Article
Pharmacology & Pharmacy
Melania Giorgetti, Nikolai Klymiuk, Andrea Baehr, Martin Hemmerling, Lisa Jinton, Robert Tarran, Anna Malmgren, Annika Astrand, Gunnar C. Hansson, Anna Ermund
Summary: Cystic fibrosis is a recessive genetic disease characterized by mucus accumulation in the airways and intestines. Research suggests that ENaC inhibitors can alleviate mucus in CF patients, indicating that drug design should focus on NHE rather than ENaC inhibition.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2021)
Article
Cell Biology
Rosy Ghanem, Philippe Roquefort, Sophie Ramel, Veronique Laurent, Tanguy Haute, Tony Le Gall, Thierry Aubry, Tristan Montier
Summary: The mucus in CF patients' airways is a yield stress fluid with unique rheological properties. Rheological analyses can provide biophysical markers for disease management. Treatment with rhDNAse appears to lower the apparent yield stress of CF sputum, which could be a predictive biomarker for prognosis and aid in the development of new mucolytic agents.
Review
Medicine, General & Internal
Kak-Ming Ling, Stephen Michael Stick, Anthony Kicic
Summary: For individuals with cystic fibrosis (CF), hyper-concentrated mucus provides an ideal environment for bacterial colonization and chronic infection. Antibiotic treatment initially limits bacterial pathogens but leads to resistance and long-term consequences. Bacteriophage therapy is a potential alternative, but its effectiveness and dynamics with mucus in respiratory infections are poorly understood. This review examines CF-related lung diseases, the impact of CF mucus, and the therapeutic potential of phage, as well as the interaction between phage and mucus in CF.
FRONTIERS IN MEDICINE
(2023)
Article
Pharmacology & Pharmacy
Lena Wucherpfennig, Felix Wuennemann, Monika Eichinger, Angelika Seitz, Ingo Baumann, Mirjam Stahl, Simon Y. Graeber, Shengkai Zhao, Jaehi Chung, Jens-Peter Schenk, Abdulsattar Alrajab, Hans-Ulrich Kauczor, Marcus A. Mall, Olaf Sommerburg, Mark O. Wielpuetz
Summary: Chronic rhinosinusitis (CRS) in cystic fibrosis (CF) can cause nasal congestion, rhinorrhea, and anosmia, affecting the quality of life. Previous studies using MRI showed early onset and progression of CRS in CF patients from infancy to school age, as well as mid-term improvements in preschool and school-age CF children with lumacaftor/ivacaftor treatment. However, there is a lack of long-term data on the treatment effects on paranasal sinus abnormalities in CF children.
FRONTIERS IN PHARMACOLOGY
(2023)
Review
Pharmacology & Pharmacy
Rosy Ghanem, Veronique Laurent, Philippe Roquefort, Tanguy Haute, Sophie Ramel, Tony Le Gall, Thierry Aubry, Tristan Montier
Summary: The respiratory epithelium is susceptible to diseases like cystic fibrosis, which impact airway function. Artificial mucus models play a crucial role in evaluating gene transfer systems' effectiveness in reaching the epithelium.
Article
Multidisciplinary Sciences
Maria Pino-Argumedo, Anthony J. Fischer, Brieanna M. Hilkin, Nicholas D. Gansemer, Patrick D. Allen, Eric A. Hoffman, David A. Stoltz, Michael J. Welsh, Mahmoud H. Abou Alaiwa
Summary: Defective mucociliary transport in cystic fibrosis (CF) lungs is caused by abnormally elastic mucus strands that impair clearance. Breaking these mucus strands can improve mucociliary clearance in CF.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Multidisciplinary Sciences
Wenjie Yu, Thomas O. Moninger, Andrew L. Thurman, Yuliang Xie, Akansha Jain, Keyan Zarei, Linda S. Powers, Alejandro A. Pezzulo, David A. Stoltz, Michael J. Welsh
Summary: Submucosal glands (SMGs) play a crucial role in protecting the lungs but can also contribute to disease. In cystic fibrosis (CF), SMGs produce abnormal mucus that disrupts mucociliary transport. This study used single-cell RNA sequencing, immunohistochemistry, and in situ hybridization to investigate the expression and distribution of ion transporters and cell types in SMGs. The results suggest that loss of epithelial anion secretion, rather than intrinsic cell defects, causes CF mucus abnormalities. The study also revealed different functions of acinar mucous cells and acinar serous cells in producing mucins and antimicrobials, respectively.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Immunology
Yun Mao, Sonika Patial, Yogesh Saini
Summary: This study investigated the role of airway epithelium-specific HMGB1 in the pathogenesis of muco-obstructive lung disease in Tg+ mice. The deficiency of HMGB1 in airway epithelial cells in Tg+ mice resulted in increased inflammation and impaired bacterial clearance.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Respiratory System
Ana M. Rodriguez-Pineiro, Florian Jaudas, Nikolai Klymiuk, Andrea Baehr, Gunnar C. Hansson, Anna Ermund
Summary: Proteins in the airway surface liquid and mucus fraction separate into distinct clusters, with increased levels of MUC5AC and MUC5B after carbachol stimulation. In newborn CF piglets, an additional cluster containing acute phase proteins suggests early inflammatory response or altered lung development. Treatment for CF airway disease should start immediately after diagnosis.
RESPIRATORY RESEARCH
(2023)
Article
Medicine, General & Internal
Nauman Chaudary, Gabriella Balasa
Summary: Cystic fibrosis is a genetic disease characterized by accumulation of mucus leading to airway obstruction and respiratory infections. Effective care for CF patients requires knowledge of treatment options such as airway clearance therapy and ability to adapt to changing patient treatments. Training programs often do not provide sufficient knowledge of ACT technologies for CF patients, resulting in knowledge gaps for practicing physicians.
INTERNATIONAL JOURNAL OF GENERAL MEDICINE
(2021)
Review
Biochemistry & Molecular Biology
Caitlyn Harvey, Sinead Weldon, Stuart Elborn, Damian G. Downey, Clifford Taggart
Summary: The advent of CFTR modulators in cystic fibrosis treatment has transformed the management of the disease, shifting it from being a life-limiting condition to one that can be effectively managed. These genotype-specific therapies have shown significant improvements in various clinical endpoints, but their effects on pathogenic burden and airway infection need further exploration.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Bethany D. Batson, Bryan T. Zorn, Giorgia Radicioni, Stephanie S. Livengood, Tadahiro Kumagai, Hong Dang, Agathe Ceppe, Phillip W. Clapp, Michael Tunney, J. Stuart Elborn, Noel G. McElvaney, Marianne S. Muhlebach, Richard C. Boucher, Michael Tiemeyer, Matthew C. Wolfgang, Mehmet Kesimer
Summary: The study investigates the effect of CF airway environment on mucin quantity and quality, and the correlation between mucin parameters and microbiome and clinical data. The results show elevated concentrations of MUC5AC and MUC5B in CF compared to healthy subjects, and mucin parameters correlate with age and neutrophil elastase activity. The findings suggest the interaction of mucins, pathogens, epithelium, and inflammatory cells leads to proteomic and glycomic changes, reflecting a persistent mucoobstructive, infectious, and inflammatory state.
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
(2022)
Article
Respiratory System
Nicole Filipow, Sanja Stanojevic, Emma Raywood, Harriet Shannon, Gizem Tanriver, Kunal Kapoor, Helen Douglas, Gwyneth Davies, Rachel O'Connor, Nicky Murray, Eleanor Main
Summary: This study aimed to evaluate the associations between the quality and quantity of airway clearance techniques (ACTs) and lung function in children and young people with cystic fibrosis (CF). The results showed that conformant ACTs had a positive effect on lung function, while most people use techniques that do not improve lung function. Further efforts are needed to monitor and improve the quality of ACTs and increase the proportion of effective airway clearance at home.
EUROPEAN RESPIRATORY JOURNAL
(2023)
Review
Biochemistry & Molecular Biology
Carla M. P. Ribeiro, Matthew G. Higgs, Marianne S. Muhlebach, Matthew C. Wolfgang, Monica Borgatti, Ilaria Lampronti, Giulio Cabrini
Summary: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have provided a significant therapeutic advantage for people with cystic fibrosis (pwCF). However, these modulators face limitations in reducing chronic lung bacterial infection and inflammation, which are the main causes of respiratory damage and insufficiency in pwCF, especially in adults. This article revisits the debated issues of pulmonary bacterial infection and inflammatory processes in pwCF, highlighting the mechanisms favoring bacterial infection, the interplay between Pseudomonas aeruginosa and Staphylococcus aureus, and the cross-talk among bacteria, bronchial epithelial cells, and host immune defenses. The recent findings on the effect of CFTR modulators on bacterial infection and inflammation are also presented to identify potential therapeutic targets for respiratory pathology in pwCF.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Nanoscience & Nanotechnology
Gemma Conte, Gabriella Costabile, Domizia Baldassi, Valeria Rondelli, Rosaria Bassi, Diego Colombo, Giulia Linardos, Ersilia Fiscarelli, Raffaella Sorrentino, Agnese Miro, Fabiana Quaglia, Paola Brocca, Ivana D'Angelo, Olivia M. Merkel, Francesca Ungaro
Summary: Inhaled siRNA therapy shows potential for treating severe lung diseases. This study demonstrates the use of lipid-polymer hybrid nanoparticles (hNPs) to enhance siRNA gene silencing in the airway epithelium and investigates the impact of PEGylation. The results suggest that non-PEGylated hNPs can overcome mucus and cellular barriers, making them a potential carrier for treating CF lung disease.
ACS APPLIED MATERIALS & INTERFACES
(2022)
Article
Immunology
Alaullah Sheikh, Tamding Wangdi, Tim J. Vickers, Bailey Aaron, Margot Palmer, Mark J. Miller, Seonyoung Kim, Cassandra Herring, Rita Simoes, Jennifer A. Crainic, Jeffrey C. Gildersleeve, Sjoerd van der Post, Gunnar C. Hansson, James M. Fleckenstein
Summary: Enterotoxigenic Escherichia coli (ETEC) strains produce heat-labile and/or heat-stable toxins. Recent studies have found a significant association between strains that produce EatA protein and symptomatic infection. The heat-labile toxin enhances the protective barrier, while EatA degrades the mucin barrier to promote bacterial access to host cells and toxin delivery.
INFECTION AND IMMUNITY
(2022)
Article
Multidisciplinary Sciences
Jack D. A. Sharpen, Brendan Dolan, Elisabeth E. L. Nystrom, George M. H. Birchenough, Liisa Arike, Beatriz Martinez-Abad, Malin E. Johansson, Gunnar C. Hansson, Christian Recktenwald
Summary: This study demonstrates the importance of transglutaminase 3 activity in maintaining the stability of the colonic mucus layer. Lack of this enzymatic activity increases susceptibility to DSS-induced colitis in mice.
NATURE COMMUNICATIONS
(2022)
Article
Critical Care Medicine
Oanh N. Hoang, Anna Ermund, Ana M. Jaramillo, Dalia Fakih, Cory B. French, Jose R. Flores, Harry Karmouty-Quintana, Jesper M. Magnusson, Giorgio Fois, Michael Fauler, Manfred Frick, Peter Braubach, Joshua B. Hales, Richard C. Kurten, Reynold Panettieri, Leoncio Vergara, Camille Ehre, Roberto Adachi, Michael J. Tuvim, Gunnar C. Hansson, Burton F. Dickey
Summary: MUC5AC and MUC5B can be packaged within individual secretory granules in both mice and humans, either together or separately. This study provides important insights into the pathogenesis of chronic lung diseases.
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
(2022)
Review
Respiratory System
Camille Ehre, Gunnar C. Hansson, David J. Thornton, Lynda S. Ostedgaard
Summary: Cystic fibrosis (CF) is a genetic disorder caused by dysfunction of the CFTR protein, leading to mucus accumulation in the lungs, intestines, and pancreatic ducts. This review article discusses recent progress in understanding CFTR expression in different airway regions and cells, as well as the production and clearance of mucus from the lungs. Animal models are also explored for insights into the organization of the mucin network and the protective role of mucus and antimicrobial activities against invading pathogens.
JOURNAL OF CYSTIC FIBROSIS
(2023)
Article
Biochemistry & Molecular Biology
Brendan Dolan, Anna Ermund, Beatriz Martinez-Abad, Malin E. Johansson, Gunnar C. Hansson
Summary: This study found that cholinergic stimulation can coordinate and rapidly eliminate bacteria from the small intestinal crypt through the activation of muscarinic acetylcholine receptors. Cholinergic stimulation induces the expansion and intracellular rupture of mucin granules, leading to the secretion of expanding mucus. Mucus secretion and expansion rely on calcium signaling, gap junctions, and ion and water transport by neighboring enterocytes.
Editorial Material
Biochemistry & Molecular Biology
Gunnar C. Hansson
Summary: This study identifies QSOX1 as a novel regulator of mucus by controlling mucin sialylation, which is important for the balance of mucus and bacteria.
Article
Cell Biology
George M. H. Birchenough, Bjoern O. Schroeder, Sinan Sharba, Liisa Arike, Christian V. Recktenwald, Fabiola Puertolas-Balint, Mahadevan V. Subramani, Karl T. Hansson, Bahtiyar Yilmaz, Sara K. Linden, Fredrik Backhed, Gunnar C. Hansson
Summary: Intestinal mucus barriers are important for preventing microbial infections but can be disrupted by a Western-style diet, leading to susceptibility to pathogen colonization.
Article
Multidisciplinary Sciences
Pablo Gallego, Maria-Jose Garcia-Bonete, Sergio Trillo-Muyo, Christian V. Recktenwald, Malin E. V. Johansson, Gunnar C. Hansson
Summary: The MUC2 mucin is crucial for building the intestinal mucus layers that separate the intestinal microbiota from the host epithelium. Researchers have generated a structural model of MUC2-C, which reveals its different domains and an additional disulfide bond at the N-terminal, essential for a stable mucus barrier.
NATURE COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Cynthia Buelck, Elisabeth E. L. Nystroem, Tomas Koudelka, Michael Mannbar-Frahm, Gerrit Andresen, Mariem Radhouani, Florian Tran, Franka Scharfenberg, Friederike Schrell, Fred Armbrust, Eileen Dahlke, Bei Zhao, Alex Vervaeke, Franziska Theilig, Philip Rosenstiel, Philipp Starkl, Stephan P. Rosshart, Helmut Fickenscher, Andreas Tholey, Gunnar C. Hansson, Christoph Becker-Pauly
Summary: The metalloproteases meprin alpha and meprin beta are highly expressed in the healthy gut but significantly decreased in inflammatory bowel disease. They form covalently linked heterodimers in the colon, and the major intestinal substrate for these heterodimers is galectin-3. The cleavage of galectin-3 by meprin alpha/beta heterodimers may play a key role in colon host-microbiome homeostasis.
Article
Multidisciplinary Sciences
Michael Stirm, Bachuki Shashikadze, Andreas Blutke, Elisabeth Kemter, Andreas Lange, Jan B. Stoeckl, Florian Jaudas, Laeticia Laane, Mayuko Kurome, Barbara Kessler, Valeri Zakhartchenko, Andrea Baehr, Nikolai Klymiuk, Hiroshi Nagashima, Maggie C. Walter, Wolfgang Wurst, Christian Kupatt, Thomas Froehlich, Eckhard Wolf
Summary: Skipping DMD exon 51 can restore dystrophin expression and improve cardiac function in DMD patients and animal models.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Medicine, Research & Experimental
Anastasia Milusev, Jianfang Ren, Alain Despont, Jane Shaw, Matthias Laengin, Martin Bender, Jan-Michael Abicht, Maren Mokelke, Julia Radan, Elisabeth Neumann, Elisabeth Kemter, Nikolai Klymiuk, David Ayares, Eckhard Wolf, Bruno Reichart, Nicoletta Sorvillo, Robert Rieben
Summary: Xenotransplantation is a promising solution to organ shortage, and genetic modification of donor pigs has reduced the immunogenic burden. However, organ rejection remains a challenge. This study investigated the dynamics of the glycocalyx, a sugar-rich surface on endothelial cells, in genetically modified porcine arterial and venous cells after activation. The results showed that arterial cells, as well as venous cells, did not shed the glycocalyx after activation, and this was associated with reduced complement deposition. However, simultaneous perfusion with human serum and TNF? resulted in glycocalyx shedding and increased complement deposition, suggesting a proinflammatory phenotype in genetically modified endothelial cells in an inflammatory xenotransplantation setting.
XENOTRANSPLANTATION
(2023)
Article
Multidisciplinary Sciences
Henriette Arnesen, Turhan Markussen, George Birchenough, Signe Birkeland, Elisabeth E. L. Nystroem, Gunnar C. Hansson, Harald Carlsen, Preben Boysen
Summary: By raising laboratory mice in a farmyard-type environment, the intestinal barrier properties can be altered, leading to a stronger protection against disease.
SCIENTIFIC REPORTS
(2023)
Article
Respiratory System
Ana M. Rodriguez-Pineiro, Florian Jaudas, Nikolai Klymiuk, Andrea Baehr, Gunnar C. Hansson, Anna Ermund
Summary: Proteins in the airway surface liquid and mucus fraction separate into distinct clusters, with increased levels of MUC5AC and MUC5B after carbachol stimulation. In newborn CF piglets, an additional cluster containing acute phase proteins suggests early inflammatory response or altered lung development. Treatment for CF airway disease should start immediately after diagnosis.
RESPIRATORY RESEARCH
(2023)
Article
Cell & Tissue Engineering
Kazutoshi Okamoto, Hitomi Matsunari, Kazuaki Nakano, Kazuhiro Umeyama, Koki Hasegawa, Ayuko Uchikura, Shuko Takayanagi, Masahito Watanabe, Jun Ohgane, Michael Stirm, Mayuko Kurome, Nikolai Klymiuk, Masaki Nagaya, Eckhard Wolf, Hiroshi Nagashima
Summary: This study demonstrated that DMD-XKOXWT pigs could serve as a suitable large animal model for understanding the pathogenic mechanism in DMD carriers and developing therapies for female DMD carriers.
REGENERATIVE THERAPY
(2023)