scholarly journals Actin-Resistant DNase1L2 as a Potential Therapeutics for CF Lung Disease

Biomolecules ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 410
Author(s):  
Danila Delfino ◽  
Giulia Mori ◽  
Claudio Rivetti ◽  
Antonella Grigoletto ◽  
Gloria Bizzotto ◽  
...  
Keyword(s):  
Lung Disease ◽  
Plasmid Dna ◽  
Actin Binding ◽  
Recurrent Infections ◽  
Binding Interface ◽  
Airway Clearance ◽  
Dependent Endonuclease ◽  
Model Structures ◽  
Potential Therapeutics ◽  
Pegylated Form

In cystic fibrosis (CF), the accumulation of viscous lung secretions rich in DNA and actin is a major cause of chronic inflammation and recurrent infections leading to airway obstruction. Mucolytic therapy based on recombinant human DNase1 reduces CF mucus viscosity and promotes airway clearance. However, the marked susceptibility to actin inhibition of this enzyme prompts the research of alternative treatments that could overcome this limitation. Within the human DNase repertoire, DNase1L2 is ideally suited for this purpose because it exhibits metal-dependent endonuclease activity on plasmid DNA in a broad range of pH with acidic optimum and is minimally inhibited by actin. When tested on CF artificial mucus enriched with actin, submicromolar concentrations of DNase1L2 reduces mucus viscosity by 50% in a few seconds. Inspection of superimposed model structures of DNase1 and DNase1L2 highlights differences at the actin-binding interface that justify the increased resistance of DNase1L2 toward actin inhibition. Furthermore, a PEGylated form of the enzyme with preserved enzymatic activity was obtained, showing interesting results in terms of activity. This work represents an effort toward the exploitation of natural DNase variants as promising alternatives to DNase1 for the treatment of CF lung disease.

scholarly journals New insights in phenotype and treatment of lung disease immuno-deficiency and chromosome breakage syndrome (LICS)

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Brigitte W. M. Willemse ◽  
Saskia N. van der Crabben ◽  
Wilhelmina S. Kerstjens-Frederikse ◽  
Wim Timens ◽  
Joris M. van Montfrans ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Lung Disease ◽  
Chromosome Breakage ◽  
Recurrent Infections ◽  
Hematopoietic Stem ◽  
Chromosome Breakage Syndrome ◽  
Severe Immunodeficiency ◽  
Extended Survival ◽  
Immunological Abnormalities

AbstractWe report five patients with lung disease immuno-deficiency and chromosome breakage syndrome (LICS) but without recurrent infections and severe immunodeficiency. One patient had extended survival to 6.5 years. Hematopoietic stem-cell transplantation failed to cure another patient. Our findings suggest that the immunological abnormalities can be limited and do not fully explain the LICS phenotype.

scholarly journals Visualization of Head–Head Interactions in the Inhibited State of Smooth Muscle Myosin

1999 ◽  
Vol 147 (7) ◽  
pp. 1385-1390 ◽  
Author(s):  
Thomas Wendt ◽  
Dianne Taylor ◽  
Terri Messier ◽  
Kathleen M. Trybus ◽  
Kenneth A. Taylor
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Myosin ◽  
Intramolecular Interactions ◽  
Actin Binding ◽  
Structural Basis ◽  
Binding Interface ◽  
Structural Differences ◽  
Muscle Myosin ◽  
Positively Charged ◽  
Phosphoryla Tion

The structural basis for the phosphoryla- tion-dependent regulation of smooth muscle myosin ATPase activity was investigated by forming two- dimensional (2-D) crystalline arrays of expressed unphosphorylated and thiophosphorylated smooth muscle heavy meromyosin (HMM) on positively charged lipid monolayers. A comparison of averaged 2-D projections of both forms at 2.3-nm resolution reveals distinct structural differences. In the active, thiophosphorylated form, the two heads of HMM interact intermolecularly with adjacent molecules. In the unphosphorylated or inhibited state, intramolecular interactions position the actin-binding interface of one head onto the converter domain of the second head, thus providing a mechanism whereby the activity of both heads could be inhibited.

Improving airway clearance in cystic fibrosis lung disease

2014 ◽  
pp. 169-187
Author(s):  
Judy M. Bradley ◽  
Katherine O’Neill ◽  
Ruth Dentice ◽  
Mark Elkins
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Cystic Fibrosis Lung ◽  
Airway Clearance ◽  
Cystic Fibrosis Lung Disease

scholarly journals Effects of exercise and airway clearance (positive expiratory pressure) on mucus clearance in cystic fibrosis: a randomised crossover trial

2019 ◽  
Vol 53 (4) ◽  
pp. 1801793 ◽  
Author(s):  
Tiffany J. Dwyer ◽  
Evangelia Daviskas ◽  
Rahizan Zainuldin ◽  
Jordan Verschuer ◽  
Stefan Eberl ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Crossover Trial ◽  
Treadmill Exercise ◽  
Forced Expiratory Volume ◽  
Mean Difference ◽  
Peak Oxygen Consumption ◽  
Mucus Clearance ◽  
Airway Clearance ◽  
Positive Expiratory Pressure

Exercise improves mucus clearance in people without lung disease and those with chronic bronchitis. No study has investigated exercise alone for mucus clearance in cystic fibrosis (CF). The aim of this study was to compare the effects of treadmill exercise to resting breathing and airway clearance with positive expiratory pressure (PEP) therapy on mucus clearance in adults with CF.This 3-day randomised, controlled, crossover trial included 14 adults with mild to severe CF lung disease (forced expiratory volume in 1 s % predicted 31–113%). Interventions were 20 min of resting breathing (control), treadmill exercise at 60% of the participant's peak oxygen consumption or PEP therapy (including huffing and coughing). Mucus clearance was measured using the radioaerosol technique and gamma camera imaging.Treadmill exercise improved whole lung mucus clearance compared to resting breathing (mean difference 3%, 95% CI 2–4); however, exercise alone was less effective than PEP therapy (mean difference −7%, 95% CI −6– −8). When comparing treadmill exercise to PEP therapy, there were no significant differences in mucus clearance from the intermediate and peripheral lung regions, but significantly less clearance from the central lung region (likely reflecting the huffing and coughing that was only in PEP therapy).It is recommended that huffing and coughing are included to maximise mucus clearance with exercise.

scholarly journals Redox-sensitive residue in the actin-binding interface of myosin

2014 ◽  
Vol 453 (3) ◽  
pp. 345-349 ◽  
Author(s):  
Rebecca J. Moen ◽  
Sinziana Cornea ◽  
Daniel E. Oseid ◽  
Benjamin P. Binder ◽  
Jennifer C. Klein ◽  
...  
Keyword(s):  
Actin Binding ◽  
Binding Interface

scholarly journals P166 The emerging role of airway clearance techniques in the treatment of interstitial lung disease

Thorax ◽  
2016 ◽  
Vol 71 (Suppl 3) ◽  
pp. A174.1-A174
Author(s):  
L Skevington-Postles ◽  
S Akers ◽  
P George ◽  
G Housley ◽  
J Beadle ◽  
...  
Keyword(s):  
Interstitial Lung Disease ◽  
Lung Disease ◽  
Airway Clearance

scholarly journals The Role of Serine Proteases and Antiproteases in the Cystic Fibrosis Lung

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Matthew S. Twigg ◽  
Simon Brockbank ◽  
Philip Lowry ◽  
S. Peter FitzGerald ◽  
Clifford Taggart ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Immune Responses ◽  
Lung Disease ◽  
Healthy Individual ◽  
Chronic Infection ◽  
Serine Proteases ◽  
High Concentration ◽  
Mucus Clearance ◽  
Potential Therapeutics

Cystic fibrosis (CF) lung disease is an inherited condition with an incidence rate of approximately 1 in 2500 new born babies. CF is characterized as chronic infection of the lung which leads to inflammation of the airway. Sputum from CF patients contains elevated levels of neutrophils and subsequently elevated levels of neutrophil serine proteases. In a healthy individual these proteases aid in the phagocytic process by degrading microbial peptides and are kept in homeostatic balance by cognate antiproteases. Due to the heavy neutrophil burden associated with CF the high concentration of neutrophil derived proteases overwhelms cognate antiproteases. The general effects of this protease/antiprotease imbalance are impaired mucus clearance, increased and self-perpetuating inflammation, and impaired immune responses and tissue. To restore this balance antiproteases have been suggested as potential therapeutics or therapeutic targets. As such a number of both endogenous and synthetic antiproteases have been trialed with mixed success as therapeutics for CF lung disease.

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