A glycopolymer improves vascoelasticity and mucociliary transport of abnormal cystic fibrosis mucus

Fernandez-Petty, Courtney M; Hughes, Gareth W.; Bowers, Hannah; Watson, John D.; Rosen, Bradley H.; Townsend, Stacy M.; Santos, Carlo; Ridley, Caroline; Chu, Kengyeh K.; Li, Yao; Leung, Hui Min; Garcia, Bryan; Evans, T. Idil Apak; Libby, Emily Falk; Hathorne, Heather; Tearney, Guillermo J.; Engelhardt, John F.; Swords, W. Edward; Thornton, David J.; Wiesmann, William P.; Baker, Shenda M.; Rowe, Steven M.

doi:10.1172/jci.insight.125954

Cited by 43 publications

(70 citation statements)

References 65 publications

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“…However, HMW-HA (but interestingly, not low-MW HA) changes the nanostructure of mucin, possibly through entanglement with mucin proteins [ 53 ] and could thus improve the functional rheology of the mucociliary layer [ 47 ] and promote MCT through this mechanism. In support of this interpretation, recent studies have shown that normalizing mucin structure can improve MCT in cystic fibrosis airways [ 54 ].…”

Section: Discussionmentioning

confidence: 82%

Inhaled high molecular weight hyaluronan ameliorates respiratory failure in acute COPD exacerbation: a pilot study

Pedone

McGee

et al. 2021

Respir Res

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Background Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) carry significant morbidity and mortality. AECOPD treatment remains limited. High molecular weight hyaluronan (HMW-HA) is a glycosaminoglycan sugar, which is a physiological constituent of the lung extracellular matrix and has notable anti-inflammatory and hydrating properties. Research question We hypothesized that inhaled HMW-HA will improve outcomes in AECOPD. Methods We conducted a single center, randomized, placebo-controlled, double-blind study to investigate the effect of inhaled HMW-HA in patients with severe AECOPD necessitating non-invasive positive-pressure ventilation (NIPPV). Primary endpoint was time until liberation from NIPPV. Results Out of 44 screened patients, 41 were included in the study (21 for placebo and 20 for HMW-HA). Patients treated with HMW-HA had significantly shorter duration of NIPPV. HMW-HA treated patients also had lower measured peak airway pressures on the ventilator and lower systemic inflammation markers after liberation from NIPPV. In vitro testing showed that HMW-HA significantly improved mucociliary transport in air–liquid interface cultures of primary bronchial cells from COPD patients and healthy primary cells exposed to cigarette smoke extract. Interpretation Inhaled HMW-HA shortens the duration of respiratory failure and need for non-invasive ventilation in patients with AECOPD. Beneficial effects of HMW-HA on mucociliary clearance and inflammation may account for some of the effects (NCT02674880, www.clinicaltrials.gov).

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Section: Discussionmentioning

confidence: 82%

Inhaled high molecular weight hyaluronan ameliorates respiratory failure in acute COPD exacerbation: a pilot study

Pedone

McGee

et al. 2021

Respir Res

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“…Uncoupling of these noncovalent interactions in mucus is critical for the transition to an expanded linear chains underpinning normal flowing mucus that can be transported by MCC to keep the lung free from infection. Addition of agents to mucus that displace calcium from mucins has been shown to normalize mucin conformation and decrease mucus viscoelasticity and improve MCC (64, 65).…”

Section: Discussionmentioning

confidence: 99%

The C-terminal dimerization domain of the respiratory mucin MUC5B functions in mucin stability and intracellular packaging before secretion

Ridley

Lockhart-Cairns

Collins

et al. 2019

Journal of Biological Chemistry

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Mucin 5B (MUC5B) has an essential role in mucociliary clearance that protects the pulmonary airways. Accordingly, knowledge of MUC5B structure and its interactions with itself and other proteins is critical to better understand airway mucus biology and improve the management of lung diseases such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease (COPD). The role of an N-terminal multimerization domain in the supramolecular organization of MUC5B has been previously described, but less is known about its C-terminal dimerization domain. Here, using cryogenic electron microscopy (cryo-EM) and small-angle X-ray scattering (SAXS) analyses of recombinant disulfide-linked dimeric MUC5B dimerization domain we identified an asymmetric, elongated twisted structure, with a double globular base. We found that the dimerization domain is more resistant to disruption than the multimerization domain suggesting the twisted structure of the dimerization domain confers additional stability to MUC5B polymers. Size-exclusion chromatography-multiangle light scattering (SEC-MALS), SPR-based biophysical analyses and microscale thermophoresis of the dimerization domain disclosed no further assembly, but did reveal reversible, calcium-dependent interactions between the dimerization and multimerization domains that were most active at acidic pH, suggesting that these domains have a role in MUC5B intragranular organization. In summary, our results suggest a role for the C-terminal dimerization domain of MUC5B in compaction of mucin chains during granular packaging via interactions with the N-terminal multimerization domain. Our findings further suggest that the less stable multimerization domain provides a potential target for mucin depolymerization to remove mucus plugs in COPD and other lung pathologies.

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“…In P. aeruginosa, PAAG is has been shown to effectively eradicate persister cells, which is important for the prevention of recurrent P. aeruginosa infections and subsequent exacerbations in people with CF (Narayanaswamy et al, 2018). In addition to serving as an effective antibiotic adjuvant, PAAG also reduces inflammation and promotes viscoelasticity and mucociliary clearance, making it a suitable drug candidate to improve the quality of life for patients with a variety of mucus diseases (Fernandez-Petty et al, 2019).…”

Section: Paag (Snsp113)mentioning

confidence: 99%

The Building Blocks of Antimicrobial Resistance in Pseudomonas aeruginosa: Implications for Current Resistance-Breaking Therapies

Langendonk

Neill

Fothergill

2021

Front. Cell. Infect. Microbiol.

139

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P. aeruginosa is classified as a priority one pathogen by the World Health Organisation, and new drugs are urgently needed, due to the emergence of multidrug-resistant (MDR) strains. Antimicrobial-resistant nosocomial pathogens such as P. aeruginosa pose unwavering and increasing threats. Antimicrobial stewardship has been a challenge during the COVID-19 pandemic, with a majority of those hospitalized with SARS-CoV2 infection given antibiotics as a safeguard against secondary bacterial infection. This increased usage, along with increased handling of sanitizers and disinfectants globally, may further accelerate the development and spread of cross-resistance to antibiotics. In addition, P. aeruginosa is the primary causative agent of morbidity and mortality in people with the life-shortening genetic disease cystic fibrosis (CF). Prolonged periods of selective pressure, associated with extended antibiotic treatment and the actions of host immune effectors, results in widespread adaptive and acquired resistance in P. aeruginosa found colonizing the lungs of people with CF. This review discusses the arsenal of resistance mechanisms utilized by P. aeruginosa, how these operate under high-stress environments such as the CF lung and how their interconnectedness can result in resistance to multiple antibiotic classes. Intrinsic, adaptive and acquired resistance mechanisms will be described, with a focus on how each layer of resistance can serve as a building block, contributing to multi-tiered resistance to antimicrobial activity. Recent progress in the development of anti-resistance adjuvant therapies, targeting one or more of these building blocks, should lead to novel strategies for combatting multidrug resistant P. aeruginosa. Anti-resistance adjuvant therapy holds great promise, not least because resistance against such therapeutics is predicted to be rare. The non-bactericidal nature of anti-resistance adjuvants reduce the selective pressures that drive resistance. Anti-resistance adjuvant therapy may also be advantageous in facilitating efficacious use of traditional antimicrobials, through enhanced penetration of the antibiotic into the bacterial cell. Promising anti-resistance adjuvant therapeutics and targets will be described, and key remaining challenges highlighted. As antimicrobial stewardship becomes more challenging in an era of emerging and re-emerging infectious diseases and global conflict, innovation in antibiotic adjuvant therapy can play an important role in extending the shelf-life of our existing antimicrobial therapeutic agents.

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A glycopolymer improves vascoelasticity and mucociliary transport of abnormal cystic fibrosis mucus

Cited by 43 publications

References 65 publications

Inhaled high molecular weight hyaluronan ameliorates respiratory failure in acute COPD exacerbation: a pilot study

Inhaled high molecular weight hyaluronan ameliorates respiratory failure in acute COPD exacerbation: a pilot study

The C-terminal dimerization domain of the respiratory mucin MUC5B functions in mucin stability and intracellular packaging before secretion

The Building Blocks of Antimicrobial Resistance in Pseudomonas aeruginosa: Implications for Current Resistance-Breaking Therapies

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