Leukocyte adhesion defect: Where do we stand circa 2019?

Genes Dis. 2020 Mar;7(1):107-114

Authors: Das J, Sharma A, Jindal A, Aggarwal V, Rawat A

Abstract
Migration of polymorphonuclear leukocytes from bloodstream to the site of inflammation is an important event required for surveillance of foreign antigens. This trafficking of leukocytes from bloodstream to the tissue occurs in several distinct steps and involves several adhesion molecules. Defect in adhesion of leukocytes to vascular endothelium affecting their subsequent migration to extravascular space gives rise to a group of rare primary immunodeficiency diseases (PIDs) known as Leukocyte Adhesion Defects (LAD). Till date, four classes of LAD are discovered with LAD I being the most common form. LAD I is caused by loss of function of common chain, cluster of differentiation (CD)18 of β2 integrin family. These patients suffer from life-threatening bacterial infections and in its severe form death usually occurs in childhood without bone marrow transplantation. LAD II results from a general defect in fucose metabolism. These patients suffer from less severe bacterial infections and have growth and mental retardation. Bombay blood group phenotype is also observed in these patients. LAD III is caused by abnormal integrin activation. LAD III patients suffer from severe bacterial and fungal infections. Patients frequently show delayed detachment of umbilical cord, impaired wound healing and increased tendency to bleed. LAD IV is the most recently described class. It is caused by defects in β2 and α4β1 integrins which impairs lymphocyte adhesion. LAD IV patients have monogenic defect in cystic-fibrosis-transmembrane-conductance-regulator (CFTR) gene, resulting in cystic fibrosis. Pathophysiology and genetic etiology of all LAD syndromes are discussed in detail in this paper.

PMID: 32181281 [PubMed]

Screening practices for nontuberculous mycobacteria at us cystic fibrosis centers.

J Cyst Fibros. 2020 Mar 13;:

Authors: Low D, Wilson DA, Flume PA

Abstract
BACKGROUND: Current guidelines recommend at least once yearly screening for nontuberculous mycobacteria (NTM) in Cystic Fibrosis (CF), however screening practices remain widely variable. This study evaluates current practices among United States CF centers with specific focus on clinical predictive factors for NTM screening.
METHODS: The CF Patient Registry (CFFPR) was queried for CF patients ages 10 and older with NTM cultures completed between 2010-2014. Predictors for screening were assessed using univariate and multivariate logistic regression. Centers were evaluated by groups based on screening rates for analysis of clinical drivers of screening.
RESULTS: From 2010-2014 a total of 22,739 patients were identified with 17,177 (75.5%) tested for NTM during this time. In the overall cohort, those who were tested for NTM had lower pulmonary function (70.7% vs 83.9%), higher annual average of visits with pulmonary exacerbations (1.0 vs 0.3), and higher rate of coinfection with Pseudomonas aeruginosa (PA) as well as Methicillin resistant Staphylococcus aureus (MRSA). Among CF centers, pulmonary function, exacerbations, and coinfections with PA and MRSA were predictive of NTM screening in the lower screening cohort while pulmonary function was not predictive of screening in the highest screening cohort. Those programs who screened at a higher rate were successful in identifying NTM in more CF patients.
CONCLUSION: NTM screening practices vary widely among United States CF centers with many centers testing only on clinical changes. With higher rates of testing shown as successful in identifying more patients with NTM, routine screening should be emphasized in CF care going forward.

PMID: 32178969 [PubMed - as supplied by publisher]

Measurement of Multi Ion Transport through Human Bronchial Epithelial Cell Line Provides an Insight into the Mechanism of Defective Water Transport in Cystic Fibrosis.

Membranes (Basel). 2020 Mar 12;10(3):

Authors: Zajac M, Lewenstam A, Bednarczyk P, Dolowy K

Abstract
We measured concentration changes of sodium, potassium, chloride ions, pH and the transepithelial potential difference by means of ion-selective electrodes, which were placed on both sides of a human bronchial epithelial 16HBE14σ cell line grown on a porous support in the presence of ion channel blockers. We found that, in the isosmotic transepithelial concentration gradient of either sodium or chloride ions, there is an electroneutral transport of the isosmotic solution of sodium chloride in both directions across the cell monolayer. The transepithelial potential difference is below 3 mV. Potassium and pH change plays a minor role in ion transport. Based on our measurements, we hypothesize that in a healthy bronchial epithelium, there is a dynamic balance between water absorption and secretion. Water absorption is caused by the action of two exchangers, Na/H and Cl/HCO3, secreting weakly dissociated carbonic acid in exchange for well dissociated NaCl and water. The water secretion phase is triggered by an apical low volume-dependent factor opening the Cystic Fibrosis Transmembrane Regulator CFTR channel and secreting anions that are accompanied by paracellular sodium and water transport.

PMID: 32178452 [PubMed]

Looking into a Crystal Ball: An Interview with Ron Crystal.

Hum Gene Ther Clin Dev. 2019 09;30(3):97-101

Authors: Davies K

PMID: 31535944 [PubMed - indexed for MEDLINE]

20 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Cystic Fibrosis"

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18 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Cystic Fibrosis"

These pubmed results were generated on 2020/03/17

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Cystic Fibrosis Transmembrane Conductance Regulator Modulator Therapy: A Review for the Otolaryngologist.

Am J Rhinol Allergy. 2020 Mar 13;:1945892420912368

Authors: Lee SE, Farzal Z, Daniels MLA, Thorp BD, Zanation AM, Senior BA, Ebert CS, Kimple AJ

PMID: 32168995 [PubMed - as supplied by publisher]

A Novel Genetically Encoded Single Use Sensory Cellular Test System Measures Bicarbonate Concentration Changes in Living Cells.

Sensors (Basel). 2020 Mar 11;20(6):

Authors: Bernhard K, Stahl C, Martens R, Frey M

Abstract
Bicarbonate plays a central role in human physiology from cellular respiration to pH homeostasis. However, so far, the measurement of bicarbonate concentration changes in living cells has only been possible by measuring intracellular pH changes. In this article, we report the development of a genetically encoded pH-independent fluorescence-based single-use sensory cellular test system for monitoring intracellular bicarbonate concentration changes in living cells. We describe the usefulness of the developed biosensor in characterizing the bicarbonate transport activities of anionophores-small molecules capable of facilitating the membrane permeation of this anion. We also demonstrate the ability of the bicarbonate sensory cellular test system to measure intracellular bicarbonate concentration changes in response to activation and specific inhibition of wild-type human CFTR protein when co-expressed with the bicarbonate sensing and reporting units in living cells. A valuable benefit of the bicarbonate sensory cellular test system could be the screening of novel anionophore library compounds for bicarbonate transport activity with efficiencies close to the natural anion channel CFTR, which is not functional in the respiratory epithelia of cystic fibrosis patients.

PMID: 32168979 [PubMed - as supplied by publisher]

Neurotoxicity in adult patients with cystic fibrosis using polymyxin B for acute pulmonary exacerbations.

Pediatr Pulmonol. 2020 Mar 13;:

Authors: Rekis N, Ambrose M, Sakon C

Abstract
We present four case reports that describe neurotoxicity experienced in adult patients with cystic fibrosis (CF) receiving intravenous polymyxin B. Paresthesia was observed after the first dose of polymyxin B in all patients. These symptoms resolved after discontinuation of polymyxin B and switching treatment to colistin. All four patients completed therapy with colistin without experiencing additional adverse reactions. This report contributes to the small body of literature currently available on the use of polymyxin B in the CF population.

PMID: 32168426 [PubMed - as supplied by publisher]

Update on SLC6A14 in lung and gastrointestinal physiology and physiopathology: focus on cystic fibrosis.

Cell Mol Life Sci. 2020 Mar 12;:

Authors: Ruffin M, Mercier J, Calmel C, Mésinèle J, Bigot J, Sutanto EN, Kicic A, Corvol H, Guillot L

Abstract
The solute carrier family 6 member 14 (SLC6A14) protein imports and concentrates all neutral amino acids as well as the two cationic acids lysine and arginine into the cytoplasm of different cell types. Primarily described as involved in several cancer and colonic diseases physiopathological mechanisms, the SLC6A14 gene has been more recently identified as a genetic modifier of cystic fibrosis (CF) disease severity. It was indeed shown to have a pleiotropic effect, modulating meconium ileus occurrence, lung disease severity, and precocity of P. aeruginosa airway infection. The biological mechanisms explaining the impact of SLC6A14 on intestinal and lung phenotypes of CF patients are starting to be elucidated. This review focuses on SLC6A14 in lung and gastrointestinal physiology and physiopathology, especially its involvement in the pathophysiology of CF disease.

PMID: 32166393 [PubMed - as supplied by publisher]

Health-related quality-of-life in children with cystic fibrosis aged 5-years and associations with health outcomes.

J Cyst Fibros. 2020 Mar 09;:

Authors: Cheney J, Vidmar S, Gailer N, Wainwright C, Douglas TA, Australasian Cystic Fibrosis Bronchoalveolar Lavage (ACFBAL) study group

Abstract
BACKGROUND: The impact of early cystic fibrosis (CF) on health-related quality-of-life (HRQOL) in preschool children is poorly characterised, and data on relationships between HRQOL and health outcomes in young children with CF are limited. We aimed to characterise and compare parent-proxy and child-reported HRQOL and evaluate relationships with clinical outcomes at age 5-years.
METHODS: Subjects were participating in the multi-centre Australasian Cystic Fibrosis Bronchoalveolar Lavage (ACFBAL) trial investigating BAL-directed versus standard CF therapy. Children aged 5-years and their parents rated HRQOL using the Pediatric Quality of Life Inventory (PedsQL™) and Cystic Fibrosis Questionnaire-Revised (CFQ-R) questionnaires.
RESULTS: PedsQL and CFQ-R questionnaires were completed by 141 primary caregivers and 135 and 130 children, respectively. There were no differences in HRQOL between children randomised to BAL-directed versus standard CF therapy. Children with CF rated worse HRQOL than healthy children and there was poor parent-child concordance across HRQOL domains. Nutritional status, CF-CT scan score, forced expiratory volume in 1-second (FEV1), and pulmonary exacerbations correlated with HRQOL at age 5-years. FEV1 z-scores positively correlated with parent-proxy HRQOL in CFQ-R Respiratory (p = 0.018), Physical (<0.001), Emotional (p = 0.007) subscales and PedsQL Total-score (p = 0.021), Physical (p = 0.019) domains. Pulmonary exacerbation rates were inversely associated with parent-proxy CFQ-R Respiratory (p = 0.004), Physical (p = 0.022), PedsQL Total (p = 0.009) and Physical (p = 0.009) scores.
CONCLUSION: Parent-reported HRQOL is a meaningful clinical endpoint to evaluate interventions in young children. Parent and child HRQOL reports provide different, complementary information. A preschool version of the CFQ-R is needed to assess relationships between HRQOL and clinical outcomes in young children.

PMID: 32165156 [PubMed - as supplied by publisher]

Intrinsic alterations in peripheral neutrophils from cystic fibrosis newborn piglets.

J Cyst Fibros. 2020 Mar 09;:

Authors: Bréa D, Soler L, Fleurot I, Melo S, Chevaleyre C, Berri M, Labas V, Teixeira-Gomes AP, Pujo J, Cenac N, Bähr A, Klymiuk N, Guillon A, Si-Tahar M, Caballero I

Abstract
BACKGROUND: The hallmark of the cystic fibrosis (CF) lung disease is a neutrophil dominated lung environment that is associated to chronic lung tissue destruction and ultimately the patient's death. It is unclear whether the exacerbated neutrophil response is primary related to a defective CFTR or rather secondary to chronic bacterial colonization and inflammation. Here, we hypothesized that CF peripheral blood neutrophils present intrinsic alteration at birth before the start of an inflammatory process.
METHODS: Peripheral blood neutrophils were isolated from newborn CFTR+/+ and CFTR-/- piglets. Neutrophils immunophenotype was evaluated by flow cytometry. Lipidomic and proteomic profile were characterized by liquid chromatography/tandem mass spectrometry (LC-MS/MS), intact cell matrix-assisted laser desorption/ionization mass spectrometry (ICM-MS) followed by top-down high-resolution mass spectrometry (HRMS), respectively. The ability of CF neutrophils to kill pseudomonas aeruginosa was also evaluated.
RESULTS: Polyunsaturated fatty acid metabolites analysis did not show any difference between CFTR+/+ and CFTR-/- neutrophils. On the other hand, a predictive mathematical model based on the ICM-MS proteomic profile was able to discriminate between both genotypes. Top-down proteomic analysis identified 19 m/z differentially abundant masses that corresponded mainly to proteins related to the antimicrobial response and the generation of reactive oxygen species (ROS). However, no alteration in the ability of CFTR-/- neutrophils to kill pseudomonas aeruginosa in vitro was observed.
CONCLUSIONS: ICM-MS demonstrated that CFTR-/- neutrophils present intrinsic alterations already at birth, before the presence of any infection or inflammation.

PMID: 32165155 [PubMed - as supplied by publisher]

Effectiveness and cost-effectiveness of guided Internet- and mobile-based CBT for adolescents and young adults with chronic somatic conditions and comorbid depression and anxiety symptoms (youthCOACHCD): study protocol for a multicentre randomized controlled trial.

Trials. 2020 Mar 12;21(1):253

Authors: Lunkenheimer F, Domhardt M, Geirhos A, Kilian R, Mueller-Stierlin AS, Holl RW, Meissner T, Minden K, Moshagen M, Ranz R, Sachser C, Staab D, Warschburger P, Baumeister H, COACH consortium

Abstract
BACKGROUND: Adolescents and young adults (AYA) with chronic somatic conditions have an increased risk of comorbid depression and anxiety symptoms. Internet- and mobile-based cognitive behavioural therapy (iCBT) might be one possibility to extend the access to evidence-based treatments. Studies suggest that guided iCBT can reduce anxiety and depression symptoms in AYA. However, little is known about the effectiveness of iCBT for AYA with chronic somatic conditions and comorbid symptoms of anxiety and/or depression in routine care. Evidence on the (cost-)effectiveness of iCBT is essential for its implementation in health care.
OBJECTIVES AND METHODS: This multicentre two-armed randomized controlled trial (RCT) aims to evaluate the (cost-) effectiveness of guided iCBT (youthCOACHCD) in addition to treatment as usual (TAU) compared to enhanced treatment as usual (TAU+) in AYA aged 12-21 years with one of three chronic somatic conditions (type 1 diabetes, cystic fibrosis, or juvenile idiopathic arthritis). AYA with one of the chronic somatic conditions and elevated symptoms of anxiety or depression (Patient Health Questionnaire [PHQ-9] and/or Generalized Anxiety Disorder [GAD-7] Screener score ≥ 7) will be eligible for inclusion. We will recruit 212 patients (2 × n = 106) in routine care through three German patient registries. Assessments will take place at baseline and at 6 weeks, 3 months, 6 months, and 12 months post-randomization. The primary outcome will be combined depression and anxiety symptom severity as measured with the PHQ Anxiety and Depression Scale. Secondary outcomes will include health-related quality of life, coping strategies, self-efficacy, stress-related personal growth, social support, behavioural activation, adjustment and trauma-related symptoms, automatic thoughts, intervention satisfaction, working alliance, and Internet usage. The cost-effectiveness will be determined, and potential moderators and mediators of intervention effects will be explored.
DISCUSSION: iCBT might implicate novel ways to increase the access to evidence-based interventions in this specific population. The distinct focus on effectiveness and cost-effectiveness of youthCOACHCD in patients with chronic somatic conditions, as well as intervention safety, will most likely provide important new insights in the field of paediatric e-mental health. A particular strength of the present study is its implementation directly into routine collaborative health care. As such, this study will provide important insights for health care policy and stakeholders and indicate how iCBT can be integrated into existing health care systems.
TRIAL REGISTRATION: German Clinical Trials Register (DRKS), DRKS00017161. Registered on 17 September 2019.

PMID: 32164723 [PubMed - in process]

Pseudomonas Quinolone Signal molecule PQS behaves like a B Class inhibitor at the IQ site of mitochondrial complex I.

FASEB Bioadv. 2020 Mar;2(3):188-202

Authors: Rieger B, Thierbach S, Ommer M, Dienhart FSV, Fetzner S, Busch KB

Abstract
Pseudomonas aeruginosa is a Gram-negative bacterium of the proteobacteria class, and one of the most common causes of nosocomial infections. For example, it causes chronic pneumonia in cystic fibrosis patients. Patient sputum contains 2-heptyl-4-hydroxyquinoline N-oxide [HQNO] and Pseudomonas quorum sensing molecules such as the Pseudomonas quinolone signal [PQS]. It is known that HQNO inhibits the enzyme activity of mitochondrial and bacterial complex III at the Qi (quinone reduction) site, but the target of PQS is not known. In this work we have shown that PQS has a negative effect on mitochondrial respiration in HeLa and A549 cells. It specifically inhibits the complex I of the respiratory chain. In vitro analyses showed a partially competitive inhibition with respect to ubiquinone at the IQ site. In competing studies with Rotenone, PQS suppressed the ROS-promoting effect of Rotenone, which is typical for a B-type inhibitor. Prolonged incubation with PQS also had an effect on the activity of complex III.

PMID: 32161908 [PubMed]

A molecular mechanism for how sigma factor AlgT and transcriptional regulator AmrZ inhibit twitching motility in Pseudomonas aeruginosa.

Environ Microbiol. 2020 Mar 12;:

Authors: Xu A, Zhang M, Du W, Wang D, Ma LZ

Abstract
Pseudomonas aeruginosa isolates from cystic fibrosis patients are often mucoid (due to the overexpression of exopolysaccharide alginate) yet lost motility. It remains unclear about how P. aeruginosa coordinately regulates alginate production and the type IV pili-driven twitching motility. Here we showed that sigma 22 factor (AlgT/U), an activator of alginate biosynthesis, repressed twitching motility by inhibiting the expression of pilin (PilA) through the intermediate transcriptional regulator AmrZ, which directly bound to the promoter region of pilA in both mucoid strain FRD1 and non-mucoid strain PAO1. Four conserved AmrZ-binding sites were found in pilA promoters among 10 P. aeruginosa strains although their entire pilA promoters had low identity. AmrZ has been reported to be essential for twitching in PAO1. We found that AmrZ was also required for twitching in mucoid FRD1, yet a high level of AmrZ inhibited twitching motility. This result was consistent with the phenomenon that twitching is frequently repressed in mucoid strains, in which the expression of AmrZ was highly activated by AlgT. Additionally, AlgT also inhibited the transcription of pilMNOP operon, which is involved in efficient pilus assembly. Our data elucidated a mechanism for how AlgT and AmrZ coordinately controlled twitching motility in P. aeruginosa. This article is protected by copyright. All rights reserved.

PMID: 32162778 [PubMed - as supplied by publisher]

Lung T1 mapping magnetic resonance imaging in the assessment of pulmonary disease in children with cystic fibrosis: a pilot study.

Pediatr Radiol. 2020 Mar 11;:

Authors: Neemuchwala F, Ghadimi Mahani M, Pang Y, Lee E, Johnson TD, Galbán CJ, Fortuna AB, Sanchez-Jacob R, Flask CA, Nasr SZ

Abstract
BACKGROUND: Assessment tools for early cystic fibrosis (CF) lung disease are limited. Detecting early pulmonary disease is crucial to increasing life expectancy by starting interventions to slow the progression of the pulmonary disease with the many treatment options available.
OBJECTIVE: To compare the utility of lung T1-mapping MRI with ultrashort echo time (UTE) MRI in children with cystic fibrosis in detecting early stage lung disease and monitoring pulmonary exacerbations.
MATERIALS AND METHODS: We performed a prospective study in 16 children between September 2017 and January 2018. In Phase 1, we compared five CF patients with normal spirometry (mean 11.2 years) to five age- and gender-matched healthy volunteers. In Phase 2, we longitudinally evaluated six CF patients (median 11 years) in acute pulmonary exacerbation. All children had non-contrast lung T1-mapping and UTE MRI and spirometry testing. We compared the mean normalized T1 value and percentage lung volume without T1 value in CF patients and healthy subjects in Phase 1 and during treatment in Phase 2. We also performed cystic fibrosis MRI scoring. We evaluated differences in continuous variables using standard statistical tests.
RESULTS: In Phase 1, mean normalized T1 values of the lung were significantly lower in CF patients in comparison to healthy controls (P=0.02) except in the right lower lobe (P=0.29). The percentage lung volume without T1 value was also significantly higher in CF patients (P=0.006). UTE MRI showed no significant differences between CF patients and healthy volunteers (P=0.11). In Phase 2, excluding one outlier case who developed systemic disease in the course of treatment, the whole-lung T1 value increased (P=0.001) and perfusion scoring improved (P=0.02) following therapy. We observed no other significant changes in the MRI scoring.
CONCLUSION: Lung T1-mapping MRI can detect early regional pulmonary CF disease in children and might be helpful in the assessment of acute pulmonary exacerbations.

PMID: 32162080 [PubMed - as supplied by publisher]

Impaired Airway Epithelial Barrier Integrity in Response to Stenotrophomonas maltophilia Proteases, Novel Insights Using Cystic Fibrosis Bronchial Epithelial Cell Secretomics.

Front Immunol. 2020;11:198

Authors: Molloy K, Cagney G, Dillon ET, Wynne K, Greene CM, McElvaney NG

Abstract
Stenotrophomonas maltophilia is a Gram-negative opportunistic pathogen that can chronically colonize the lungs of people with cystic fibrosis (CF) and is associated with lethal pulmonary hemorrhage in immunocompromised patients. Its secreted virulence factors include the extracellular serine proteases StmPR1, StmPR2, and StmPR3. To explore the impact of secreted virulence determinants on pulmonary mucosal defenses in CF, we examined the secretome of human CFBE41o- bronchial epithelial cells in response to treatment with S. maltophilia K279a cell culture supernatant (CS) using a liquid-chromatography-tandem mass spectrometry (LC-MS/MS) based label-free quantitative (LFQ) shotgun proteomics approach for global profiling of the cell secretome. Secretome analysis identified upregulated pathways mainly relating to biological adhesion and epithelial cell signaling in infection, whereas no specific pathways relating to the immune response were enriched. Further exploration of the potentially harmful effects of K279a CS on CF bronchial epithelial cells, demonstrated that K279a CS caused CFBE41o- cell condensation and detachment, reversible by the serine protease inhibitor PMSF. K279a CS also decreased trans-epithelial electrical resistance in CFBE41o- cell monolayers suggestive of disruption of tight junction complexes (TJC). This finding was corroborated by an observed increase in fluorescein isothiocyanate (FITC) dextran permeability and by demonstrating PMSF-sensitive degradation of the tight junction proteins ZO-1 and occludin, but not JAM-A or claudin-1. These observations demonstrating destruction of the CFBE41o- TJC provide a novel insight regarding the virulence of S. maltophilia and may explain the possible injurious effects of this bacterium on the CF bronchial epithelium and the pathogenic mechanism leading to lethal pulmonary hemorrhage.

PMID: 32161586 [PubMed - in process]

Infection prevention and chronic disease management in cystic fibrosis and noncystic fibrosis bronchiectasis.

Ther Adv Respir Dis. 2020 Jan-Dec;14:1753466620905272

Authors: Lommatzsch ST

Abstract
Bronchiectasis is a chronic lung disease (CLD) characterized by irreversible bronchial dilatation noted on computed tomography associated with chronic cough, ongoing viscid sputum production, and recurrent pulmonary infections. Patients with bronchiectasis can be classified into two groups: those with cystic fibrosis and those without cystic fibrosis. Individuals with either cystic fibrosis related bronchiectasis (CFRB) or noncystic fibrosis related bronchiectasis (NCFRB) experience continuous airway inflammation and suffer airway architectural changes that foster the acquisition of a unique polymicrobial community. The presence of microorganisms increases airway inflammation, triggers pulmonary exacerbations (PEx), reduces quality of life (QOL), and, in some cases, is an independent risk factor for increased mortality. As there is no cure for either condition, prevention and control of infection is paramount. Such an undertaking incorporates patient/family and healthcare team education, immunoprophylaxis, microorganism source control, antimicrobial chemoprophylaxis, organism eradication, daily pulmonary disease management, and, in some cases, thoracic surgery. This review is a summary of recommendations aimed to thwart patient acquisition of pathologic organisms, and those therapies known to mitigate the effects of chronic airway infection. A thorough discussion of airway clearance techniques and treatment of or screening for nontuberculous mycobacteria (NTM) is beyond the scope of this discussion.

PMID: 32160809 [PubMed - in process]

Acid exposure disrupts mucus secretion and impairs mucociliary transport in neonatal piglet airways.

Am J Physiol Lung Cell Mol Physiol. 2020 Mar 11;:

Authors: Liao YSJ, Kuan SP, Guevara MV, Collins EN, Atanasova KR, Dadural JS, Vogt KM, Schurmann V, Bravo L, Eken E, Sponchiado M, Reznikov LR

Abstract
Tenacious mucus produced by tracheal and bronchial submucosal glands is a defining feature of several airway diseases, including cystic fibrosis (CF). Airway acidification as a driving force of CF airway pathology has been controversial. Here we tested the hypothesis that transient airway acidification produces pathologic mucus and impairs mucociliary transport. We studied pigs challenged with intra-airway acid. Acid had a minimal effect on mucus properties under basal conditions. However, cholinergic stimulation in acid-challenged pigs revealed retention of mucin 5B (MUC5B) in the submucosal glands, decreased concentrations of MUC5B in the lung lavage fluid, and airway obstruction. To more closely mimic a CF-like environment, we also examined mucus secretion and transport following cholinergic stimulation under diminished bicarbonate and chloride transport conditions ex vivo. Under these conditions, airways from acid-challenged pigs displayed extensive mucus films and decreased mucociliary transport. Pre-treatment with diminazene aceturate, a small molecule with the ability to inhibit acid detection through blockade of the acid-sensing ion channel (ASIC) at the doses provided, did not prevent acid-induced pathologic mucus or transport defects but did mitigate airway obstruction. These findings suggest that transient airway acidification early in life has significant impacts on mucus secretion and transport properties. Further, they highlight diminazene aceturate as an agent that might be beneficial in alleviating airway obstruction.

PMID: 32160007 [PubMed - as supplied by publisher]

Airway hyperresponsiveness, remodeling and inflammation in infants with wheeze.

Clin Exp Allergy. 2020 Mar 11;:

Authors: Malmström K, Lohi J, Malmberg LP, Kotaniemi-Syrjänen A, Lindahl H, Sarna S, Pelkonen AS, Mäkelä MJ

Abstract
BACKGROUND: The relationship of airway hyperresponsiveness to airway remodeling and inflammation in infants with wheeze is unclear.
OBJECTIVE: To investigate airway hyperresponsiveness, remodeling and inflammation in infants with wheeze and troublesome breathing.
METHODS: Inclusion criteria: full-term, 3-23 months of age; doctor diagnosed wheeze and persistent recurrent troublesome breathing; without obvious structural defect, suspicion of ciliary dyskinesia, cystic fibrosis, immune deficiency or specified use of corticosteroids. Airway hyperresponsiveness (AHR) was evaluated by performing a methacholine bronchial challenge test combined with whole body pletysmography and rapid thoracoabdominal compression. Endobronchial biopsies were analyzed for remodeling (thickness of reticular basement membrane and amount of airway smooth muscle) and for inflammation (numbers of inflammatory cells). Correlation analyses were performed.
RESULTS: Forty-nine infants fulfilled the inclusion criteria for the present study. Median age was 1.06 years (IQR 0.6; 1.5). Lung function was impaired in 39/49 (80%) children, at the median age of 1.1 years. Methacholine challenge was successfully performed in 38/49 children. Impaired baseline lung function correlated with AHR (p=0.047, Spearman). In children with the most sensitive quartile of AHR, the percentage of median bronchial airway smooth muscle % and the number of bronchial mast cells in airway smooth muscle were not significantly higher compared to others (p=0.057 and 0.056 respectively). No association was found between AHR and thickness of reticular basement membrane or inflammatory cells. Only a small group of children with both atopy and AHR (the most reactive quartile) had thicker airway smooth muscle area than non-atopics with AHR (p=0.031).
CONCLUSIONS & CLINICAL RELEVANCE: These findings don not support the concept that AHR in very young children with wheeze is determined by eosinophilic inflammation or clear-cut remodeling although it is associated with impaired baseline lung function. The possible association of increased airway smooth muscle area among atopic children with AHR remains to be confirmed.

PMID: 32159879 [PubMed - as supplied by publisher]