An Improved Inhaled Mucolytic to Treat Airway Muco-obstructive Diseases

Ehré, Camille; Rushton, Zachary L.; Wang, Boya; Hothem, Lauren N.; Morrison, Cameron B.; N.C., Fontana,; Markovetz, Matthew R.; Delion, M.; Kato, Takafumi; Villalon, Diane E. Grove; Thelin, William R.; Esther, Charles R.; Hill, David B.; Grubb, Barbara R.; Livraghi‐Butrico, Alessandra; Donaldson, Scott H.; Boucher, Richard C.

doi:10.1164/rccm.201802-0245oc

Cited by 92 publications

(91 citation statements)

References 26 publications

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“…Currently, N -acetylcysteine is employed to target these linkages in mucins and thus act as a mucus-solubilising agent (mucolytic). However, its efficacy is limited [ 89 ], and more effective and potent mucolytics are being developed [ 57 , 90 ].…”

Section: Polymeric Mucins In Airway Diseasesmentioning

confidence: 99%

Mucins: the frontline defence of the lung

Ridley

Thornton

2018

Biochemical Society Transactions

154

152

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Mucus plays a vital role in protecting the lungs from environmental factors, but conversely, in muco-obstructive airway disease, mucus becomes pathologic. In its protective role, mucus entraps microbes and particles removing them from the lungs via the co-ordinated beating of motile cilia. This mechanism of lung defence is reliant upon a flowing mucus gel, and the major macromolecular components that determine the rheological properties of mucus are the polymeric mucins, MUC5AC and MUC5B. These large O-linked glycoproteins have direct roles in maintaining lung homeostasis. MUC5B is essential for interaction with the ciliary clearance system and MUC5AC is up-regulated in response to allergic inflammatory challenge. Mucus with abnormal biophysical properties is a feature of muco-obstructive respiratory disease and can result from many different mechanisms including alterations in mucin polymer assembly, mucin concentration and the macromolecular form in mucus, as well as changes in airway surface hydration, pH and ion composition. The abnormal mucus results in defective lung protection via compromised ciliary clearance, leading to infection and inflammation.

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Section: Polymeric Mucins In Airway Diseasesmentioning

confidence: 99%

Mucins: the frontline defence of the lung

Ridley

Thornton

2018

Biochemical Society Transactions

154

152

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“…These internal cysteine thiols add to the antioxidant effects of mucins. High levels of oxidative stress in COPD mucus might increase mucin oxidative cross linkage through disulfide bonds, resulting in highly cross linked, elastic mucus [ 90 ]. Thus, antioxidant therapy may be effective against airway mucus hypersecretion.…”

Section: Signaling Pathways Associated With Airway Mucus Hypersecrmentioning

confidence: 99%

The Potential Role and Regulatory Mechanisms of MUC5AC in Chronic Obstructive Pulmonary Disease

2020

Molecules

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Chronic obstructive pulmonary disease (COPD) is associated with high morbidity and mortality globally. Studies show that airway mucus hypersecretion strongly compromises lung function, leading to frequent hospitalization and mortality, highlighting an urgent need for effective COPD treatments. MUC5AC is known to contribute to severe muco-obstructive lung diseases, worsening COPD pathogenesis. Various pathways are implicated in the aberrant MUC5AC production and secretion MUC5AC. These include signaling pathways associated with mucus-secreting cell differentiation [nuclear factor-κB (NF-κB)and IL-13-STAT6- SAM pointed domain containing E26 transformation-specific transcription factor (SPDEF), as well as epithelial sodium channel (ENaC) and cystic fibrosis transmembrane conductance regulator (CFTR)], and signaling pathways related to mucus transport and excretion-ciliary beat frequency (CBF). Various inhibitors of mucus hypersecretion are in clinical use but have had limited benefits against COPD. Thus, novel therapies targeting airway mucus hypersecretion should be developed for effective management of muco-obstructive lung disease. Here, we systematically review the mechanisms and pathogenesis of airway mucus hypersecretion, with emphasis on multi-target and multi-link intervention strategies for the elucidation of novel inhibitors of airway mucus hypersecretion.

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“…Several other drugs aimed at improving mucociliary clearance or reducing inflammatory response are also being studied. [123][124][125] All of these developments have been made possible through major advances in physiology, new technologies such as high-throughput screening, better surrogate readouts for drug discovery, improved animal models, and highquality clinical trials. Collaborations between investigators in the basic sciences and clinicians have been exemplary in CF research.…”

Section: Future Directionsmentioning

confidence: 99%

Cystic Fibrosis: Pathophysiology of Lung Disease

Bergeron

Cantin

2019

Semin Respir Crit Care Med

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Cystic fibrosis (CF) is a common, life-threatening, multisystemic, autosomal recessive disorder. In the last few years, giant steps have been made with regard to the understanding of CF pathophysiology, allowing the scientific community to propose mechanisms that cause the myriad of CF clinical manifestations. Following the discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in 1989, the structure and function of the CFTR protein were described. Since then, more than 2,000 variants of the CFTR gene and their impact on the amount and function of the CFTR protein have been reported. The role of the CFTR protein as an ion channel transporting chloride and bicarbonate and its repercussions on different epithelial cell-lined organs and mucus are now better understood. Mechanisms behind susceptibility to infection in CF have also been proposed and include abnormalities in the composition, volume and acidity of the airway surface liquid, changes in the submucosal gland's anatomy and function, and deficiencies in the mucociliary clearance system. Numerous hypotheses explaining the excessive inflammatory response in CF are also debated and involve impaired mucociliary clearance, persistent hypoxia, lipid abnormalities, protease and antiprotease disproportion, and oxidant and antioxidant imbalance. The purpose of this review is to summarize our current knowledge of CF pathophysiology, including significant historic discoveries and most recent breakthroughs, and to improve understanding and awareness of this fatal disease.

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An Improved Inhaled Mucolytic to Treat Airway Muco-obstructive Diseases

Abstract: These results suggest that reducing the viscoelasticity of airway mucus is an achievable therapeutic goal with P-3001 class mucolytic agents.

Cited by 92 publications

References 26 publications

Mucins: the frontline defence of the lung

Mucins: the frontline defence of the lung

The Potential Role and Regulatory Mechanisms of MUC5AC in Chronic Obstructive Pulmonary Disease

Cystic Fibrosis: Pathophysiology of Lung Disease

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