Article
Pharmacology & Pharmacy
Licia Totani, Concetta Amore, Antonio Piccoli, Giuseppe Dell'Elba, Angelo Di Santo, Roberto Plebani, Romina Pecce, Nicola Martelli, Alice Rossi, Serena Ranucci, Ida De Fino, Paolo Moretti, Alessandra Bragonzi, Mario Romano, Virgilio Evangelista
Summary: This study demonstrates that PDE4 inhibitors can control NETosis in CF-relevant models, showing efficacy in neutrophils from both healthy volunteers and CF patients. In a mouse model of chronic Pseudomonas aeruginosa infection, aerosol treatment with the selective PDE4 inhibitor roflumilast resulted in reduced free DNA in the BALF along with decreased citrullination of histone H3 in neutrophils in the airways.
FRONTIERS IN PHARMACOLOGY
(2021)
Review
Immunology
Samantha L. Tucker, Demba Sarr, Balazs Rada
Summary: Cystic Fibrosis is a genetic disease that causes chronic lung inflammation and infections, leading to high mortality rates. Immune system disruption in CF results in impaired immune responses, chronic infections with pathogens, and alterations in T cell and neutrophil functions. The role of P. aeruginosa and gMDSCs in T cell suppression and immune evasion in CF remains a subject of ongoing research.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Ganimeta Bakalovic, Dejan Bokonjic, Dusan Mihajlovic, Miodrag Colic, Vanja Malis, Marija Drakul, Sergej Tomic, Ivan Jojic, Sara Rakocevic, Darinka Popovic, Ljiljana Kozic, Milos Vasiljevic, Marina Bekic, Srdan Masic, Olivera Ljuboja
Summary: The dysfunction of neutrophils in children with cystic fibrosis (CF) is characterized by reduced apoptosis, lower production of neutrophil elastase (NE) and interleukin-18 (IL-18), and increased IL-8 levels. After stimulation, neutrophils showed higher reactive oxygen species (ROS) production, as well as up-regulation of CD11b and IL-10 expression. NET-osis was only increased in moderate-severe CF patients treated with Pseudomonas aeruginosa and correlated with forced expiratory volume in the first second (FEV1). Phagocytosis was not significantly affected.
Article
Biochemistry & Molecular Biology
Apparao B. Kummarapurugu, Shuo Zheng, Abigail Pulsipher, Justin R. Savage, Jonathan Ma, Bruce K. Rubin, Thomas P. Kennedy, Judith A. Voynow
Summary: In this study, the synthetic compound GM-1111 showed effective anti-NE activity in CF sputum, facilitating DNA depolymerization and reducing sputum elasticity. These findings suggest that GM-1111 could be a promising therapeutic option for CF patients, with potential advantages over traditional unfractionated heparin.
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
(2021)
Article
Respiratory System
Lael M. Yonker, Anika Marand, Sinan Muldur, Alex Hopke, Hui Min Leung, Denis De La Flor, Grace Park, Hanna Pinsky, Lauren B. Guthrie, Guillermo J. Tearney, Daniel Irimia, Bryan P. Hurley
Summary: The study characterized neutrophil function in CF patients using advanced technologies and found significantly altered migratory responses, cell-to-cell clustering, and microbe containment, particularly faster migration towards Staphylococcus aureus but less efficient clearing of Candida albicans.
JOURNAL OF CYSTIC FIBROSIS
(2021)
Article
Immunology
Kelly Kweng, Andrea Benedetti, Yvonne Yau, Valerie Waters, Dao Nguyen
Summary: This study found that PA isolates from new-onset CF infections exhibit strain-specific susceptibility to neutrophil antibacterial functions, and PA isolates resistant to neutrophil phagocytosis are independent risk factors for failed tobramycin eradication. Experimental results on neutrophil phagocytosis and intracellular killing showed that isolates from persistent infections were more resistant compared to those from eradicated infections.
JOURNAL OF INFECTIOUS DISEASES
(2022)
Article
Immunology
Samantha L. Tucker, Demba Sarr, Balazs Rada
Summary: This study identified the presence of NETs in the airways of beta ENaC-Tg mice, even in the absence of bacterial infections, suggesting the potential use of beta ENaC-Tg mice as a model for studying the role of NETs in chronic CF airway inflammation.
Article
Respiratory System
Ama-Tawiah Essilfie, Neralee Houston, Pramila Maniam, Gunter Hartel, Satomi Okano, David W. W. Reid
Summary: Imbalance of proteases and anti-proteases in the lung can lead to tissue damage, especially in patients with cystic fibrosis. Deficiency of SLPI in the airway is associated with reduced lung function. Treatment with antibiotics after infection can improve anti-protease defenses and enhance lung function.
Article
Immunology
Manon Ruffin, Jeanne Bigot, Claire Calmel, Julia Mercier, Maelle Givelet, Justine Oliva, Andres Pizzorno, Manuel Rosa-Calatrava, Harriet Corvol, Viviane Balloy, Olivier Terrier, Loic Guillot
Summary: In this study, it was found that Pseudomonas aeruginosa increases the expression of TMPRSS2 in airway epithelial cells and Calu-3 cells, potentially enhancing susceptibility to SARS-CoV-2 infection. The mechanism is through the activation of Toll-like receptor-5 and p38 MAPK. This result may have clinical significance for cystic fibrosis patients who are frequently infected with P. aeruginosa.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Immunology
Margalida Mateu-Borras, Alex Gonzalez-Alsina, Antonio Domenech-Sanchez, Javier Querol-Garcia, Francisco J. Fernandez, Ma Cristina Vega, Sebastian Alberti
Summary: This study investigates how isolates from CF patients modulate the levels of C5a and identifies the bacterial factors involved. The results show that most isolates from airway chronic infections induce the production and accumulation of C5a, which is attributed to the loss of C5a cleavage by the exoproteases AprA and LasB. Furthermore, it is found that lack of bacterial protease-dependent C5a degradation is due to mutations in the master regulator LasR. These findings suggest that non-cleaving C5a phenotype acquired by LasR variants may contribute to the strong neutrophilia and neutrophil dysfunction in CF patients.
Article
Biochemistry & Molecular Biology
Alexander L. Reese-Petersen, Federica Genovese, Lei Zhao, Glen Banks, David A. Gordon, Morten A. Karsdal
Summary: Extracellular matrix proteins contain signaling domains that can activate cellular responses when released. Endotrophin, a fragment of type VI collagen, has been linked to increased risk of adverse outcome in heart failure with preserved ejection fraction (HFpEF). This study demonstrates that endotrophin stimulation of human cardiac fibroblasts leads to increased synthesis of type I collagen, which accumulates in the myocardium during fibrogenesis. These findings provide a possible mechanistic explanation for the association between circulating endotrophin levels and HFpEF outcomes.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2023)
Article
Gastroenterology & Hepatology
Ying Xie, Lindsey Fontenot, Andrea Chupina Estrada, Becca Nelson, Jiani Wang, David Q. Shih, Wendy Ho, S. Anjani Mattai, Florian Rieder, Dane D. Jensen, Nigel W. Bunnett, Hon Wai Koon
Summary: The study demonstrates that Elafin can suppress collagen synthesis in intestinal fibroblasts by inhibiting protease-activated receptor 2, which is dependent on cathelin S, leading to a reduction in intestinal fibrosis.
CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
(2022)
Article
Pediatrics
Umit Aslanhan, Erkan Cakir, Leyla Pur Ozyigit, Umut Can Kucuksezer, Yusuf Metin Gelmez, Mine Yuksel, Gunnur Deniz, Esin Cetin Aktas
Summary: The functional properties of neutrophils in CF patients with P. aeruginosa colonization were analyzed in this study. Differences in migration, phagocytosis, oxidative burst, IL-8 production, and inflammatory cytokine secretion were noted among CF patients based on their colonization status, potentially leading to further airway damage and unfavorable prognosis in children with CF and colonization.
PEDIATRIC PULMONOLOGY
(2021)
Article
Microbiology
Kayla Fantone, Samantha L. Tucker, Arthur Miller, Ruchi Yadav, Eryn E. Bernardy, Rachel Fricker, Arlene A. Stecenko, Joanna B. Goldberg, Balizs Rada
Summary: The CF airway environment impairs the ability of polymorphonuclear granulocytes to kill S. aureus, inhibiting their antibacterial functions despite maintaining binding and phagocytosis abilities. The respiratory burst and neutrophil extracellular trap release induced by S. aureus also remain unaffected by the CF sputum, providing a new in vitro model for studying this phenomenon and its mechanism.
Article
Biochemistry & Molecular Biology
Marco Artini, Esther Imperlini, Francesco Buonocore, Michela Relucenti, Fernando Porcelli, Orlando Donfrancesco, Vanessa Tuccio Guarna Assanti, Ersilia Vita Fiscarelli, Rosanna Papa, Laura Selan
Summary: This study demonstrates the anti-biofilm and anti-virulence activity of KHS-Cnd against clinical strains of Pseudomonas aeruginosa. It impairs biofilm development and causes biofilm disaggregation, while also reducing adhesion to host cells and inhibiting invasion. The potential of KHS-Cnd as a therapeutic agent against P. aeruginosa is highlighted.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Respiratory System
Kevin W. Southern, Carlo Castellani, Elise Lammertyn, Alan Smyth, Donald VanDevanter, Silke van Koningsbruggen-Rietschel, Juerg Barben, Amanda Bevan, Edwin Brokaar, Sarah Collins, Gary J. Connett, Thomas W. V. Daniels, Jane Davies, Dimitri Declercq, Silvia Gartner, Andrea Gramegna, Naomi Hamilton, Jenny Hauser, Nataliya Kashirskaya, Laurence Kessler, Jacqueline Lowdon, Halyna Makukh, Clemence Martin, Lisa Morrison, Dilip Nazareth, Jacquelien Noordhoek, Ciaran O'Neill, Elizabeth Owen, Helen Oxley, Karen S. Raraigh, Caroline Raynal, Karen Robinson, Jobst Roehmel, Carsten Schwarz, Isabelle Sermet, Michal Shteinberg, Ian Sinha, Constance Takawira, Peter van Mourik, Marieke Verkleij, Michael D. Waller, Alistair Duff
Summary: Cystic fibrosis (CF) has entered the era of variant-specific therapy, tailored to the genetic variants in the CFTR gene, and CFTR modulators, the first available therapy, have transformed CF management. Interim standards have been produced to guide healthcare professionals in providing variant-specific therapy for CF patients using evidence-based guidance and stakeholder consultation.
JOURNAL OF CYSTIC FIBROSIS
(2023)
Article
Pediatrics
Christopher Short, Mary Abkir, Sophie Pinnell, Owain Proctor, Clare J. Saunders, Jane C. Davies
Summary: A cross-talk error in commercial MBWN2 software was found, causing over-reading of N-2. Research compared migrated or rerun data to directly collected data, and found significant differences. Caution should be taken when comparing corrected legacy data and 3.3.1 collected data in clinical interpretation.
PEDIATRIC PULMONOLOGY
(2023)
Article
Microbiology
Luca A. Robinson, Alice C. Z. Collins, Ronan A. Murphy, Jane C. Davies, Luke P. Allsopp
Summary: This study conducted a comprehensive bioinformatic analysis of 52 high-quality clinical P. aeruginosa genomes isolated from CF patients. The results showed that the clinical CF isolate genome consists mainly of accessory and unique genes, which may provide strain-specific advantages. The study found genetic variability in some effector/immunity encoding genes and identified the presence of orphan vgrG islands in some isolates. The study also revealed disruption to T6SS genomic loci through transposon, prophage, and mobile genetic element insertions.
FRONTIERS IN MICROBIOLOGY
(2023)
Review
Immunology
Sejal Saglani, Laura Yates, Clare M. Lloyd
Summary: Asthma is a disease characterized by type 2 immune dysfunction, with excess secretion of cytokines and eosinophil inflammation. Efforts have been made to develop drugs targeting these immune pathways, but they are not curative and may not fully alleviate key features of the disease. This review discusses the current landscape of therapeutic options targeting type 2 immune cytokines and their efficacy and limitations in both adults and children with asthma.
EUROPEAN JOURNAL OF IMMUNOLOGY
(2023)
Editorial Material
Immunology
Franz Puttur, Clare M. Lloyd
Summary: In this study, Cao et al. uncover the crucial role of dopamine in inhibiting ILC2 function via metabolic restriction, leading to the improvement of key features in asthma pathogenesis.
Review
Immunology
James A. Harker, Clare M. Lloyd
Summary: Harker and Lloyd review the multifaceted roles of Th2 cells in human asthma, emphasizing the influence of tissue location and disease severity. They also discuss the use of biologic therapies targeting Th2 cells and their cytokines. This review highlights the complex functions of Th2 cells in asthma and how they are affected by tissue location, disease stage, and severity, while also exploring the impact of biologics on asthma and the potential for uncovering new roles for Th2 cells in lung inflammation.
JOURNAL OF EXPERIMENTAL MEDICINE
(2023)
Editorial Material
Pediatrics
Ediane De Queiroz Andrade, Brooke Bailey, Jane C. C. Davies, Renee Jensen, Felix Ratjen, Clare J. J. Saunders, Christopher Short, Paul D. D. Robinson
PEDIATRIC PULMONOLOGY
(2023)
Article
Infectious Diseases
Isaac Martin, Sandra Morales, Eric W. F. W. Alton, Jane C. Davies
Summary: This study found that bacteriophages can be used as adjuncts to treatment for antibiotic refractory infections, and the combination of phages with certain antibiotics may have synergistic effects. Furthermore, phages showed good bactericidal effects against antibiotic resistant Pseudomonas aeruginosa (Pa), which may be relevant to ongoing clinical trials.
Article
Critical Care Medicine
Paul McNally, Karen Lester, Gavin Stone, Basil Elnazir, Michael Williamson, Des Cox, Barry Linnane, Laura Kirwan, David Rea, Paul O'Regan, Tom Semple, Clare Saunders, Harm A. W. M. Tiddens, Edward McKone, Jane C. Davies
Summary: This study demonstrates that treatment with ETI leads to significant improvements in lung function, lung clearance index, and CT scores in people with cystic fibrosis. The treatment also improves nutrition and quality of life for the patients.
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
(2023)
Article
Cell Biology
Erik Melen, Bart N. Lambrecht, Clare M. Lloyd, Marc E. Rothenberg, Kenji Kabashima, Fabio Luciani, Jonathan M. Coquet, Carole Ober, Martijn C. Nawijn, Thomas Platts-Mills, Erika von Mutius
Summary: Allergy is a group of disorders, affecting over 1 billion people worldwide, which includes asthma, atopic dermatitis, rhinitis, and food allergies. Its incidence has dramatically increased since the start of the 20th century, indicating that both genetics and environmental factors play important roles in its development.
IMMUNOLOGY AND CELL BIOLOGY
(2023)
Review
Immunology
Clare M. M. Lloyd, Sejal Saglani
Summary: Lloyd and Saglani provide an overview of the immunology of respiratory infections in early life and how it impacts lifelong lung health. Respiratory infections are common in infants and young children, and their effects during this developmental stage can have long-term consequences. The immune system and microbiome in the respiratory tract develop simultaneously, and any disruption to this development can have implications for lung health throughout one's life. The authors emphasize the importance of understanding the molecular mechanisms underlying the interplay between immune and structural cells in the lung and the local microorganisms to mitigate harmful effects and restore lung immune health.
Article
Multidisciplinary Sciences
Richard J. Hewitt, Franz Puttur, David C. A. Gaboriau, Frederic Fercoq, Maryline Fresquet, William J. Traves, Laura L. Yates, Simone A. Walker, Philip L. Molyneaux, Samuel V. Kemp, Andrew G. Nicholson, Alexandra Rice, Edward Roberts, Rachel Lennon, Leo M. Carlin, Adam J. Byrne, Toby M. Maher, Clare M. Lloyd
Summary: This study reveals the impact of changes in extracellular matrix (ECM) composition secreted by lung fibroblasts on the migration and function of KRT5(+) cells in idiopathic pulmonary fibrosis (IPF), contributing to tissue remodeling in the fibrotic lung.
NATURE COMMUNICATIONS
(2023)
Article
Critical Care Medicine
Nicole Mayer-Hamblett, John Paul Clancy, Raksha Jain, Scott H. Donaldson, Isabelle Fajac, Christopher H. Goss, Deepika Polineni, Felix Ratjen, Bradley S. Quon, Edith Zemanick, Scott C. Bell, Jane C. Davies, Manu Jain, Michael W. Konstan, Natanya R. Kerper, Tre LaRosa, Marcus A. Mall, Edward McKone, Kelsie Pearson, Joseph M. Pilewski, Lynne Quittell, Jonathan H. Rayment, Steven M. Rowe, Jennifer L. Taylor-Cousar, George Retsch-Bogart, Damian Downey
Summary: The use of modulator therapies for cystic fibrosis has changed clinical trial strategies, dividing the patient population based on eligibility. The development of nucleic acid-based therapies faces challenges due to limited resources and the inability to conduct placebo-controlled trials. Advancing symptomatic therapies is also difficult in a population already receiving modulator treatment.
LANCET RESPIRATORY MEDICINE
(2023)
Article
Respiratory System
Paul McNally, Barry Linnane, Michael Williamson, Basil Elnazir, Christopher Short, Clare Saunders, Laura Kirwan, Rea David, Mariette P. C. van de Corput, Harm A. W. M. Tiddens, Jane C. Davies, Des W. Cox
Summary: In this real-world study, the use of LUM/IVA in children aged 6-11 with CF resulted in improvements in air trapping on CT but worsening in bronchiectasis scores, suggesting that LUM/IVA treatment can improve respiratory function but cannot prevent the progression of bronchiectasis.
RESPIRATORY RESEARCH
(2023)
Meeting Abstract
Biotechnology & Applied Microbiology
Kamran M. Miah, Mario Chan, Uta Griesenbach, Eric W. F. W. Alton, Stephen C. Hyde, Deborah R. Gill