalizable approaches for improving model accuracy, and as proof of concept, we apply these approaches to improve models of Pseudomonas aeruginosa infecting the cystic fibrosis (CF) lung. First, we identify two models, an in vitro synthetic CF sputum medium model (SCFM2) and an epithelial cell model, that accurately recapitulate different gene sets. By combining these models, we developed the epithelial cell-SCFM2 model which improves the accuracy of over 500 genes. Second, to improve the accuracy of specific genes, we mined publicly available transcriptome data, which identified zinc limitation as a cue present in the CF lung and absent in SCFM2. Induction of zinc limitation in SCFM2 resulted in accurate expression of 90% of P. aeruginosa genes. These approaches provide generalizable, quantitative frameworks for microbiological model improvement that can be applied to any system of interest.

PMID:37126703 | DOI:10.1073/pnas.2221542120

Diabetes Care. 2023 May 1:dc230380. doi: 10.2337/dc23-0380. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is a recessive disorder arising from mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. CFTR is expressed in numerous tissues, with high expression in the airways, small and large intestine, pancreatic and hepatobiliary ducts, and male reproductive tract. CFTR loss in these tissues disrupts regulation of salt, bicarbonate, and water balance across their epithelia, resulting in a systemic disorder with progressive organ dysfunction and damage. Pancreatic exocrine damage ultimately manifests as pancreatic exocrine insufficiency that begins as early as infancy. Pancreatic remodeling accompanies this early damage, during which abnormal glucose tolerance can be observed in toddlers. With increasing age, however, insulin secretion defects progress such that CF-related diabetes (CFRD) occurs in 20% of teens and up to half of adults with CF. The relevance of CFRD is highlighted by its association with increased morbidity, mortality, and patient burden. While clinical research on CFRD has greatly assisted in the care of individuals with CFRD, key knowledge gaps on CFRD pathogenesis remain. Furthermore, the wide use of CFTR modulators to restore CFTR activity is changing the CFRD clinical landscape and the field's understanding of CFRD pathogenesis. For these reasons, the National Institute of Diabetes and Digestive and Kidney Diseases and the Cystic Fibrosis Foundation sponsored a CFRD Scientific Workshop, 23-25 June 2021, to define knowledge gaps and needed research areas. This article describes the findings from this workshop and plots a path for CFRD research that is needed over the next decade.

PMID:37125948 | DOI:10.2337/dc23-0380

Diabetes. 2023 May 1:db220949. doi: 10.2337/db22-0949. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is a recessive disorder arising from mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. CFTR is expressed in numerous tissues, with high expression in the airways, small and large intestine, pancreatic and hepatobiliary ducts, and male reproductive tract. CFTR loss in these tissues disrupts regulation of salt, bicarbonate, and water balance across their epithelia, resulting in a systemic disorder with progressive organ dysfunction and damage. Pancreatic exocrine damage ultimately manifests as pancreatic exocrine insufficiency that begins as early as infancy. Pancreatic remodeling accompanies this early damage, during which abnormal glucose tolerance can be observed in toddlers. With increasing age, however, insulin secretion defects progress such that CF-related diabetes (CFRD) occurs in 20% of teens and up to half of adults with CF. The relevance of CFRD is highlighted by its association with increased morbidity, mortality, and patient burden. While clinical research on CFRD has greatly assisted in the care of individuals with CFRD, key knowledge gaps on CFRD pathogenesis remain. Furthermore, the wide use of CFTR modulators to restore CFTR activity is changing the CFRD clinical landscape and the field's understanding of CFRD pathogenesis. For these reasons, the National Institute of Diabetes and Digestive and Kidney Diseases and the Cystic Fibrosis Foundation sponsored a CFRD Scientific Workshop, 23-25 June 2021, to define knowledge gaps and needed research areas. This article describes the findings from this workshop and plots a path for CFRD research that is needed over the next decade.

PMID:37125945 | DOI:10.2337/db22-0949

Am J Physiol Cell Physiol. 2023 May 1. doi: 10.1152/ajpcell.00374.2022. Online ahead of print.

ABSTRACT

Control of the movement of ions and water across epithelia is essential for homeostasis. Changing the number or activity of ion channels at the plasma membrane is a significant regulator of epithelial transport. In polarized epithelia, the intermediate-conductance calcium-activated potassium channel, KCa3.1 is delivered to the basolateral membrane where it generates and maintains the electrochemical gradients required for epithelial transport. The mechanisms that control the delivery of KCa3.1 to the basolateral membrane are still emerging. Herein we investigated the role of the highly conserved tethering complex exocyst. In epithelia, exocyst is involved in the tethering of post-Golgi secretory vesicles with the basolateral membrane, which is required before membrane fusion. In our Fisher rat thyroid cell line that stably expresses KCa3.1, siRNA knockdown of either of the exocyst subunits Sec3, Sec6, or Sec8 significantly decreased KCa3.1-specific current. Additionally, knockdown of exocyst complex subunits significantly reduced the basolateral membrane protein level of KCa3.1. Finally, co-immunoprecipitation experiments, suggest associations between Sec6 and KCa3.1, but not between Sec8 and KCa3.1. Collectively, based on these data and our previous studies, we suggest that components of exocyst complex are crucially important in the tethering of KCa3.1 to the basolateral membrane. After which, SNARE proteins aid in the insertion of KCa3.1-containing vesicles into the basolateral membrane of polarized epithelia.

PMID:37125772 | DOI:10.1152/ajpcell.00374.2022

Front Cell Infect Microbiol. 2023 Apr 14;13:1092317. doi: 10.3389/fcimb.2023.1092317. eCollection 2023.

ABSTRACT

INTRODUCTION: M. avium subsp. hominissuis (M. avium) is an intracellular, facultative bacterium known to colonize and infect the human host through ingestion or respiratory inhalation. The majority of pulmonary infections occur in association with pre- existing lung diseases, such as bronchiectasis, cystic fibrosis, or chronic obstructive pulmonary disease. M. avium is also acquired by the gastrointestinal route in immunocompromised individuals such as human immunodeficiency virus HIV-1 patients leading to disseminated disease. A hallmark of M. avium pulmonary infections is the ability of pathogen to form biofilms. In addition, M. avium can reside within granulomas of low oxygen and limited nutrient conditions while establishing a persistent niche through metabolic adaptations.

METHODS: Bacterial metabolic pathways used by M. avium within the host environment, however, are poorly understood. In this study, we analyzed M. avium proteome with a focus on core metabolic pathways expressed in the anaerobic, biofilm and aerobic conditions and that can be used by the pathogen to transition from one environment to another.

RESULTS: Overall, 3,715 common proteins were identified between all studied conditions and proteins with increased synthesis over the of the level of expression in aerobic condition were selected for analysis of in specific metabolic pathways. The data obtained from the M. avium proteome of biofilm phenotype demonstrates in enrichment of metabolic pathways involved in the fatty acid metabolism and biosynthesis of aromatic amino acid and cofactors. Here, we also highlight the importance of chloroalkene degradation pathway and anaerobic fermentationthat enhance during the transition of M. avium from aerobic to anaerobic condition. It was also found that the production of fumarate and succinate by MAV_0927, a conserved hypothetical protein, is essential for M. avium survival and for withstanding the stress condition in biofilm. In addition, the participation of regulatory genes/proteins such as the TetR family MAV_5151 appear to be necessary for M. avium survival under biofilm and anaerobic conditions.

CONCLUSION: Collectively, our data reveal important core metabolic pathways that M. avium utilize under different stress conditions that allow the pathogen to survive in diverse host environments.

PMID:37124045 | PMC:PMC10140322 | DOI:10.3389/fcimb.2023.1092317

Front Cell Infect Microbiol. 2023 Apr 14;13:1117844. doi: 10.3389/fcimb.2023.1117844. eCollection 2023.

ABSTRACT

The rise of antimicrobial-resistant bacterial infections is a crucial health concern in the 21st century. In particular, antibiotic-resistant Pseudomonas aeruginosa causes difficult-to-treat infections associated with high morbidity and mortality. Unfortunately, the number of effective therapeutic interventions against antimicrobial-resistant P. aeruginosa infections continues to decline. Therefore, discovery and development of alternative treatments are necessary. Here, we present pre-clinical efficacy studies on an anti-P. aeruginosa therapeutic monoclonal antibody. Using hybridoma technology, we generated a monoclonal antibody and characterized its binding to P. aeruginosa in vitro using ELISA and fluorescence correlation spectroscopy. We also characterized its function in vitro and in vivo against P. aeruginosa. The anti-P. aeruginosa antibody (WVDC-5244) bound P. aeruginosa clinical strains of various serotypes in vitro, even in the presence of alginate exopolysaccharide. In addition, WVDC-5244 induced opsonophagocytic killing of P. aeruginosa in vitro in J774.1 murine macrophage, and complement-mediated killing. In a mouse model of acute pneumonia, prophylactic administration of WVDC-5244 resulted in an improvement of clinical disease manifestations and reduction of P. aeruginosa burden in the respiratory tract compared to the control groups. This study provides promising pre-clinical efficacy data on a new monoclonal antibody with therapeutic potential for P. aeruginosa infections.

PMID:37124031 | PMC:PMC10140502 | DOI:10.3389/fcimb.2023.1117844

RSC Med Chem. 2023 Mar 7;14(4):745-756. doi: 10.1039/d2md00439a. eCollection 2023 Apr 26.

ABSTRACT

Millions of people worldwide have been impacted by biofilm-associated disorders, which are impregnable owing to frequent changes in surface antigens and gene expression. Globally, about 11% of nosocomial infections, including cystic fibrosis, chronic wound infections, and post-surgical infections, are caused by Pseudomonas aeruginosa, the most prevalent Gram-negative bacterial species. Moreover, biofilms are highly resistant to the host's immune system, and exhibit increased tolerance to stress factors such as starvation, dehydration, and antimicrobials. Here, we have isolated a rare halophilic actinobacteria, Nocardiopsis lucentensis EMB25, and utilized the secondary metabolites for inhibition and eradication of P. aeruginosa biofilm. For the first time, N. lucentensis EMB25 bacteria was explored to study the anti-effect of secondary metabolites on pre-established biofilm. The secondary metabolites targeted the quorum sensing pathway and were found to bind to LasR and RhlR, as confirmed via molecular docking. Also, the reduction in virulence factors, rhamnolipids and pyocyanin further supported the study as these two are regulated by LasR and RhlR. In addition, the downregulation of various QS system genes lasA, lasB, rhlA, rhlB, and pqsA confirmed that the secondary metabolites act on two main regulators of the quorum sensing pathway, LasR, and RhlR. The findings of this study support the bioprospecting of previously unknown and extreme-condition actinobacteria as a rich source of novel bioactives against infections caused by bacterial biofilms.

PMID:37122537 | PMC:PMC10131674 | DOI:10.1039/d2md00439a

J Child Health Care. 2023 Apr 25:13674935231171453. doi: 10.1177/13674935231171453. Online ahead of print.

ABSTRACT

This study's primary objective was to establish differences in beliefs about medicines, levels of asthma-related anxiety and diet and exercise behaviours between parents of children with well controlled and poorly controlled asthma. Secondary objectives were to explore how asthma control might shape relationships between parental cognitions and parenting practices concerning paediatric asthma. Parents of children with asthma aged 10-16 years (N = 310) completed standardised questionnaires measuring beliefs about medicines, parental asthma-related anxiety, parenting attitudes towards child activity, parental feeding and asthma control. Parents of children with poorly controlled asthma reported significantly greater asthma medication necessity and concern, asthma-related anxiety, control of child activity, pressure to exercise and unhealthy feeding practices. Moderation analyses indicated that the relationship between parental concern about asthma medicine and parental control of child activity was strongest in children with poorly controlled asthma. Also, the relationship between parental asthma-related anxiety and use of food to regulate child emotion was only significant when asthma was poorly controlled. Parental beliefs about asthma medicines and asthma-related anxiety may indirectly influence asthma outcomes through unhealthy parenting practices around exercise and diet. Eliciting and understanding parents' perceptions of asthma medications and anxiety may facilitate personalised interventions to improve asthma control.

PMID:37122084 | DOI:10.1177/13674935231171453

Heart Rhythm. 2023 Apr 28:S1547-5271(23)02180-X. doi: 10.1016/j.hrthm.2023.04.021. Online ahead of print.

ABSTRACT

Long QT syndrome type 2 (LQT2) is a genetic disorder caused by mutations in the KCNH2 gene, also known as the human ether-a-go-go-related gene (hERG). Over 30% of hERG mutations result in a premature termination codon (PTC) that triggers a process called nonsense-mediated mRNA decay (NMD), where the mRNA transcript is degraded. NMD is a quality control mechanism that removes faulty mRNA to prevent the translation of truncated proteins. Recent advances in antisense oligonucleotide (ASO) technology in the field of cystic fibrosis (CF) have yielded significant progress, including the ASO-mediated comprehensive characterization of key NMD factors and exon-skipping therapy. These advances have contributed to our understanding of the role of PTC-containing mutations in disease phenotypes and have also led to the development of potentially useful therapeutic strategies. Historically, studies of CF have provided valuable insights for the research on LQT2, particularly concerning increasing the expression of hERG. In this article, we outline the current state of knowledge regarding ASO, NMD, and hERG and discuss the introduction of ASO technology in the CF to elucidate the pathogenic mechanisms through targeting NMD. We also discuss the potential clinical therapeutic benefits and limitations of ASO for the management of LQT2. By drawing on lessons learned from CF research, we explore the potential translational values of these advances into LQT2 studies.

PMID:37121422 | DOI:10.1016/j.hrthm.2023.04.021

Redox Biol. 2023 Apr 25;63:102717. doi: 10.1016/j.redox.2023.102717. Online ahead of print.

ABSTRACT

Hemoglobin (Hb) present in the lung epithelium is of unknown significance. However Hb being an nitric oxide (NO) scavenger can bind to NO and reduce its deleterious effects. Hence we postulated an NO scavenging role for this lung Hb. Doing transwell co-culture with bronchial epithelial cells, A549/16-HBE (apical) and human airway smooth muscle cells (HASMCs as basal), we found that Hb can protect the smooth muscle soluble guanylyl cyclase (sGC) from excess NO. Inducing the apical A549/16-HBE cells with cytokines to trigger iNOS expression and NO generation caused a time dependent increase in SNO-sGC and this was accompanied with a concomitant drop in sGC-α1β1 heterodimerization. Silencing Hbαβ in the apical cells further increased the SNO on sGC with a faster drop in the sGC heterodimer and these effects were additive along with further silencing of thioredoxin 1 (Trx1). Since heme of Hb is critical for NO scavenging we determined the Hb heme in a mouse model of allergic asthma (OVA) and found that Hb in the inflammed OVA lungs was low in heme or heme-free relative to those of naïve lungs. Further we established a direct correlation between the status of the sGC heterodimer and the Hb heme from lung samples of human asthma, iPAH, COPD and cystic fibrosis. These findings present a new mechanism of protection of lung sGC by the epithelial Hb, and suggests that this protection maybe lost in asthma or COPD where lung Hb is unable to scavenge the NO due to it being heme-deprived.

PMID:37120930 | DOI:10.1016/j.redox.2023.102717

J Cyst Fibros. 2023 Apr 28:S1569-1993(23)00112-1. doi: 10.1016/j.jcf.2023.04.008. Online ahead of print.

ABSTRACT

BACKGROUND: MRT5005, a codon-optimized CFTR mRNA, delivered by aerosol in lipid nanoparticles, was designed as a genotype-agnostic treatment for CF lung disease.

METHODS: This was a randomized, double-blind, placebo-controlled Phase 1/2 study performed in the US. Adults with 2 severe class I and/or II CFTR mutations and baseline ppFEV1 values between 50 and 90% were randomized 3:1 (MRT5005: placebo). Six dose levels of MRT5005 (4, 8, 12, 16, 20, and 24 mg) or placebo (0.9% Sodium Chloride) were administered by nebulization. The single ascending dose cohort was treated over a range from 8 to 24 mg; the multiple ascending dose cohort received five weekly doses (range 8-20 mg); and the daily dosing cohort received five daily doses (4 mg).

RESULTS: A total of 42 subjects were assigned to MRT5005 [31] or placebo [11]. A total of 14 febrile reactions were observed in 10 MRT5005-treated participants, which were mild [3] or moderate [11] in severity; two subjects discontinued related to these events. Additionally, two MRT5005-treated patients experienced hypersensitivity reactions, which were managed conservatively. The most common treatment emergent adverse events were cough and headache. No consistent effects on FEV1 were noted.

CONCLUSIONS: MRT5005 was generally safe and well tolerated through 28 days of follow-up after the last dose, though febrile and hypersensitivity reactions were noted. The majority of these reactions resolved within 1-2 days with supportive care allowing continued treatment with MRT5005 and careful monitoring. In this small first-in-human study, FEV1 remained stable after treatment, but no beneficial effects on FEV1 were observed.

PMID:37121795 | DOI:10.1016/j.jcf.2023.04.008

J Cyst Fibros. 2023 Apr 26:S1569-1993(23)00122-4. doi: 10.1016/j.jcf.2023.04.018. Online ahead of print.

ABSTRACT

Some studies have evaluated the sweat test (ST) intra individual variability in CRMS/CFSPID. Here, we retrospectively evaluated this in a cohort followed at the CF center in Florence, Italy. We enrolled 37 CRMS/CFSPID and 37 CF children, born between 2011 and 2019. A total of 327 ST were retrospectively recovered, of which 17 (5.2%) were quantity not sufficient. After a median follow-up of 33.8 months (range 1.7-88.2), 11 (24.3%) became CF with at least two pathological sweat chloride (SC) values at a median age of 46.9 months (range 1.4-49). The coefficient of variation was 6.2% in CF patients and 32.5% in the CRMS/CFSPID that transitioned to CF (P<.001). Our data highlight a more variability of SC values in CRMS/CFSPID, especially in those that transitioned to a diagnosis of CF. Further studies are needed to understand whether it is correct to define an asymptomatic CRMS/CFSPID with pathological SC as CF.

PMID:37117083 | DOI:10.1016/j.jcf.2023.04.018

BMJ Open. 2023 Apr 28;13(4):e072461. doi: 10.1136/bmjopen-2023-072461.

ABSTRACT

OBJECTIVES: Regular exercise testing is recommended for people with cystic fibrosis (pwCF), as is the provision and regular review of exercise training programmes. A previous survey on exercise testing and training for pwCF in the UK was conducted over a decade ago. With the landscape of CF changing considerably during this time, this survey aimed to evaluate UK-based exercise testing and training practices for pwCF a decade on.

DESIGN: Cross-sectional, online survey.

PARTICIPANTS: A survey was distributed electronically to UK CF clinics and completed by the individual primarily responsible for exercise services. Descriptive statistics and qualitative analyses were undertaken.

RESULTS: In total, 31 CF centres participated, representing ~50% of UK specialist clinics. Of these, 94% reported using exercise testing, 48% of which primarily use cardiopulmonary exercise testing. Exercise testing mostly occurs at annual review (93%) and is most often conducted by physiotherapists (62%). A wide variation in protocols, exercise modalities, normative reference values and cut-offs for exercise-induced desaturation are currently used. All centres reportedly discuss exercise training with pwCF; 94% at every clinic appointment. However, only 52% of centres reportedly use exercise testing to inform individualised exercise training. Physiotherapists typically lead discussions around exercise training (74%).

CONCLUSIONS: These data demonstrate that the majority of respondent centres in the UK now offer some exercise testing and training advice for pwCF, representing a marked improvement over the past decade. However, continued efforts are now needed to standardise exercise practices, particularly regarding field testing practices and the translation of test results into personalised training programmes for pwCF.

PMID:37116999 | DOI:10.1136/bmjopen-2023-072461

Curr Opin Immunol. 2023 Apr 26;83:102328. doi: 10.1016/j.coi.2023.102328. Online ahead of print.

ABSTRACT

The chronic infections of cystic fibrosis (CF) airways with Pseudomonas aeruginosa are a paradigm of how environmental bacteria can conquer, adapt, and persist in an atypical habitat and successfully evade defense mechanisms and chemotherapy in a susceptible host. The within-host evolution of intraclonal diversity has been examined by whole-genome sequencing, phenotyping, and competitive fitness experiments of serial P. aeruginosa isolates collected from CF airways since onset of colonization for a period of up to 40 years. The spectrum of de novo mutations and the adaptation of phenotype and fitness of the bacterial progeny were more influenced by the living conditions in the CF lung than by the clone type of their ancestor and its genetic repertoire.

PMID:37116385 | DOI:10.1016/j.coi.2023.102328

Turk J Pediatr. 2023;65(2):257-268. doi: 10.24953/turkjped.2021.4930.

ABSTRACT

BACKGROUND: We aimed to determine the number of cystic fibrosis (CF) patients recorded in the Cystic Fibrosis Registry of Türkiye (CFRT) who were in need of lung transplantation (LT) referral and examine clinical differences between patients who were LT candidates due to rapid forced expiratory volume in one second (FEV₁) decline and LT candidates without rapid FEV₁ decline in the last year to identify a preventable cause in patients with such rapid FEV₁ decline.

METHODS: All CF patients recorded in the CFRT in 2018 were evaluated in terms of LT. Patients were divided into those with FEV₁ below 50% and in need of LT due to a decrease of 20% or more in the previous year (Group 1) and those who did not have FEV₁ decline of more than 20% in the previous year but had other indications for LT (Group 2). Demographic and clinical features were compared between the two groups.

RESULTS: Of 1488 patients registered in CFRT, 58 had a need for LT. Twenty patients were included in Group 1 and others in Group 2. Our findings did not reveal any significant variations in treatment, chronic infection status, or complications between the two groups. The average weight z-score was significantly higher in Group 1. Positive correlations were detected between weight z-score and FEV₁ in 2017 in Group 1 and between FEV₁ values in 2017 and 2018 in Group 2.

CONCLUSIONS: There appears to be a relationship between the nutritional status and weight z-scores of CF patients and pulmonary function, which may indirectly affect the need for lung transplantation referral.

PMID:37114691 | DOI:10.24953/turkjped.2021.4930

Front Pharmacol. 2023 Apr 11;14:1147348. doi: 10.3389/fphar.2023.1147348. eCollection 2023.

ABSTRACT

Background: Newly developed quantitative chest computed tomography (CT) outcomes designed specifically to assess structural abnormalities related to cystic fibrosis (CF) lung disease are now available. CFTR modulators potentially can reduce some structural lung abnormalities. We aimed to investigate the effect of CFTR modulators on structural lung disease progression using different quantitative CT analysis methods specific for people with CF (PwCF). Methods: PwCF with a gating mutation (Ivacaftor) or two Phe508del alleles (lumacaftor-ivacaftor) provided clinical data and underwent chest CT scans. Chest CTs were performed before and after initiation of CFTR modulator treatment. Structural lung abnormalities on CT were assessed using the Perth Rotterdam Annotated Grid Morphometric Analysis for CF (PRAGMA-CF), airway-artery dimensions (AA), and CF-CT methods. Lung disease progression (0-3 years) in exposed and matched unexposed subjects was compared using analysis of covariance. To investigate the effect of treatment in early lung disease, subgroup analyses were performed on data of children and adolescents aged <18 years. Results: We included 16 modulator exposed PwCF and 25 unexposed PwCF. Median (range) age at the baseline visit was 12.55 (4.25-36.49) years and 8.34 (3.47-38.29) years, respectively. The change in PRAGMA-CF %Airway disease (-2.88 (-4.46, -1.30), p = 0.001) and %Bronchiectasis extent (-2.07 (-3.13, -1.02), p < 0.001) improved in exposed PwCF compared to unexposed. Subgroup analysis of paediatric data showed that only PRAGMA-CF %Bronchiectasis (-0.88 (-1.70, -0.07), p = 0.035) improved in exposed PwCF compared to unexposed. Conclusion: In this preliminary real-life retrospective study CFTR modulators improve several quantitative CT outcomes. A follow-up study with a large cohort and standardization of CT scanning is needed to confirm our findings.

PMID:37113757 | PMC:PMC10127680 | DOI:10.3389/fphar.2023.1147348

Pharmaceuticals (Basel). 2023 Apr 13;16(4):584. doi: 10.3390/ph16040584.

ABSTRACT

Unfractionated heparin has multiple pharmacological activities beyond anticoagulation. These anti-inflammatory, anti-microbial, and mucoactive activities are shared in part by low molecular weight and non-anticoagulant heparin derivatives. Anti-inflammatory activities include inhibition of chemokine activity and cytokine synthesis, inhibitory effects on the mechanisms of adhesion and diapedesis involved in neutrophil recruitment, inhibition of heparanase activity, inhibition of the proteases of the coagulation and complement cascades, inhibition of neutrophil elastase activity, neutralisation of toxic basic histones, and inhibition of HMGB1 activity. This review considers the potential for heparin and its derivatives to treat inflammatory lung disease, including COVID-19, ALI, ARDS, cystic fibrosis, asthma, and COPD via the inhaled route.

PMID:37111341 | DOI:10.3390/ph16040584

Nutrients. 2023 Apr 12;15(8):1851. doi: 10.3390/nu15081851.

ABSTRACT

Cystic fibrosis (CF) belongs to the most common inherited diseases. The severity of the disease and chronic bacterial infections are associated with a lower body index, undernutrition, higher number of pulmonary exacerbations, more hospital admissions, and increased mortality. The aim of our study was to determine the impact of the severity of the disease and the type of bacterial infection in 38 CF patients on the serum level of appetite-regulating hormones including leptin, ghrelin, neuropeptide Y, agouti-signaling protein, proopiomelanocortin, kisspeptin, putative protein Y, and α-melanocyte-stimulating hormone. The patients were divided according to the severity of the disease according to spirometry and the type of chronic bacterial infection. We found that leptin level was significantly higher in patients with severe CF than in patients with mild disease (20.02 ± 8.09 vs. 12.38 ± 6.03 ng/mL, p = 0.028). Furthermore, leptin level was elevated in patients with chronic infection with Pseudomonas aeruginosa compared to uninfected participants (15.74 ± 7.02 vs. 9.28 ± 1.72 ng/mL, p = 0.043). The severity of the disease and the type of bacterial infection did not affect the levels of other appetite-regulating hormones. Moreover, we found a positive correlation between pro-inflammatory interleukin-6 and leptin level (p = 0.0426, R = 0.333). Taken together, our results indicate that both the severity of the disease and the type of bacterial infection are associated with elevated leptin levels in CF patients. Future CF treatment strategies should consider possible disturbances in the hormones that regulate appetite and the factors that influence their levels.

PMID:37111072 | DOI:10.3390/nu15081851

Microorganisms. 2023 Mar 31;11(4):916. doi: 10.3390/microorganisms11040916.

ABSTRACT

Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen that causes high morbidity and mortality in cystic fibrosis (CF) and immunocompromised patients, including patients with ventilator-associated pneumonia (VAP), severely burned patients, and patients with surgical wounds. Due to the intrinsic and extrinsic antibiotic resistance mechanisms, the ability to produce several cell-associated and extracellular virulence factors, and the capacity to adapt to several environmental conditions, eradicating P. aeruginosa within infected patients is difficult. Pseudomonas aeruginosa is one of the six multi-drug-resistant pathogens (ESKAPE) considered by the World Health Organization (WHO) as an entire group for which the development of novel antibiotics is urgently needed. In the United States (US) and within the last several years, P. aeruginosa caused 27% of deaths and approximately USD 767 million annually in health-care costs. Several P. aeruginosa therapies, including new antimicrobial agents, derivatives of existing antibiotics, novel antimicrobial agents such as bacteriophages and their chelators, potential vaccines targeting specific virulence factors, and immunotherapies have been developed. Within the last 2-3 decades, the efficacy of these different treatments was tested in clinical and preclinical trials. Despite these trials, no P. aeruginosa treatment is currently approved or available. In this review, we examined several of these clinicals, specifically those designed to combat P. aeruginosa infections in CF patients, patients with P. aeruginosa VAP, and P. aeruginosa-infected burn patients.

PMID:37110338 | DOI:10.3390/microorganisms11040916

Life (Basel). 2023 Apr 1;13(4):928. doi: 10.3390/life13040928.

ABSTRACT

BACKGROUND: During the first two years after lung transplantation (LTx), the incidence of fragility fractures (FX) is estimated to be 15-50% and it is lower in patients with cystic fibrosis (CF) as compared with other end-stage lung diseases (nCF). The aim of our study is to compare the skeletal outcomes, after the first 2 years post-LTx, in long-term survivors with CF and nCF.

MATERIALS AND METHODS: We evaluated the FX rate, the changes in bone mineral density (BMD) and trabecular bone score (TBS) in 68 patients (38 CF and 30 nCF) who underwent LTx in our center and with a follow-up after LTx longer than 5 years (7.3 ± 2.0 years).

RESULTS: After the second year post-LTx: (i) the FX rate was lower than during the first two years post-LTx (4.4 vs. 20.6%, p = 0.004), with no difference between CF and nCF patients (5.3 vs. 3.3%, p = 0.589); (ii) BMD at lumbar spine, femoral neck and total hip remained stable (-1.6 ± 1.0 vs. -1.4 ± 1.1, p = 0.431, -1.8 ± 0.9 vs. -1.9 ± 0.9, p = 0.683, -1.5 ± 0.9 vs. -1.4 ± 0.9, p = 0.678, respectively) as well as TBS (1.200 ± 0.124 vs. 1.199 ± 0.205, p = 0.166).

CONCLUSIONS: After the second year post-LTx, the skeletal complications become less frequent and have similar incidence in patients with CF and nCF.

PMID:37109457 | DOI:10.3390/life13040928