scholarly journals Observations of, and Insights into, Cystic Fibrosis Mucus Heterogeneity in the Pre-Modulator Era: Sputum Characteristics, DNA and Glycoprotein Content, and Solubilization Time

2020 ◽  
Vol 1 (1) ◽  
pp. 8-29
Author(s):  
Deborah L. Chance ◽  
Thomas P. Mawhinney
Keyword(s):  
Electron Microscopy ◽  
Cystic Fibrosis ◽  
Respiratory Tract ◽  
Immune Cell ◽  
Dry Weight ◽  
Therapeutic Strategies ◽  
Lung Damage ◽  
Therapeutic Interventions ◽  
3D Analysis ◽  
Predictive Relationship

Airway obstruction with chronic inflammation and infection are major contributors to the lung damage and mortality of cystic fibrosis (CF). A better understanding of the congested milieu of CF airways will aid in improving therapeutic strategies. This article retrospectively reports our observations, and discusses insights gained in the handling and analysis of CF sputa. CF and non-CF mucus samples were surveyed for morphological features by electron microscopy and analyzed for the macromolecular dry weight (MDW), total protein, lipid, carbohydrate, and DNA. Mucus character was investigated with chemical solubilization time as a comparative tool. CF mucus appeared distinctly thick, viscous, and heterogeneous, with neutrophils as the dominant immune cell. CF sputum DNA content varied markedly for and between individuals (~1–10% MDW), as did solubilization times (~1–20 h). CF Sputum DNA up to 7.1% MDW correlated positively with solubilization time, whereas DNA >7.1% MDW correlated negatively. 3D analysis of CF sputa DNA, GP, and solubilization times revealed a dynamic and predictive relationship. Reflecting on the heterogeneous content and character of CF mucus, and the possible interplay in space and time in the respiratory tract of polymeric DNA and mucous glycoproteins, we highlight it’s potential to affect infection-related airway pathologies and the success of therapeutic interventions.

scholarly journals Deletion of cftr leads to an excessive neutrophilic response and defective tissue repair in a zebrafish model of sterile inflammation

2019 ◽  
Author(s):  
Audrey Bernut ◽  
Catherine A. Loynes ◽  
R. Andres Floto ◽  
Stephen A. Renshaw
Keyword(s):  
Cystic Fibrosis ◽  
Tissue Repair ◽  
Cell Function ◽  
Immune Cell ◽  
Genetic Disorder ◽  
Innate Immune ◽  
Lung Damage ◽  
Tanshinone Iia ◽  
Sterile Inflammation ◽  
Inflammatory Status

AbstractInflammation-related progressive lung destruction is the leading causes of premature death in cystic fibrosis (CF), a genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. However, therapeutic targeting of inflammation has been hampered by a lack of understanding of the links between a dysfunctional CFTR and the deleterious innate immune response in CF. Herein, we used CFTR-depleted zebrafish larvae as an innovative in vivo vertebrate model, mimicking aspects of the inflammatory pathology of CF-related lung, to understand how CFTR dysfunction leads to abnormal inflammatory status in CF.We show that impaired CFTR-mediated inflammation correlates with an exuberant neutrophilic response after injury: CF zebrafish exhibit enhanced and sustained accumulation of neutrophils at wounds. Excessive epithelial oxidative responses drive enhanced neutrophil recruitment towards wounds. Persistence of neutrophils at inflamed sites is associated with impaired reverse migration of neutrophils and reduction in neutrophil apoptosis. As a consequence, the increased number of neutrophils at wound sites causes tissue damage and abnormal tissue repair. Importantly, the pro-resolution molecule Tanshinone IIA successfully re-balances inflammation both by accelerating inflammation resolution and by improving tissue repair in CFTR-deficient animal.Larval zebrafish giving a unique insight into innate immune cell function in CFTR deficiency, our findings bring important new understanding of the mechanisms underlying the inflammatory pathology in CF, which could be addressed therapeutically to prevent inflammatory lung damage in CF patients with potential improvements in disease outcomes.

scholarly journals Pseudomonas aeruginosa: An Audacious Pathogen with an Adaptable Arsenal of Virulence Factors

2021 ◽  
Vol 22 (6) ◽  
pp. 3128
Author(s):  
Irene Jurado-Martín ◽  
Maite Sainz-Mejías ◽  
Siobhán McClean
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Respiratory Tract ◽  
Adaptive Capacity ◽  
Virulence Factors ◽  
Deep Understanding ◽  
Therapeutic Strategies ◽  
Chronic Infections ◽  
Genomic Studies ◽  
Hostile Environments

Pseudomonas aeruginosa is a dominant pathogen in people with cystic fibrosis (CF) contributing to morbidity and mortality. Its tremendous ability to adapt greatly facilitates its capacity to cause chronic infections. The adaptability and flexibility of the pathogen are afforded by the extensive number of virulence factors it has at its disposal, providing P. aeruginosa with the facility to tailor its response against the different stressors in the environment. A deep understanding of these virulence mechanisms is crucial for the design of therapeutic strategies and vaccines against this multi-resistant pathogen. Therefore, this review describes the main virulence factors of P. aeruginosa and the adaptations it undergoes to persist in hostile environments such as the CF respiratory tract. The very large P. aeruginosa genome (5 to 7 MB) contributes considerably to its adaptive capacity; consequently, genomic studies have provided significant insights into elucidating P. aeruginosa evolution and its interactions with the host throughout the course of infection.

scholarly journals Early Interleukin-22 and Neutrophil Proteins Are Correlated to Future Lung Damage in Children With Cystic Fibrosis

2021 ◽  
Vol 9 ◽  
Author(s):  
Julie Renwick ◽  
Emma Reece ◽  
Jamie Walsh ◽  
Ross Walsh ◽  
Thara Persaud ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Early Life ◽  
Rank Order ◽  
Severe Disease ◽  
Early Years ◽  
Lung Damage ◽  
Therapeutic Interventions ◽  
Complement C3 ◽  
Lung Function Decline ◽  
High Resolution Computed Tomography

Cystic Fibrosis (CF) lung damage begins early in life. Lung function decline is associated with pulmonary infections, neutrophil infiltration and inflammation. In CF, neutrophils have an altered phenotype. In this pilot study, we aimed to determine if signals of dysfunctional neutrophil responses were evident early in life and whether these signals may be associated with lung damage in later childhood. We examined the pulmonary protein profiles of 14 clinical stable infants and pre-school children with CF employing the aptamer-based affinity platform, SOMAscan®. High resolution computed tomography (HRCT) was performed on all children after age 6 years and Brody score calculated. A Spearman's rank order correlation analysis and Benjamini-Hochberg adjustment was used to correlate protein concentrations in early life to Brody scores in later childhood. Early life concentrations of azurocidin and myeloperoxidase, were positively correlated with Brody score after age 6 (p = 0.0041 and p = 0.0182, respectively). Four other neutrophil associated proteins; Complement C3 (p = 0.0026), X-ray repair CCP 6 (p = 0.0059), C3a anaphylatoxin des Arginine (p = 0.0129) and cytokine receptor common subunit gamma (p = 0.0214) were all negatively correlated with Brody scores. Interestingly, patients with more severe lung damage after age 6 had significantly lower levels of IL-22 in early years of life (p = 0.0243). IL-22 has scarcely been reported to have implications in CF. Identification of early biomarkers that may predict more severe disease progression is particularly important for the future development of early therapeutic interventions in CF disease. We recommend further corroboration of these findings in prospective validation studies.

Respiratory tract microbiocenosis in children with cystic fibrosis in Kharkiv region

2016 ◽  
Vol 78 (6) ◽  
pp. 24-26
Author(s):  
V.A. Klymenko ◽  
◽  
Y.A. Yanovskaya ◽  
Y.V. Pasichnik ◽  
◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Respiratory Tract

Preliminary Report of In vitro and In vivo Effectiveness of Dornase Alfa on SARS-CoV-2 Infection (Preprint)

2020 ◽  
Author(s):  
Hacer Kuzu Okur ◽  
Koray Yalcin ◽  
Cihan Tastan ◽  
Sevda Demir ◽  
Bulut Yurtsever ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Respiratory Tract ◽  
Mononuclear Cells ◽  
Multiple Organ ◽  
Peripheral Blood Mononuclear ◽  
Dornase Alfa ◽  
Tract Infections ◽  
Adult Peripheral Blood

UNSTRUCTURED Dornase alfa, the recombinant form of the human DNase I enzyme, breaks down neutrophil extracellular traps (NET) that include a vast amount of DNA fragments, histones, microbicidal proteins and oxidant enzymes released from necrotic neutrophils in the highly viscous mucus of cystic fibrosis patients. Dornase alfa has been used for decades in patients with cystic fibrosis to reduce the viscoelasticity of respiratory tract secretions, to decrease the severity of respiratory tract infections, and to improve lung function. Previous studies have linked abnormal NET formations to lung diseases, especially to acute respiratory distress syndrome (ARDS). Coronavirus disease 2019 (COVID-19) pandemic affected more than two million people over the world, resulting in unprecedented health, social and economic crises. The COVID-19, viral pneumonia that progresses to ARDS and even multiple organ failure, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). High blood neutrophil levels are an early indicator of SARS-CoV-2 infection and predict severe respiratory diseases. A similar mucus structure is detected in COVID-19 patients due to the accumulation of excessive NET in the lungs. Here, we show our preliminary results with dornase alfa that may have an in-vitro anti-viral effect against SARS-CoV-2 infection in a bovine kidney cell line, MDBK without drug toxicity on healthy adult peripheral blood mononuclear cells. In this preliminary study, we also showed that dornase alfa can promote clearance of NET formation in both an in-vitro and three COVID-19 cases who showed clinical improvement in radiological analysis (2-of-3 cases), oxygen saturation (SpO2), respiratory rate, disappearing of dyspnea and coughing.

scholarly journals Single-cell biology to decode the immune cellular composition of kidney inflammation

2021 ◽  
Author(s):  
Yu Zhao ◽  
Ulf Panzer ◽  
Stefan Bonn ◽  
Christian F. Krebs
Keyword(s):  
Single Cell ◽  
Cell Biology ◽  
Computational Analysis ◽  
Immune Cell ◽  
Therapeutic Interventions ◽  
Experimental Setup ◽  
Disease Etiology ◽  
Rna Profiling ◽  
Immune Mediated ◽  
Health And Disease

AbstractSingle-cell biology is transforming the ability of researchers to understand cellular signaling and identity across medical and biological disciplines. Especially for immune-mediated diseases, a single-cell look at immune cell subtypes, signaling, and activity might yield fundamental insights into the disease etiology, mechanisms, and potential therapeutic interventions. In this review, we highlight recent advances in the field of single-cell RNA profiling and their application to understand renal function in health and disease. With a focus on the immune system, in particular on T cells, we propose some key directions of understanding renal inflammation using single-cell approaches. We detail the benefits and shortcomings of the various technological approaches outlined and give advice on potential pitfalls and challenges in experimental setup and computational analysis. Finally, we conclude with a brief outlook into a promising future for single-cell technologies to elucidate kidney function.

scholarly journals Gut Microbiota and NAFLD: Pathogenetic Mechanisms, Microbiota Signatures, and Therapeutic Interventions

2021 ◽  
Vol 9 (5) ◽  
pp. 957
Author(s):  
Tomas Hrncir ◽  
Lucia Hrncirova ◽  
Miloslav Kverka ◽  
Robert Hromadka ◽  
Vladimira Machova ◽  
...  
Keyword(s):  
Liver Disease ◽  
Gut Microbiota ◽  
Therapeutic Strategies ◽  
Therapeutic Interventions ◽  
Faecal Microbiota ◽  
Alcoholic Fatty Liver ◽  
The Metabolic Syndrome ◽  
Immunological Mechanisms ◽  
Major Factors ◽  
Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Its worldwide prevalence is rapidly increasing and is currently estimated at 24%. NAFLD is highly associated with many features of the metabolic syndrome, including obesity, insulin resistance, hyperlipidaemia, and hypertension. The pathogenesis of NAFLD is complex and not fully understood, but there is increasing evidence that the gut microbiota is strongly implicated in the development of NAFLD. In this review, we discuss the major factors that induce dysbiosis of the gut microbiota and disrupt intestinal permeability, as well as possible mechanisms leading to the development of NAFLD. We also discuss the most consistent NAFLD-associated gut microbiota signatures and immunological mechanisms involved in maintaining the gut barrier and liver tolerance to gut-derived factors. Gut-derived factors, including microbial, dietary, and host-derived factors involved in NAFLD pathogenesis, are discussed in detail. Finally, we review currently available diagnostic and prognostic methods, summarise latest knowledge on promising microbiota-based biomarkers, and discuss therapeutic strategies to manipulate the microbiota, including faecal microbiota transplantation, probiotics and prebiotics, deletions of individual strains with bacteriophages, and blocking the production of harmful metabolites.

scholarly journals Therapeutic Strategies for Diabetic Kidney Disease

Diabetology ◽  
2021 ◽  
Vol 2 (1) ◽  
pp. 31-35
Author(s):  
Keiichiro Matoba
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Intensive Therapy ◽  
Therapeutic Strategies ◽  
Therapeutic Interventions ◽  
Hemodynamic Changes ◽  
Diabetic Kidney ◽  
Global Epidemic ◽  
Stage Renal Disease ◽  
End Stage

Diabetic kidney disease (DKD) is a global epidemic leading to end-stage renal disease (ESRD) and susceptibility to cardiovascular disease, with few therapeutic interventions. A hallmark of DKD is the activation of the renin-angiotensin-aldosterone system and hemodynamic changes in glomerulus. Although intensive therapy with agents that targets those abnormalities lowers the risk of DKD progression, it does not completely abolish the risk of ESRD and cardiovascular events. Recent studies have illustrated the importance of renal inflammation, oxidative stress, and activated Rho-associated protein kinase (ROCK) signaling as essential pathogenesis for the development of DKD. In this commentary, these topics will be discussed.

scholarly journals Determination of intermediate state structures in the opening pathway of SARS-CoV-2 spike using cryo-electron microscopy

2021 ◽  
Author(s):  
Z. Faidon Brotzakis ◽  
Thomas Lohr ◽  
Michele Vendruscolo
Keyword(s):  
Infectious Disease ◽  
Electron Microscopy ◽  
Severe Acute Respiratory Syndrome ◽  
Intermediate State ◽  
Therapeutic Interventions ◽  
Cryo Electron Microscopy ◽  
Welfare Systems

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a highly infectious disease that is severely affecting our society and welfare systems. In order to develop therapeutic interventions against this...

scholarly journals Serial Analysis of the Gut and Respiratory Microbiome in Cystic Fibrosis in Infancy: Interaction between Intestinal and Respiratory Tracts and Impact of Nutritional Exposures

mBio ◽  
2012 ◽  
Vol 3 (4) ◽  
Author(s):  
J. C. Madan ◽  
D. C. Koestler ◽  
B. A. Stanton ◽  
L. Davidson ◽  
L. A. Moulton ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Respiratory Tract ◽  
Microbial Communities ◽  
Effective Means ◽  
Significant Proportion ◽  
Gut Colonization ◽  
Pulmonary Damage ◽  
Chronic Colonization ◽  
High Degree ◽  
Over Time

ABSTRACT Pulmonary damage caused by chronic colonization of the cystic fibrosis (CF) lung by microbial communities is the proximal cause of respiratory failure. While there has been an effort to document the microbiome of the CF lung in pediatric and adult patients, little is known regarding the developing microflora in infants. We examined the respiratory and intestinal microbiota development in infants with CF from birth to 21 months. Distinct genera dominated in the gut compared to those in the respiratory tract, yet some bacteria overlapped, demonstrating a core microbiota dominated by Veillonella and Streptococcus. Bacterial diversity increased significantly over time, with evidence of more rapidly acquired diversity in the respiratory tract. There was a high degree of concordance between the bacteria that were increasing or decreasing over time in both compartments; in particular, a significant proportion (14/16 genera) increasing in the gut were also increasing in the respiratory tract. For 7 genera, gut colonization presages their appearance in the respiratory tract. Clustering analysis of respiratory samples indicated profiles of bacteria associated with breast-feeding, and for gut samples, introduction of solid foods even after adjustment for the time at which the sample was collected. Furthermore, changes in diet also result in altered respiratory microflora, suggesting a link between nutrition and development of microbial communities in the respiratory tract. Our findings suggest that nutritional factors and gut colonization patterns are determinants of the microbial development of respiratory tract microbiota in infants with CF and present opportunities for early intervention in CF with altered dietary or probiotic strategies. IMPORTANCE While efforts have been focused on assessing the microbiome of pediatric and adult cystic fibrosis (CF) patients to understand how chronic colonization by these microbes contributes to pulmonary damage, little is known regarding the earliest development of respiratory and gut microflora in infants with CF. Our findings suggest that colonization of the respiratory tract by microbes is presaged by colonization of the gut and demonstrated a role of nutrition in development of the respiratory microflora. Thus, targeted dietary or probiotic strategies may be an effective means to change the course of the colonization of the CF lung and thereby improve patient outcomes.

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