Review
Biochemistry & Molecular Biology
Laura Carrasco-Hernandez, Esther Quintana-Gallego, Carmen Calero, Rocio Reinoso-Arija, Borja Ruiz-Duque, Jose Luis Lopez-Campos
Summary: The role of CFTR in the pathophysiology of COPD is becoming increasingly important, with its dysfunction leading to thicker and more viscous secretions in the airway, reduced mucociliary clearance, and promotion of airway inflammation. Studying CFTR in the context of COPD pathogenesis is crucial for a comprehensive understanding of COPD's complex pathophysiology and exploring potential therapeutic approaches to address this dysfunction.
Review
Biochemistry & Molecular Biology
Evelina Moliteo, Monica Sciacca, Antonino Palmeri, Maria Papale, Sara Manti, Giuseppe Fabio Parisi, Salvatore Leonardi
Summary: There is substantial evidence that patients with cystic fibrosis (CF) have higher oxidative stress levels, which contribute to the progression of chronic lung damage. CF patients exhibit an abnormal proinflammatory environment in their airways even before infection, possibly due to elevated oxidative stress and abnormal lipid metabolism. CFTR deficiency appears to cause a redox imbalance in epithelial cells and extracellular fluids.
Article
Pediatrics
Qiyu Li, Siyuan Liu, Xuemei Ma, Jiaping Yu
Summary: This meta-analysis evaluated the effectiveness and safety of small molecule therapy in children diagnosed with cystic fibrosis (CF). The results showed that CFTR modulators can improve respiratory function, lung clearance index, sweat chloride concentration, and other aspects of function in children with CF, with comparable adverse events compared to the placebo group.
FRONTIERS IN PEDIATRICS
(2022)
Review
Pharmacology & Pharmacy
Yizi Wang, Bin Ma, Wenya Li, Peiwen Li
Summary: Triple combination therapy for cystic fibrosis patients achieves better clinical results and comparable adverse events compared to the control group.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Pharmacology & Pharmacy
Jia Liu, Allison P. Berg, Yiting Wang, Walailak Jantarajit, Katy J. Sutcliffe, Edward B. Stevens, Lishuang Cao, Marko J. Pregel, David N. Sheppard
Summary: This study investigates the action of a new CFTR potentiator, CP-628006, and compares it with the marketed CFTR potentiator ivacaftor. CP-628006 has distinct effects compared to ivacaftor, suggesting a different mechanism of CFTR potentiation. The emergence of CFTR potentiators with diverse modes of action makes therapy with combinations of potentiators a possibility.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Article
Medicine, Research & Experimental
Michael D. Kim, Charles D. Bengtson, Makoto Yoshida, Asef J. Niloy, John S. Dennis, Nathalie Baumlin, Matthias Salathe
Summary: Highly effective modulator therapies greatly improve prognosis for cystic fibrosis patients. However, not all patients with the most common F508del mutation in CFTR benefit from ETI therapy. The study found that elevated levels of active TGF-??1 in the upper airway were associated with poor response to ETI, as evidenced by low sweat chloride concentrations and lack of lung function improvements. TGF-??1 impaired the function of corrected F508del-CFTR and led to increased absorption rates of airway surface liquid and mucus hyperconcentration in vitro. Losartan reversed the negative effects of TGF-??1 and improved ASL hydration in CF airway epithelium.
JOURNAL OF CLINICAL INVESTIGATION
(2022)
Article
Chemistry, Medicinal
Marc J. C. Scanio, Xenia B. Searle, Bo Liu, John R. Koenig, Robert J. Altenbach, Gregory A. Gfesser, Andrew Bogdan, Stephen Greszler, Gang Zhao, Ashvani Singh, Yihong Fan, Andrew M. Swensen, Timothy Vortherms, Arlene Manelli, Corina Balut, Wenqing Gao, Hong Yong, Michael Schrimpf, Chris Tse, Philip Kym, Xueqing Wang
Summary: Cystic fibrosis (CF) is a disease caused by mutations in both copies of the CFTR gene, with the most common mutation being the deletion of phenylalanine at position 508 of the CFTR protein. The most effective treatment for CF currently involves using a combination of CFTR correctors and potentiators. This study focuses on the identification and exploration of the structure-activity relationship of C2 correctors for CFTR, to be used in conjunction with existing C1 correctors.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Medicine, General & Internal
Lotte Vanherle, Darcy Lidington, Franziska E. Uhl, Saskia Steiner, Stefania Vassallo, Cecilia Skoug, Joao M. N. Duarte, Sangeetha Ramu, Lena Uller, Jean-Francois Desjardins, Kim A. Connelly, Steffen-Sebastian Bolz, Anja Meissner
Summary: Our study investigated the mechanisms that alter hippocampal neurons following myocardial infarction (MI) and explored the therapeutic potential of correcting cystic fibrosis transmembrane regulator (CFTR) as an intervention. We found that MI leads to reduced hippocampal dendrite length and spine density, which is associated with decreased neuronal CFTR expression and inflammatory responses. Blocking CFTR activity down-regulates synaptic regulator PSD-95 expression in neurons, while pharmacologically correcting CFTR expression rescues the down-regulation. Increasing hippocampal neuron CFTR expression improves MI-associated alterations in neuronal structure and memory function. These findings suggest that CFTR therapeutics can attenuate cognitive impairment in heart failure patients.
Article
Biochemistry & Molecular Biology
Ho K. Lee, Jinhong Park, Bo-Rahm Kim, Ikhyun Jun, Tae-im Kim, Wan Namkung
Summary: The study identified isorhamnetin as a novel CFTR activator for treating dry eye disease, which increased tear volume and reduced ocular surface damage and inflammatory cytokine expression in an experimental mouse model of dry eye. The findings suggest that isorhamnetin could be a potential therapeutic agent for dry eye disease.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Critical Care Medicine
Pierre-Regis Burgel, Isabelle Durieu, Raphael Chiron, Sophie Ramel, Isabelle Danner-Boucher, Anne Prevotat, Dominique Grenet, Christophe Marguet, Martine Reynaud-Gaubert, Julie Macey, Laurent Mely, Annlyse Fenton, Sebastien Quetant, Lydie Lemonnier, Jean-Louis Paillasseur, Jennifer Da Silva, Clemence Martin
Summary: An observational study in France found that the use of elexacaftor-tezacaftor-ivacaftor in CF patients led to significant improvements in lung function and weight within a short period of time, with most patients no longer requiring long-term oxygen, noninvasive ventilation, and/or enteral tube feeding. Compared to the previous two years, there was a twofold decrease in the number of lung transplantations in CF patients in 2020.
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
(2021)
Article
Respiratory System
Helene Le Ribeuz, Lucie To, Maria-Rosa Ghigna, Clemence Martin, Chandran Nagaraj, Elise Dreano, Catherine Rucker-Martin, Barbara Girerd, Jerome Bouligand, Christine Pechoux, Melanie Lambert, Angele Boet, Justin Issard, Olaf Mercier, Konrad Hoetzenecker, Boris Manoury, Frederic Becq, Pierre-Regis Burgel, Charles-Henry Cottart, Andrea Olschewski, Isabelle Sermet-Gaudelus, Frederic Perros, Marc Humbert, David Montani, Fabrice Antigny
Summary: Reduced CFTR expression in pulmonary arteries and CFTR inhibition lead to vascular cell proliferation and decreased pulmonary artery relaxation in both human and animal models of PH. This highlights the important role of CFTR in the pathogenesis of PAH.
EUROPEAN RESPIRATORY JOURNAL
(2021)
Article
Respiratory System
Kevin P. Sheahan, Alexander O'Mahony, David Morrissy, Hisham Ibrahim, Claire Crowley, Michael G. Waldron, Darek Sokol-Randell, Aisling McMahon, Michael M. Maher, Owen J. O'Connor, Barry J. Plant
Summary: This study aimed to assess and quantify the cumulative effective dose (CED) in patients with cystic fibrosis (PWCF) in the context of CFTR-modulator therapy and dose reduction techniques. The results showed an increasing utilization of chest CT in PWCF and a reduction in mean annual CED, primarily due to CT dose reduction strategies.
JOURNAL OF CYSTIC FIBROSIS
(2023)
Article
Biochemistry & Molecular Biology
Chiara Brandas, Alessandra Ludovico, Alice Parodi, Oscar Moran, Enrico Millo, Elena Cichero, Debora Baroni
Summary: Cystic fibrosis is caused by loss-of-function mutations in the CFTR protein, with F508del being the most common mutation. Small molecules called correctors have been developed to rescue defective F508del CFTR, showing better results when used in combinations. Targeting different structural and functional defects of mutant CFTR with corrector combinations appears to be the most promising therapeutic approach for a larger cohort of CF patients.
Article
Biochemistry & Molecular Biology
Kavisha Arora, Pramodha Liyanage, Qing Zhong, Anjaparavanda P. Naren
Summary: The study reveals that under nutritional stress and bacterial infection, the autophagic SNARE protein syntaxin17 (Stx17) interacts with CFTR to facilitate efficient lysosomal clearance, playing a critical role in preventing defective autophagy.
Article
Medicine, Research & Experimental
Jie Xu, Alessandra Livraghi-Butrico, Xia Hou, Carthic Rajagopalan, Jifeng Zhang, Jun Song, Hong Jiang, Hong-Guang Wei, Hui Wang, Mohamad Bouhamdan, Jinxue Ruan, Dongshan Yang, Yining Qiu, Youming Xie, Ronald Barrett, Sharon McClellan, Hongmei Mou, Qingtian Wu, Xuequn Chen, Troy D. Rogers, Kristen J. Wilkinson, Rodney C. Gilmore, Charles R. Esther, Khalequz Zaman, Xiubin Liang, Michael Sobolic, Linda Hazlett, Kezhong Zhang, Raymond A. Frizzell, Martina Gentzsch, Wanda K. O'Neal, Barbara R. Grubb, Y. Eugene Chen, Richard C. Boucher, Fei Sun
Summary: The CF rabbit model generated through CRISPR/Cas9 technology provides insights into CF pathogenesis and potential therapeutic development, with long lifespan and cost-effective maintenance. The CF rabbits exhibited characteristics similar to human CF, showing abnormalities in nasal and tracheal epithelial properties, as well as surrogate markers of exocrine pancreas disorders. The model could be valuable for studying gut and lung CF pathogenesis.
Article
Biotechnology & Applied Microbiology
Chiara De Santi, Elena Fernandez Fernandez, Rachel Gau, Sebastian Vencken, Arlene Glasgow, Irene K. Oglesby, Killian Hurley, Finn Hawkins, Nilay Mitash, Fangping Mu, Rana Raoof, David C. Henshall, Meritxell B. Cutrona, Jeremy C. Simpson, Brian J. Harvey, Barry Linnane, Paul McNally, Sally Ann Cryan, Ronan MacLoughlin, Agnieszka Swiatecka-Urban, Catherine M. Greene
Letter
Respiratory System
Laura Gribaldo, Killian Hurley, Pieter Hiemstra, Catherine Greene
EUROPEAN RESPIRATORY JOURNAL
(2021)
Editorial Material
Biochemistry & Molecular Biology
Chiara De Santi, Catherine M. Greene
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
(2021)
Article
Infectious Diseases
Elena Fernandez Fernandez, Mary Joyce, Andrew O'Sullivan, Ronan MacLoughlin
Summary: The study investigated the variability of aerosolized dose delivery in CF patients receiving aerosol therapy under different clinical interventions and treatment environments. It was found that vibrating mesh nebulizers delivered significantly more medication compared to jet nebulizers in both home and hospital settings. These findings will be crucial for the development of effective aerosol therapy strategies and new treatments for CF and other respiratory diseases.
Article
Critical Care Medicine
Davies Adeloye, Omer Elneima, Luke Daines, Krisnah Poinasamy, Jennifer K. Quint, Samantha Walker, Chris E. Brightling, Salman Siddiqui, John R. Hurst, James D. Chalmers, Paul E. Pfeffer, Petr Novotny, Thomas M. Drake, Liam G. Heaney, Igor Rudan, Aziz Sheikh, Anthony De Soyza
Summary: An international consensus exercise was conducted to identify research priorities for understanding the long-term effects of acute COVID-19, focusing on individuals with pre-existing airways disease. High priority was given to investigations on prognostic scores at hospital admission and morbidity at 3 months and 12 months after hospital discharge, as well as comparisons of prevalence and severity of post-COVID-19 symptoms between patients with and without pre-existing airways disease.
LANCET RESPIRATORY MEDICINE
(2021)
Editorial Material
Genetics & Heredity
Arlene M. A. Glasgow, Catherine M. Greene
Article
Public, Environmental & Occupational Health
Davies Adeloye, Dhiraj Agarwal, Peter J. Barnes, Marcel Bonay, Job F. van Boven, Jamie Bryant, Gaetano Caramori, David Dockrell, Anthony D'Urzo, Magnus Ekstrom, Gregory Erhabor, Cristobal Esteban, Catherine M. Greene, John Hurst, Sanjay Juvekar, Ee Ming Khoo, Fanny W. Ko, Brian Lipworth, Jose L. Lopez-Campos, Matthew Maddocks, David M. Mannino, Fernando J. Martinez, Miguel A. Martinez-Garcia, Renae J. McNamara, Marc Miravitlles, Hilary Pinnock, Alison Pooler, Jennifer K. Quint, Peter Schwarz, George M. Slavich, Peige Song, Andrew Tai, Henrik Watz, Jadwiga A. Wedzicha, Michelle C. Williams, Harry Campbell, Aziz Sheikh, Igor Rudan
Summary: The global prevalence of COPD has been increasing, emphasizing the need for defining research priorities in respiratory medicine. Through the CHNRI methodology, new effective strategies for smoking cessation and feasible pulmonary rehabilitation delivery were identified as key research priorities. Additional priorities include improved screening and accurate diagnosis methods for COPD in low-resource settings.
JOURNAL OF GLOBAL HEALTH
(2021)
Article
Genetics & Heredity
Paul J. McKiernan, Kevin P. Molloy, Arlene M. A. Glasgow, Noel G. McElvaney, Catherine M. Greene
Summary: The altered expression patterns of X-linked microRNAs in peripheral blood monocytes of cystic fibrosis patients may be correlated with exacerbation rate and lung function, particularly with miR-545-5p and miR-224-5p levels.
FRONTIERS IN GENETICS
(2021)
Review
Respiratory System
Arlene M. A. Glasgow, Catherine M. Greene
Summary: This review discusses how various host and microbial factors can contribute to airway epithelium dysfunction in the CF lung, focusing on mechanisms related to the mucociliary escalator and protease expression and function. It also explores how alterations in microRNA expression can impact the behavior of the airway epithelium.
EXPERT REVIEW OF RESPIRATORY MEDICINE
(2022)
Review
Biochemistry & Molecular Biology
Mari Ozaki, Arlene Glasgow, Irene K. Oglesby, Wan Lin Ng, Sile Kelly, Catherine M. Greene, Laura Durcan, Killian Hurley
Summary: Interstitial lung diseases (ILD) are heterogeneous progressive pulmonary disorders characterized by tissue remodeling and/or fibrotic scarring of the lung parenchyma. Men are more prone to idiopathic pulmonary fibrosis (IPF), while women are more affected by systemic or connective tissue diseases (CTD). The mechanisms underlying the sex differences in these diseases remain unclear, but environmental exposures, gene expression, and sex hormones may play a role. This article outlines the sex-related differences in incidence, progression, and mechanisms of ILD, and highlights the lack of consideration for gender differences in clinical models and underrepresentation of women in clinical trials.
Article
Biochemistry & Molecular Biology
Stephen G. J. Smith, Catherine M. Greene
Summary: This study investigates the expression of long non-coding RNAs (lncRNAs) in alpha-1 antitrypsin (AAT) deficiency and explores the effect of AAT augmentation therapy on the lncRNA expression profile in ZZ monocytes. Results show that AAT augmentation therapy alters the expression of numerous lncRNAs in ZZ monocytes, and many of these changes are consistent with the effects observed in ZZ monocytes treated ex vivo with AAT. These findings provide insights into the potential mechanisms underlying the diverse effects of AAT augmentation therapy.
Article
Chemistry, Multidisciplinary
Paula Dominguez-Molano, Rosemary Weeks, Ricardo J. Maza, Jorge J. Carbo, Elena Fernandez
Summary: Regioselective borylcupration of borylated skipped (Z)-dienes generates diborylated alkylcopper species that undergo intramolecular stereospecific B/Cu1,3-rearrangement by migration of Bpin moiety from C(sp(2)) to C(sp(3)). DFT mechanistic studies reveal that boryl migration occurs through the formation of a 4-membered boracycle intermediate with a moderate free-energy barrier. Additionally, the use of KOMe forms stable Lewis base adducts with Bpin moieties, blocking the reaction. Following the 1,3-boron shift, in situ electrophilic trapping enables selective C-H, C-C, and C-X bond formations, leading to cyclic functionalized alkylidenecyclohexanes or alkylidenecyclobutanes.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Review
Respiratory System
James D. Chalmers, Stuart Elborn, Catherine M. Greene
Summary: Bronchiectasis is a respiratory disease characterized by radiological abnormalities and a clinical syndrome of cough, sputum production, and recurrent respiratory infections. Inflammation, particularly neutrophilic inflammation, plays a central role in bronchiectasis pathophysiology. This article discusses the roles of infection, inflammation, and mucociliary clearance dysfunction in the development and progression of bronchiectasis. It also explores the concept of inflammatory endotypes and the potential of treating inflammation as a target. Current treatments for bronchiectasis focus on addressing underlying causes, improving mucociliary clearance, controlling infection, and managing complications. Additionally, the article discusses future therapies targeting host-mediated immune dysfunction.
EUROPEAN RESPIRATORY REVIEW
(2023)
Editorial Material
Genetics & Heredity
Catherine M. Greene
Meeting Abstract
Respiratory System
Irene Oglesby, Arlene Glasgow, Mari Ozaki, Catherine Greene, Killian Hurley
EUROPEAN RESPIRATORY JOURNAL
(2021)