A novel thiol-saccharide mucolytic for the treatment of muco-obstructive lung diseases

被引：24

作者：

Addante, Annalisa ^{[1
,2
,3
,4
]}

Raymond, Wilfred ^{[5
]}

Gitlin, Irina ^{[5
]}

Charbit, Annabelle ^{[5
]}

Orain, Xavier ^{[5
]}

Scheffler, Aaron Wolfe ^{[6
]}

Kuppe, Aditi ^{[1
,2
,3
,4
]}

Duerr, Julia ^{[1
,2
,3
,4
]}

Daniltchenko, Maria ^{[1
,2
,3
]}

Drescher, Marika ^{[1
,2
,3
]}

Graeber, Simon Y. ^{[2
,3
,4
,7
]}

Healy, Anne -Marie ^{[8
]}

Oscarson, Stefan ^{[1
,9
]}

Fahy, John V. ^{[5
,10
]}

Mall, Marcus A. ^{[1
,2
,3
,4
,7
]}

机构：

[1] Charite Univ Med Berlin, Dept Pediat Resp Med Immunol & Crit Care Med, Berlin, Germany

[2] Free Univ Berlin, Berlin, Germany

[3] Humboldt Univ, Berlin, Germany

[4] German Ctr Lung Res DZL Accoc Partner, Berlin, Germany

[5] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA USA

[6] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA USA

[7] Charite Univ Med Berlin, Berlin Inst Hlth BIH, Berlin, Germany

[8] Trinity Coll Dublin, Sch Pharm & Pharmaceut Sci, Dublin, Ireland

[9] Univ Coll Dublin, Ctr Synth & Chem Biol, Belfield, Ireland

[10] Univ Calif San Francisco, Div Pulm & Crit Care Med, San Francisco, CA USA

来源：

EUROPEAN RESPIRATORY JOURNAL | 2023年 / 61卷 / 05期

关键词：

CYSTIC-FIBROSIS; SURFACE DEHYDRATION; HYPERTONIC SALINE; AIRWAY MUCUS; INFLAMMATION; SPUTUM; EMPHYSEMA; MARKER; PLUGS; MICE;

D O I：

10.1183/13993003.02022-2022

中图分类号：

R56 [呼吸系及胸部疾病];

学科分类号：

摘要：

Background Mucin disulfide cross-links mediate pathologic mucus formation in muco-obstructive lung diseases. MUC-031, a novel thiol-modified carbohydrate compound, cleaves disulfides to cause mucolysis. The aim of this study was to determine the mucolytic and therapeutic effects of MUC-031 in sputum from patients with cystic fibrosis (CF) and mice with muco-obstructive lung disease (flENaC-Tg mice). Methods We compared the mucolytic efficacy of MUC-031 and existing mucolytics (N-acetylcysteine (NAC) and recombinant human deoxyribonuclease I (rhDNase)) using rheology to measure the elastic modulus (G & PRIME;) of CF sputum, and we tested effects of MUC-031 on airway mucus plugging, inflammation and survival in flENaC-Tg mice to determine its mucolytic efficacy in vivo. Results In CF sputum, compared to the effects of rhDNase and NAC, MUC-031 caused a larger decrease in sputum G & PRIME;, was faster in decreasing sputum G & PRIME; by 50% and caused mucolysis of a larger proportion of sputum samples within 15 min of drug addition. Compared to vehicle control, three treatments with MUC-031 in 1 day in adult flENaC-Tg mice decreased airway mucus content (16.8 & PLUSMN;3.2 versus 7.5 & PLUSMN;1.2 nL & BULL;mm-2, p<0.01) and bronchoalveolar lavage cells (73 833 & PLUSMN;6930 versus 47 679 & PLUSMN;7736 cells & BULL;mL-1, p<0.05). Twice-daily treatment with MUC-031 for 2 weeks also caused decreases in these outcomes in adult and neonatal flENaC-Tg mice and reduced mortality from 37% in vehicle-treated flENaC-Tg neonates to 21% in those treated with MUC-031 (p<0.05). Conclusion MUC-031 is a potent and fast-acting mucolytic that decreases airway mucus plugging, lessens airway inflammation and improves survival in flENaC-Tg mice. These data provide rationale for human trials of MUC-031 in muco-obstructive lung diseases.

引用

页数：15

共 44 条

[1] Mucolytics for COPD: negotiating a slippery slope towards proof of efficacy [J].

Aaron, Shawn D. .

EUROPEAN RESPIRATORY JOURNAL, 2017, 50 (04)

[2] N-Acetylcysteine as an antioxidant and disulphide breaking agent: the reasons why [J].

Aldini, Giancarlo ;

Altomare, Alessandra ;

Baron, Giovanna ;

Vistoli, Giulio ;

Carini, Marina ;

Borsani, Luisa ;

Sergio, Francesco .

FREE RADICAL RESEARCH, 2018, 52 (07) :751-762

[3] Effect of hypertonic saline on mucociliary clearance and clinical outcomes in chronic bronchitis [J].

Bennett, William D. ;

Henderson, Ashley G. ;

Ceppe, Agathe ;

Zeman, Kirby L. ;

Wu, Jihong ;

Gladman, Christine ;

Fuller, Fred ;

Gazda, Stephen ;

Button, Brian ;

Boucher, Richard C. ;

Donaldson, Scott H. .

ERJ OPEN RESEARCH, 2020, 6 (03)

[4] Muco-Obstructive Lung Diseases [J].

Boucher, Richard C. .

NEW ENGLAND JOURNAL OF MEDICINE, 2019, 380 (20) :1941-1953

[5] Lack of IL-1 Receptor Signaling Reduces Spontaneous Airway Eosinophilia in Juvenile Mice with Muco-Obstructive Lung Disease [J].

Brown, Ryan ;

Paulsen, Michelle ;

Schmidt, Simone ;

Schatterny, Jolanthe ;

Frank, Angela ;

Hirtz, Stephanie ;

Delaney, Rebecca ;

Doherty, Declan ;

Hagner, Matthias ;

Taggart, Cliff ;

Weldon, Sinead ;

Mall, Marcus A. .

AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 2020, 62 (03) :300-309

[6]

Department of Health and Human Services National Heart Lung and Blood Institute, TRANSL PROGR LUNG DI

[7] Mucus clearance and lung function in cystic fibrosis with hypertonic saline [J].

Donaldson, SH ;

Bennett, WD ;

Zeman, KL ;

Knowles, MR ;

Tarran, R ;

Boucher, RC .

NEW ENGLAND JOURNAL OF MEDICINE, 2006, 354 (03) :241-250

[8] Mucus Plugs and Emphysema in the Pathophysiology of Airflow Obstruction and Hypoxemia in Smokers [J].

Dunican, Eleanor M. ;

Elicker, Brett M. ;

Henry, Travis ;

Gierada, David S. ;

Schiebler, Mark L. ;

Anderson, Wayne ;

Barjaktarevic, Igor ;

Barr, R. Graham ;

Bleecker, Eugene R. ;

Boucher, Richard C. ;

Bowler, Russell ;

Christenson, Stephanie A. ;

Comellas, Alejandro ;

Cooper, Christopher B. ;

Couper, David ;

Criner, Gerard J. ;

Dransfield, Mark ;

Doerschuk, Claire M. ;

Drummond, M. Bradley ;

Hansel, Nadia N. ;

Han, MeiLan K. ;

Hastie, Annette T. ;

Hoffman, Eric A. ;

Krishnan, Jerry A. ;

Lazarus, Stephen C. ;

Martinez, Fernando J. ;

McCulloch, Charles E. ;

O'Neal, Wanda K. ;

Ortega, Victor E. ;

Paine, Robert ;

Peters, Stephen ;

Schroeder, Joyce D. ;

Woodruff, Prescott G. ;

Fahy, John, V .

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2021, 203 (08) :957-968

[9] Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction [J].

Dunican, Eleanor M. ;

Elicker, Brett M. ;

Gierada, David S. ;

Nagle, Scott K. ;

Schiebler, Mark L. ;

Newell, John D. ;

Raymond, Wilfred W. ;

Lachowicz-Scroggins, Marrah E. ;

Di Maio, Selena ;

Hoffman, Eric A. ;

Castro, Mario ;

Fain, Sean B. ;

Jarjour, Nizar N. ;

Israel, Elliot ;

Levy, Bruce D. ;

Erzurum, Serpil C. ;

Wenzel, Sally E. ;

Meyers, Deborah A. ;

Bleecker, Eugene R. ;

Phillips, Brenda R. ;

Mauger, David T. ;

Gordon, Erin D. ;

Woodruff, Prescott G. ;

Peters, Michael C. ;

Fahy, John V. .

JOURNAL OF CLINICAL INVESTIGATION, 2018, 128 (03) :997-1009

[10] An Improved Inhaled Mucolytic to Treat Airway Muco-obstructive Diseases [J].

Ehre, Camille ;

Rushton, Zachary L. ;

Wang, Boya ;

Hothem, Lauren N. ;

Morrison, Cameron B. ;

Fontana, Nicholas C. ;

Markovetz, Matthew R. ;

Delion, Martial F. ;

Kato, Takafumi ;

Villalon, Diane ;

Thelin, William R. ;

Esther, Charles R., Jr. ;

Hill, David B. ;

Grubb, Barbara R. ;

Livraghi-Butrico, Alessandra ;

Donaldson, Scott H. ;

Boucher, Richard C. .

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2019, 199 (02) :171-180

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