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Gatt D, Shaw M, Kritzinger F, Solomon M, Dell S, Ratjen F. The Impact of Age of Diagnosis in Children with Primary Ciliary Dyskinesia. Ann Am Thorac Soc 2025; 22:208-215. [PMID: 39269367 DOI: 10.1513/annalsats.202403-230oc] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Accepted: 09/13/2024] [Indexed: 09/15/2024] Open
Abstract
Rationale: The typical symptoms of primary ciliary dyskinesia (PCD) manifest after birth and in early infancy, but diagnosis is often not confirmed during infancy. There is currently a lack of evidence in PCD regarding the impact of the age of the patient at the time of diagnosis on clinical outcomes. Objective: To determine whether early diagnosis of PCD is related to improved long-term outcomes. Methods: This was a retrospective study of patients diagnosed with PCD between 2000 and 2022. We divided our cohort into three groups according to the age at diagnosis: (1) early diagnosis (age <1 year), typical diagnosis (age 1-7 years), and late diagnosis (age 8-14 years). We compared various clinical long-term outcomes between the groups. Results: During the study period, 110 patients were included in the analysis, with 41 patients in the early diagnosis group, 35 in the typical diagnosis group, and 34 in the late diagnosis group. Unexplained neonatal respiratory distress and organ laterality defect were more common in the early diagnosis group, with respective rates in the early, typical, and late diagnosis groups of 80%, 53%, and 61% for neonatal respiratory distress (P = 0.045) and 64%, 50%, and 18% for laterality defect (P < 0.001). At the end of the first decade of life, patients in the early and typical-age diagnosis groups had better forced expiratory volume in 1 second compared with the late diagnosis group (93.5% and 93.1% vs. 80.2%; P = 0.002), but there was no significant change in the annual rate of decline between the groups when diagnosis had been confirmed. Patients diagnosed late had significantly higher rates of pulmonary exacerbations than those diagnosed at a typical age (1.95 vs. 0.75 per year; P < 0.01) Conclusions: Late diagnosis (age ≥8 years) was associated with lower forced expiratory volume in 1 second throughout childhood, although, once diagnosed, the annual rate of decline was not different. These findings demonstrate the negative effect of delayed diagnosis in pediatric PCD.
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Affiliation(s)
- Dvir Gatt
- Division of Respiratory Medicine, and
| | - Michelle Shaw
- Translational Medicine, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; and
| | | | | | - Sharon Dell
- Division of Respiratory Medicine, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada
| | - Felix Ratjen
- Division of Respiratory Medicine, and
- Translational Medicine, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; and
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2
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Palla JB. Disparities and therapeutic advances in cystic fibrosis. Pediatr Pulmonol 2024; 59:3812-3818. [PMID: 37133222 PMCID: PMC11601024 DOI: 10.1002/ppul.26445] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 04/20/2023] [Indexed: 05/04/2023]
Abstract
Cystic fibrosis (CF) has seen a multitude of therapeutic advances targeting its downstream effects. This has led to a steady increase in survival over the past few decades. The recent development of disease-modifying drugs targeting the underlying CFTR mutation has revolutionized treatment for CF. Despite these advances, individuals with CF who are racial and ethnic minorities, from low socioeconomic status, or female sex have worse clinical outcomes. The inequitable access to CFTR modulators from cost and/or genetic eligibility has the potential to further worsen the existing health disparities seen within the CF community.
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Affiliation(s)
- John B. Palla
- Division of Pulmonary and Sleep MedicineAnn & Robert H. Lurie Children's HospitalChicagoIllinoisUSA
- Department of PediatricsNorthwestern University Feinberg School of MedicineChicagoIllinoisUSA
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3
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Luan X, Henao Romero N, Campanucci VA, Le Y, Mustofa J, Tam JS, Ianowski JP. Pulmonary Ionocytes Regulate Airway Surface Liquid pH in Primary Human Bronchial Epithelial Cells. Am J Respir Crit Care Med 2024; 210:788-800. [PMID: 38573173 PMCID: PMC11418883 DOI: 10.1164/rccm.202309-1565oc] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Accepted: 04/04/2024] [Indexed: 04/05/2024] Open
Abstract
Rationale: Pulmonary ionocytes are a newly discovered airway epithelial cell type proposed to be a major contributor to cystic fibrosis (CF) lung disease based on observations they express the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel at a higher level than any other cell type in the airway epithelia. Moreover, genetically manipulated experimental models that lack ionocytes develop NaCl transport abnormalities and airway surface liquid (ASL) dehydration consistent with CF. However, no direct evidence indicates ionocytes engage in NaCl transport or contribute to ASL formation, questioning the relevance of ionocytes to CF lung disease. Objectives: To determine the ion transport properties of pulmonary ionocytes and club cells in genetically intact healthy and CF airway epithelia. Methods: We measured ion transport at the single-cell level using a self-referencing ion-selective microelectrode technique in primary human bronchial epithelial cell culture. Measurements and Main Results: cAMP-stimulated non-CF ionocytes do not secrete Na+ or Cl- into the ASL, but rather modulate its pH by secreting bicarbonate via CFTR-linked Cl-/bicarbonate exchange. Non-CF club cells secrete Na+ and Cl- to the lumen side after cAMP stimulation. CF ionocytes and club cells do not transport ions in response to cAMP stimulation, but incubation with CFTR modulators elexacaftor/tezacaftor/ivacaftor restores transport properties. Conclusions: We conclude that ionocytes do not contribute to ASL formation but regulate ASL pH. Club cells secrete the bulk of airway fluid. In CF, abnormal ionocyte and club cell function results in acidic and dehydrated ASL, causing reduced antimicrobial properties and mucociliary clearance.
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Affiliation(s)
- Xiaojie Luan
- Department of Anatomy, Physiology, and Pharmacology
- Respiratory Research Centre, and
| | - Nicolas Henao Romero
- Department of Anatomy, Physiology, and Pharmacology
- Respiratory Research Centre, and
| | | | - Yen Le
- Department of Anatomy, Physiology, and Pharmacology
- Respiratory Research Centre, and
| | - Jannatul Mustofa
- Department of Anatomy, Physiology, and Pharmacology
- Respiratory Research Centre, and
| | - Julian S Tam
- Respiratory Research Centre, and
- Division of Respirology, Critical Care, and Sleep Medicine, Department of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Juan P Ianowski
- Department of Anatomy, Physiology, and Pharmacology
- Respiratory Research Centre, and
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4
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Li F, Tan Z, Chen H, Gao Y, Xia J, Huang T, Liang L, Zhang J, Zhang X, Shi X, Chen Q, Shu Q, Yu L. Integrative analysis of bulk and single-cell RNA sequencing reveals the gene expression profile and the critical signaling pathways of type II CPAM. Cell Biosci 2024; 14:94. [PMID: 39026356 PMCID: PMC11264590 DOI: 10.1186/s13578-024-01276-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Accepted: 07/10/2024] [Indexed: 07/20/2024] Open
Abstract
BACKGROUD Type II congenital pulmonary airway malformation (CPAM) is a rare pulmonary microcystic developmental malformation. Surgical excision is the primary treatment for CPAM, although maternal steroids and betamethasone have proven effective in reducing microcystic CPAM. Disturbed intercellular communication may contribute to the development of CPAM. This study aims to investigate the expression profile and analyze intercellular communication networks to identify genes potentially associated with type II CPAM pathogenesis and therapeutic targets. METHODS RNA sequencing (RNA-seq) was performed on samples extracted from both the cystic area and the adjacent normal tissue post-surgery in CPAM patients. Iterative weighted gene correlation network analysis (iWGCNA) was used to identify genes specifically expressed in type II CPAM. Single-cell RNA-seq (scRNA-seq) was integrated to unveil the heterogeneity in cell populations and analyze the communication and interaction within epithelial cell sub-populations. RESULTS A total of 2,618 differentially expressed genes were identified, primarily enriched in cilium-related biological process and inflammatory response process. Key genes such as EDN1, GPR17, FPR2, and CHRM1, involved in the G protein-coupled receptor (GPCR) signaling pathway and playing roles in cell differentiation, apoptosis, calcium homeostasis, and the immune response, were highlighted based on the protein-protein interaction network. Type II CPAM-associated modules, including ciliary function-related genes, were identified using iWGCNA. By integrating scRNA-seq data, AGR3 (related to calcium homeostasis) and SLC11A1 (immune related) were identified as the only two differently expressed genes in epithelial cells of CPAM. Cell communication analysis revealed that alveolar type 1 (AT1) and alveolar type 2 (AT2) cells were the predominant communication cells for outgoing and incoming signals in epithelial cells. The ligands and receptors between epithelial cell subtypes included COLLAGEN genes enriched in PI3K-AKT singaling and involved in epithelial to mesenchymal transition. CONCLUSIONS In summary, by integrating bulk RNA-seq data of type II CPAM with scRNA-seq data, the gene expression profile and critical signaling pathways such as GPCR signaling and PI3K-AKT signaling pathways were revealed. Abnormally expressed genes in these pathways may disrupt epithelial-mesenchymal transition and contribute to the development of CPAM. Given the effectiveness of prenatal treatments of microcystic CPAM using maternal steroids and maternal betamethasone administration, targeting the genes and signaling pathways involved in the development of CPAM presents a promising therapeutic strategy.
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Affiliation(s)
- Fengxia Li
- Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China
| | - Zheng Tan
- Department of Thoracic Surgery, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China
| | - Hongyu Chen
- Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China
| | - Yue Gao
- Department of Thoracic Surgery, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China
| | - Jie Xia
- Department of Thoracic Surgery, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China
| | - Ting Huang
- Department of Thoracic Surgery, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China
| | - Liang Liang
- Department of Thoracic Surgery, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China
| | - Jian Zhang
- Department of Thoracic Surgery, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China
| | - Xianghong Zhang
- Department of Cardiac Intensive Care Unit, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China
| | - Xucong Shi
- Department of Cardiac Surgery, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China
| | - Qiang Chen
- Department of General Surgery, Jiangxi Provincial Children's Hospital, Jiangxi, China.
| | - Qiang Shu
- Department of Cardiac Surgery, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China.
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
| | - Lan Yu
- Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China.
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Harvey BJ, McElvaney NG. Sex differences in airway disease: estrogen and airway surface liquid dynamics. Biol Sex Differ 2024; 15:56. [PMID: 39026347 PMCID: PMC11264786 DOI: 10.1186/s13293-024-00633-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Accepted: 07/03/2024] [Indexed: 07/20/2024] Open
Abstract
Biological sex differences exist for many airway diseases in which females have either worse or better health outcomes. Inflammatory airway diseases such as cystic fibrosis (CF) and asthma display a clear male advantage in post-puberty while a female benefit is observed in asthma during the pre-puberty years. The influence of menstrual cycle stage and pregnancy on the frequency and severity of pulmonary exacerbations in CF and asthma point to a role for sex steroid hormones, particularly estrogen, in underpinning biological sex differences in these diseases. There are many ways by which estrogen may aggravate asthma and CF involving disturbances in airway surface liquid (ASL) dynamics, inappropriate hyper-immune and allergenic responses, as well as exacerbation of pathogen virulence. The deleterious effect of estrogen on pulmonary function in CF and asthma contrasts with the female advantage observed in airway diseases characterised by pulmonary edema such as pneumonia, acute respiratory distress syndrome (ARDS) and COVID-19. Airway surface liquid hypersecretion and alveolar flooding are hallmarks of ARDS and COVID-19, and contribute to the morbidity and mortality of severe forms of these diseases. ASL dynamics encompasses the intrinsic features of the thin lining of fluid covering the airway epithelium which regulate mucociliary clearance (ciliary beat, ASL height, volume, pH, viscosity, mucins, and channel activating proteases) in addition to innate defence mechanisms (pathogen virulence, cytokines, defensins, specialised pro-resolution lipid mediators, and metabolism). Estrogen regulation of ASL dynamics contributing to biological sex differences in CF, asthma and COVID-19 is a major focus of this review.
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Affiliation(s)
- Brian J Harvey
- Faculty of Medicine and Health Sciences, Royal College of Surgeons in Ireland, 126 St Stephens Green, Dublin 2, Ireland.
- Department of Medicine, RCSI ERC, Beaumont Hospital, Dublin 2, Ireland.
| | - Noel G McElvaney
- Faculty of Medicine and Health Sciences, Royal College of Surgeons in Ireland, 126 St Stephens Green, Dublin 2, Ireland
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6
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Rehman T, Pezzulo AA, Thurman AL, Zemans RL, Welsh MJ. Epithelial responses to CFTR modulators are improved by inflammatory cytokines and impaired by antiinflammatory drugs. JCI Insight 2024; 9:e181836. [PMID: 38888974 PMCID: PMC11383177 DOI: 10.1172/jci.insight.181836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Accepted: 06/12/2024] [Indexed: 06/20/2024] Open
Abstract
Cystic fibrosis (CF) is a genetic disorder that disrupts CF transmembrane conductance regulator (CFTR) anion channels and impairs airway host defenses. Airway inflammation is ubiquitous in CF, and suppressing it has generally been considered to improve outcomes. However, the role of inflammation in people taking CFTR modulators, small-molecule drugs that restore CFTR function, is not well understood. We previously showed that inflammation enhances the efficacy of CFTR modulators. To further elucidate this relationship, we treated human ΔF508-CF epithelia with TNF-α and IL-17, two inflammatory cytokines that are elevated in CF airways. TNF-α+IL-17 enhanced CFTR modulator-evoked anion secretion through mechanisms that raise intracellular Cl- (Na+/K+/2Cl- cotransport) and HCO3- (carbonic anhydrases and Na+/HCO3- cotransport). This enhancement required p38 MAPK signaling. Importantly, CFTR modulators did not affect CF airway surface liquid viscosity under control conditions but prevented the rise in viscosity in epithelia treated with TNF-α+IL-17. Finally, antiinflammatory drugs limited CFTR modulator responses in TNF-α+IL-17-treated epithelia. These results provide critical insights into mechanisms by which inflammation increases responses to CFTR modulators. They also suggest an equipoise between potential benefits and limitations of suppressing inflammation in people taking modulators, call into question current treatment approaches, and highlight a need for additional studies.
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Affiliation(s)
- Tayyab Rehman
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
- Department of Internal Medicine, Pappajohn Biomedical Institute, University of Iowa, Iowa City, Iowa, USA
| | - Alejandro A. Pezzulo
- Department of Internal Medicine, Pappajohn Biomedical Institute, University of Iowa, Iowa City, Iowa, USA
| | - Andrew L. Thurman
- Department of Internal Medicine, Pappajohn Biomedical Institute, University of Iowa, Iowa City, Iowa, USA
| | - Rachel L. Zemans
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Michael J. Welsh
- Department of Internal Medicine, Pappajohn Biomedical Institute, University of Iowa, Iowa City, Iowa, USA
- Howard Hughes Medical Institute, University of Iowa, Iowa City, Iowa, USA
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7
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Liu H, Li L, Lu R. ZIP transporters-regulated Zn 2+ homeostasis: A novel determinant of human diseases. J Cell Physiol 2024; 239:e31223. [PMID: 38530191 DOI: 10.1002/jcp.31223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 01/16/2024] [Accepted: 02/06/2024] [Indexed: 03/27/2024]
Abstract
As an essential trace element for organisms, zinc participates in various physiological processes, such as RNA transcription, DNA replication, cell proliferation, and cell differentiation. The destruction of zinc homeostasis is associated with various diseases. Zinc homeostasis is controlled by the cooperative action of zinc transporter proteins that are responsible for the influx and efflux of zinc. Zinc transporter proteins are mainly categorized into two families: Zrt/Irt-like protein (SLC39A/ZIP) family and zinc transporter (SLC30A/ZNT) family. ZIP transporters contain 14 members, namely ZIP1-14, which can be further divided into four subfamilies. Currently, ZIP transporters-regulated zinc homeostasis is one of the research hotspots. Cumulative evidence suggests that ZIP transporters-regulated zinc homeostasis may cause physiological dysfunction and contribute to the onset and progression of diverse diseases, such as cancers, neurological diseases, and cardiovascular diseases. In this review, we initially discuss the structure and distribution of ZIP transporters. Furthermore, we comprehensively review the latest research progress of ZIP transporters-regulated zinc homeostasis in diseases, providing a new perspective into new therapeutic targets for treating related diseases.
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Affiliation(s)
- Huimei Liu
- Department of Pharmacology, Hengyang Medical School, University of South China, Hengyang, China
| | - Lanfang Li
- Department of Pharmacology, Hengyang Medical School, University of South China, Hengyang, China
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, China
| | - Ruirui Lu
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, China
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8
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Kashlan OB, Wang XP, Sheng S, Kleyman TR. Epithelial Na + Channels Function as Extracellular Sensors. Compr Physiol 2024; 14:1-41. [PMID: 39109974 PMCID: PMC11309579 DOI: 10.1002/cphy.c230015] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/10/2024]
Abstract
The epithelial Na + channel (ENaC) resides on the apical surfaces of specific epithelia in vertebrates and plays a critical role in extracellular fluid homeostasis. Evidence that ENaC senses the external environment emerged well before the molecular identity of the channel was reported three decades ago. This article discusses progress toward elucidating the mechanisms through which specific external factors regulate ENaC function, highlighting insights gained from structural studies of ENaC and related family members. It also reviews our understanding of the role of ENaC regulation by the extracellular environment in physiology and disease. After familiarizing the reader with the channel's physiological roles and structure, we describe the central role protein allostery plays in ENaC's sensitivity to the external environment. We then discuss each of the extracellular factors that directly regulate the channel: proteases, cations and anions, shear stress, and other regulators specific to particular extracellular compartments. For each regulator, we discuss the initial observations that led to discovery, studies investigating molecular mechanism, and the physiological and pathophysiological implications of regulation. © 2024 American Physiological Society. Compr Physiol 14:5407-5447, 2024.
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Affiliation(s)
- Ossama B. Kashlan
- Department of Medicine, Renal-Electrolyte Division,
University of Pittsburgh, Pittsburgh, Pennsylvania
- Department of Computational and Systems Biology, University
of Pittsburgh, Pittsburgh, Pennsylvania
| | - Xue-Ping Wang
- Department of Medicine, Renal-Electrolyte Division,
University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Shaohu Sheng
- Department of Medicine, Renal-Electrolyte Division,
University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Thomas R. Kleyman
- Department of Medicine, Renal-Electrolyte Division,
University of Pittsburgh, Pittsburgh, Pennsylvania
- Department of Cell Biology, University of Pittsburgh,
Pittsburgh, Pennsylvania
- Department of Pharmacology and Chemical Biology, University
of Pittsburgh, Pittsburgh, Pennsylvania
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9
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Schwarz C, Eschenhagen PN, Mainz JG, Schmidergall T, Schuette H, Romanowska E. Pulmonary Aspergillosis in People with Cystic Fibrosis. Semin Respir Crit Care Med 2024; 45:128-140. [PMID: 38286138 DOI: 10.1055/s-0043-1777267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2024]
Abstract
In the last decade, fungal respiratory diseases have been increasingly investigated for their impact on the clinical course of people with cystic fibrosis (CF), with a particular focus on infections caused by Aspergillus spp. The most common organisms from this genus detected from respiratory cultures are Aspergillus fumigatus and Aspergillus terreus, followed by Aspergillus flavus, Aspergillus niger, and Aspergillus nidulans. These species have been identified to be both chronic colonizers and sources of active infection and may negatively impact lung function in people with CF. This review article discusses definitions of aspergillosis, challenges in clinical practice, and current literature available for laboratory findings, clinical diagnosis, and treatment options for pulmonary diseases caused by Aspergillus spp. in people with CF.
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Affiliation(s)
- C Schwarz
- HMU-Health and Medical University, Potsdam, Germany
- Division Cystic Fibrosis, Clinic Westbrandenburg, Potsdam, Germany
| | - P N Eschenhagen
- HMU-Health and Medical University, Potsdam, Germany
- Division Cystic Fibrosis, Clinic Westbrandenburg, Potsdam, Germany
| | - J G Mainz
- Department of Paediatric Pneumology, Allergology, Cystic Fibrosis Center, Klinikum Westbrandenburg, Brandenburg a. d. Havel, Germany
- University Hospital of the Brandenburg Medical School, Brandenburg a. d. Havel, Germany
| | - T Schmidergall
- HMU-Health and Medical University, Potsdam, Germany
- Division Cystic Fibrosis, Clinic Westbrandenburg, Potsdam, Germany
| | - H Schuette
- Pneumology and Respiratory Medicine, Ernst von Bergmann Klinikum, Potsdam, Germany
| | - E Romanowska
- HMU-Health and Medical University, Potsdam, Germany
- Division Cystic Fibrosis, Clinic Westbrandenburg, Potsdam, Germany
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10
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Zajac M, Jakiela S, Dolowy K. Understanding Bidirectional Water Transport across Bronchial Epithelial Cell Monolayers: A Microfluidic Approach. MEMBRANES 2023; 13:901. [PMID: 38132905 PMCID: PMC10744786 DOI: 10.3390/membranes13120901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 11/24/2023] [Accepted: 12/02/2023] [Indexed: 12/23/2023]
Abstract
Deciphering the dynamics of water transport across bronchial epithelial cell monolayers is pivotal for unraveling respiratory physiology and pathology. In this study, we employ an advanced microfluidic system to explore bidirectional water transport across 16HBE14σ bronchial epithelial cells. Previous experiments unveiled electroneutral multiple ion transport, with chloride ions utilizing transcellular pathways and sodium ions navigating both paracellular and transcellular routes. Unexpectedly, under isoosmotic conditions, rapid bidirectional movement of Na+ and Cl- was observed, leading to the hypothesis of a substantial transport of isoosmotic solution (145 mM NaCl) across cell monolayers. To validate this conjecture, we introduce an innovative microfluidic device, offering a 500-fold sensitivity improvement in quantifying fluid flow. This system enables the direct measurement of minuscule fluid volumes traversing cell monolayers with unprecedented precision. Our results challenge conventional models, indicating a self-regulating mechanism governing water transport that involves the CFTR channel and anion exchangers. In healthy subjects, equilibrium is achieved at an apical potential of Δφap = -30 mV, while subjects with cystic fibrosis exhibit modulation by an anion exchanger, reaching equilibrium at [Cl] = 67 mM in the airway surface liquid. This nuanced electrochemical basis for bidirectional water transport in bronchial epithelia sheds light on physiological intricacies and introduces a novel perspective for understanding respiratory conditions.
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Affiliation(s)
- Miroslaw Zajac
- Department of Physics and Biophysics, Institute of Biology, Warsaw University of Life Sciences, 02-776 Warsaw, Poland;
| | | | - Krzysztof Dolowy
- Department of Physics and Biophysics, Institute of Biology, Warsaw University of Life Sciences, 02-776 Warsaw, Poland;
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11
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Earle K, Valero C, Conn DP, Vere G, Cook PC, Bromley MJ, Bowyer P, Gago S. Pathogenicity and virulence of Aspergillus fumigatus. Virulence 2023; 14:2172264. [PMID: 36752587 PMCID: PMC10732619 DOI: 10.1080/21505594.2023.2172264] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 12/16/2022] [Indexed: 02/09/2023] Open
Abstract
Pulmonary infections caused by the mould pathogen Aspergillus fumigatus are a major cause of morbidity and mortality globally. Compromised lung defences arising from immunosuppression, chronic respiratory conditions or more recently, concomitant viral or bacterial pulmonary infections are recognised risks factors for the development of pulmonary aspergillosis. In this review, we will summarise our current knowledge of the mechanistic basis of pulmonary aspergillosis with a focus on emerging at-risk populations.
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Affiliation(s)
- Kayleigh Earle
- Manchester Fungal Infection Group, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
| | - Clara Valero
- Manchester Fungal Infection Group, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
| | - Daniel P. Conn
- MRC Centre for Medical Mycology, University of Exeter, Exeter, UK
| | - George Vere
- MRC Centre for Medical Mycology, University of Exeter, Exeter, UK
| | - Peter C. Cook
- MRC Centre for Medical Mycology, University of Exeter, Exeter, UK
| | - Michael J. Bromley
- Manchester Fungal Infection Group, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
| | - Paul Bowyer
- Manchester Fungal Infection Group, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
| | - Sara Gago
- Manchester Fungal Infection Group, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
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12
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Delpiano L, Rodenburg LW, Burke M, Nelson G, Amatngalim GD, Beekman JM, Gray MA. Dynamic regulation of airway surface liquid pH by TMEM16A and SLC26A4 in cystic fibrosis nasal epithelia with rare mutations. Proc Natl Acad Sci U S A 2023; 120:e2307551120. [PMID: 37967223 PMCID: PMC10666107 DOI: 10.1073/pnas.2307551120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 09/28/2023] [Indexed: 11/17/2023] Open
Abstract
In cystic fibrosis (CF), defects in the CF transmembrane conductance regulator (CFTR) channel lead to an acidic airway surface liquid (ASL), which compromises innate defence mechanisms, predisposing to pulmonary failure. Restoring ASL pH is a potential therapy for people with CF, particularly for those who cannot benefit from current highly effective modulator therapy. However, we lack a comprehensive understanding of the complex mechanisms underlying ASL pH regulation. The calcium-activated chloride channel, TMEM16A, and the anion exchanger, SLC26A4, have been proposed as targets for restoring ASL pH, but current results are contradictory and often utilise nonphysiological conditions. To provide better evidence for a role of these two proteins in ASL pH homeostasis, we developed an efficient CRISPR-Cas9-based approach to knock-out (KO) relevant transporters in primary airway basal cells lacking CFTR and then measured dynamic changes in ASL pH under thin-film conditions in fully differentiated airway cultures, which better simulate the in vivo situation. Unexpectantly, we found that both proteins regulated steady-state as well as agonist-stimulated ASL pH, but only under inflammatory conditions. Furthermore, we identified two Food and Drug Administration (FDA)-approved drugs which raised ASL pH by activating SLC26A4. While we identified a role for SLC26A4 in fluid absorption, KO had no effect on cyclic adenosine monophosphate (cAMP)-stimulated fluid secretion in airway organoids. Overall, we have identified a role of TMEM16A in ASL pH homeostasis and shown that both TMEM16A and SLC26A4 could be important alternative targets for ASL pH therapy in CF, particularly for those people who do not produce any functional CFTR.
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Affiliation(s)
- Livia Delpiano
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom
| | - Lisa W Rodenburg
- Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Member of the European Reference Network-LUNG, Utrecht 3584 EA, The Netherlands
- Regenerative Medicine Center Utrecht, University Medical Center Utrecht, Utrecht University, Utrecht 3584 CT, The Netherlands
| | - Matthew Burke
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom
| | - Glyn Nelson
- Bioimaging Unit, Ageing Research Laboratories, Campus for Ageing and Vitality, Newcastle University, Newcastle Upon Tyne NE4 5PL, United Kingdom
| | - Gimano D Amatngalim
- Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Member of the European Reference Network-LUNG, Utrecht 3584 EA, The Netherlands
- Regenerative Medicine Center Utrecht, University Medical Center Utrecht, Utrecht University, Utrecht 3584 CT, The Netherlands
| | - Jeffrey M Beekman
- Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Member of the European Reference Network-LUNG, Utrecht 3584 EA, The Netherlands
- Regenerative Medicine Center Utrecht, University Medical Center Utrecht, Utrecht University, Utrecht 3584 CT, The Netherlands
- Centre for Living Technologies, Alliance Eindhoven University of Technology, Wageningen University and Research, Utrecht University, University Medical Center Utrecht, Utrecht 3584 CB, The Netherlands
| | - Michael A Gray
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom
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13
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Wajda KE, Roesch EA, Gifford AH. Chronic daily respiratory care needs in people with cystic fibrosis treated with highly effective cystic fibrosis transmembrane conductance regulator modulators. Curr Opin Pulm Med 2023; 29:580-586. [PMID: 37611027 DOI: 10.1097/mcp.0000000000001006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/25/2023]
Abstract
PURPOSE OF REVIEW Cystic fibrosis is a genetic disease that increases risk of death from respiratory failure because of impairment in mucociliary clearance. Complex daily care regimens including medications and airway clearance techniques (ACTs) aim to preserve lung function and alleviate symptoms for people with cystic fibrosis (pwCF). The success of highly effective modulator therapy (HEMT) permits evaluation of treatment simplification. In this review, we evaluate adjustments made in daily respiratory care among pwCF taking HEMT and the feasibility of treatment simplification. RECENT FINDINGS Treatment simplification has been identified as a top priority among pwCF, with recent studies showing pwCF are willing to sacrifice mild to moderate amounts of lung function and longevity to reduce treatment burden. Retrospective studies have shown that patients taking HEMT with better baseline lung function have lower adherence to and prescription of inhaled medications. A randomized, controlled trial found that short-term discontinuation of dornase alfa or hypertonic saline was clinically noninferior to continuation of these medications. Major knowledge gaps remain about withdrawing ACTs. SUMMARY This review highlights trials evaluating the feasibility of treatment simplification among pwCF taking HEMT. More data is needed to evaluate approaches to simplification in this phenotypically diverse patient population.
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Affiliation(s)
- Katherine E Wajda
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University Hospitals Cleveland Medical Center
- Department of Pediatrics, Division of Pediatric Pulmonology, University Hospitals Rainbow Babies and Children's Hospital, Cleveland, Ohio, USA
| | - Erica A Roesch
- Department of Pediatrics, Division of Pediatric Pulmonology, University Hospitals Rainbow Babies and Children's Hospital, Cleveland, Ohio, USA
| | - Alex H Gifford
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University Hospitals Cleveland Medical Center
- Department of Pediatrics, Division of Pediatric Pulmonology, University Hospitals Rainbow Babies and Children's Hospital, Cleveland, Ohio, USA
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14
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Cao R, Rossdeutcher RB, Zhong Y, Shen Y, Miller DP, Sobiech TA, Wu X, Buitrago LS, Ramcharan K, Gutay MI, Figueira MF, Luthra P, Zurek E, Szyperski T, Button B, Shao Z, Gong B. Aromatic pentaamide macrocycles bind anions with high affinity for transport across biomembranes. Nat Chem 2023; 15:1559-1568. [PMID: 37814114 DOI: 10.1038/s41557-023-01315-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Accepted: 08/08/2023] [Indexed: 10/11/2023]
Abstract
The convergent positioning of functional groups in biomacromolecules leads to good binding, catalytic and transport capabilities. Synthetic frameworks capable of convergently locking functional groups with minimized conformational uncertainty-leading to similar properties-are highly desirable but rare. Here we report C5-symmetric aromatic pentaamide macrocycles synthesized in one pot from the corresponding monomers. Their crystal structures reveal a star-shaped, fully constrained backbone that causes ten alternating NH/CH hydrogen-bond donors and five large amide dipoles to orient towards the centre of the macrocycle. With a highly electropositive cavity in a high-energy unbound state, the macrocycles bind anions in a 1:1 stoichiometry in solution, with high affinity for halides and very high affinity for oxoanions. We demonstrate that such macrocycles are able to transport anions across lipid bilayers with a high chloride selectivity and restore the depleted airway surface liquid of cystic fibrosis airway cell cultures.
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Affiliation(s)
- Ruikai Cao
- Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY, USA
| | - Robert B Rossdeutcher
- Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY, USA
| | - Yulong Zhong
- Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY, USA
| | - Yi Shen
- State Key Laboratory of Systems Medicine for Cancer, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Daniel P Miller
- Department of Chemistry, Hofstra University, Hempstead, NY, USA
| | - Thomas A Sobiech
- Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY, USA
| | - Xiangxiang Wu
- Academy of Chinese Medical Science, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | | | | | - Mark I Gutay
- Marsico Lung Institute, University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | | | - Pia Luthra
- Department of Chemistry, Hofstra University, Hempstead, NY, USA
| | - Eva Zurek
- Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY, USA
| | - Thomas Szyperski
- Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY, USA
| | - Brian Button
- Marsico Lung Institute, University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | - Zhifeng Shao
- State Key Laboratory of Systems Medicine for Cancer, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
| | - Bing Gong
- Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY, USA.
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15
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Gatt D, Shaw M, Waters V, Kritzinger F, Solomon M, Dell S, Ratjen F. Treatment response to pulmonary exacerbation in primary ciliary dyskinesia. Pediatr Pulmonol 2023; 58:2857-2864. [PMID: 37449771 DOI: 10.1002/ppul.26599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 05/19/2023] [Accepted: 07/03/2023] [Indexed: 07/18/2023]
Abstract
INTRODUCTION Pulmonary exacerbation (Pex) are common in pediatric primary ciliary dyskinesia (PCD), however changes in forced expiratory volume in 1 s precent predicted (FEV1pp) during Pex are not well described. AIM To assess the evolution of FEV1pp during Pex and to define factors associated with failure to return to baseline lung function. METHOD This was a retrospective study of patients with PCD between 2010 and 2022. Pex were defined as the presence of increased respiratory symptoms treated with intravenous (IV) antibiotics. The main outcomes were the changes in FEV1 during therapy and the proportion of patients (responders) achieving ≥90% of baseline FEV1pp values at the end of admission. RESULTS The study included 52 Pex events in 28 children with PCD. The rate of responders was 32/41 (78%) at the end of admission. Nonresponse was associated with lower median body mass index (BMI) Z-score (-2.4 vs. -0.4, p < .01) and with a history of IV treated Pex in the previous year (p = .06). For the 22 Pex with available FEV1pp measurements at mid admission, the median relative and absolute improvement from admission to Day 7 was 9.1% and 6.2%, respectively (p- .001), and from Days 7 to 14 was 4.4% and 2.8%, respectively (p = .08). CONCLUSION In children with PCD treated with IV antibiotics, the majority of lung function recovery happens during the first week of IV therapy. Lower BMI was associated with nonresponse to therapy.
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Affiliation(s)
- Dvir Gatt
- Division of Respiratory Medicine, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Michelle Shaw
- Translational Medicine, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Valerie Waters
- Department of Pediatrics, Division of Infectious Diseases, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Fiona Kritzinger
- Division of Respiratory Medicine, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Melinda Solomon
- Division of Respiratory Medicine, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Sharon Dell
- Department of Pediatrics, Division of Respiratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Felix Ratjen
- Division of Respiratory Medicine, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
- Translational Medicine, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
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16
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Parihar A, Prajapati BG, Paliwal H, Shukla M, Khunt D, Devrao Bahadure S, Dyawanapelly S, Junnuthula V. Advanced pulmonary drug delivery formulations for the treatment of cystic fibrosis. Drug Discov Today 2023; 28:103729. [PMID: 37532219 DOI: 10.1016/j.drudis.2023.103729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 05/09/2023] [Accepted: 07/26/2023] [Indexed: 08/04/2023]
Abstract
Cystic fibrosis (CF), a fatal genetic condition, causes thick, sticky mucus. It also causes pancreatic dysfunction, bacterial infection, and increased salt loss. Currently available treatments can improve the patient's quality of life. Drug delivery aided by nanotechnology has been explored to alter the pharmacokinetics and toxicity of drugs. In this short review, we aim to summarize various conventional formulations and highlight advanced formulations delivered via the pulmonary route for the treatment of CF. There is considerable interest in advanced drug delivery formulations addressing the various challenges posed by CF. Despite their potential to be translated for clinical use, we anticipate that a significant amount of effort may still be required for translation to the clinic.
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Affiliation(s)
- Akshay Parihar
- Faculty of Pharmaceutical Sciences, The ICFAI University, Baddi, Himachal Pradesh, India
| | - Bhupendra G Prajapati
- Shree S.K. Patel College of Pharmaceutical Education and Research, Ganpat University, Mehsana, Gujarat, India.
| | - Himanshu Paliwal
- Department of Pharmaceutical Technology, Prince of Songkla University, Hat Yai, Songkhla, Thailand
| | - Maheka Shukla
- Shree S.K. Patel College of Pharmaceutical Education and Research, Ganpat University, Mehsana, Gujarat, India
| | - Dignesh Khunt
- Graduate School of Pharmacy, Gujarat Technological University, Gujarat, India
| | - Sumedh Devrao Bahadure
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Guwahati, India
| | - Sathish Dyawanapelly
- Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai, India.
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17
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Ryan H, Ballard E, Stockwell RE, Duplancic C, Thomson RM, Smith K, Bell SC. A systematic review of the clinical impact of small colony variants in patients with cystic fibrosis. BMC Pulm Med 2023; 23:323. [PMID: 37658311 PMCID: PMC10474644 DOI: 10.1186/s12890-023-02611-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 08/24/2023] [Indexed: 09/03/2023] Open
Abstract
BACKGROUND Cystic fibrosis (CF) is a life-limiting disorder that is characterised by respiratory tract inflammation that is mediated by a range of microbial pathogens. Small colony variants (SCVs) of common respiratory pathogens are being increasingly recognised in CF. The aim of this systematic review is to investigate the prevalence of SCVs, clinical characteristics and health outcomes for patients with CF, and laboratory diagnostic features of SCVs compared to non-small colony variants (NCVs) for a range of Gram-positive and Gram-negative respiratory pathogens. METHODS A literature search was conducted (PubMed, Web of Science, Embase and Scopus) in April 2020 to identify articles of interest. Data pertaining to demographic characteristics of participants, diagnostic criteria of SCVs, SCV prevalence and impact on lung function were extracted from included studies for analysis. RESULTS Twenty-five of 673 studies were included in the systematic review. Individuals infected with SCVs of Staphylococcus aureus (S. aureus) were more likely to have had prior use of the broad-spectrum antibiotic trimethoprim sulfamethoxazole (p < 0.001), and the prevalence of SCVs in patients infected with S. aureus was estimated to be 19.3% (95% CI: 13.5% to 25.9%). Additionally, patients infected with SCVs of Gram-negative and Gram-positive pathogens were identified to have a lower forced expiratory volume in one second percentage predicted (-16.8, 95% CI: -23.2 to -10.4) than those infected by NCVs. Gram-positive SCVs were commonly described as small and non-haemolytic, grown on Mannitol salt or blood agar for 24 h at 35°C and confirmed using tube coagulase testing. CONCLUSION The findings of this systematic review demonstrate that SCVs of S. aureus have a high prevalence in the CF community, and that the occurrence of SCVs in Gram-positive and Gram-negative pathogens is linked to poorer respiratory function. Further investigation is necessary to determine the effect of infection by SCVs on the CF population.
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Affiliation(s)
- Harrigan Ryan
- Centre for Children's Health Research, Faculty of Medicine, The University of Queensland, South Brisbane, QLD, Australia
| | - Emma Ballard
- Statistics Unit, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Rebecca E Stockwell
- Centre for Children's Health Research, Faculty of Medicine, The University of Queensland, South Brisbane, QLD, Australia
- Adult Cystic Fibrosis Centre, The Prince Charles Hospital, Chermside, QLD, Australia
| | - Christine Duplancic
- Centre for Children's Health Research, Faculty of Medicine, The University of Queensland, South Brisbane, QLD, Australia
| | - Rachel M Thomson
- Respiratory Research Group, Gallipoli Medical Research Foundation, Greenslopes, QLD, Australia
| | - Kimberley Smith
- Centre for Children's Health Research, Faculty of Medicine, The University of Queensland, South Brisbane, QLD, Australia
| | - Scott C Bell
- Centre for Children's Health Research, Faculty of Medicine, The University of Queensland, South Brisbane, QLD, Australia.
- Adult Cystic Fibrosis Centre, The Prince Charles Hospital, Chermside, QLD, Australia.
- Translational Research Institute, Woolloongabba, QLD, Australia.
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18
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Escher A, Kieninger E, Groof SD, Savas ST, Schneiter M, Tschanz SA, Frenz M, Latzin P, Casaulta C, Müller L. In Vitro Effect of Combined Hypertonic Saline and Salbutamol on Ciliary Beating Frequency and Mucociliary Transport in Human Nasal Epithelial Cells of Healthy Volunteers and Patients with Cystic Fibrosis. J Aerosol Med Pulm Drug Deliv 2023; 36:171-180. [PMID: 37196208 DOI: 10.1089/jamp.2022.0026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/19/2023] Open
Abstract
Background: Inhalation of hypertonic saline (HS) is standard of care in patients with cystic fibrosis (CF). However, it is unclear if adding salbutamol has-besides bronchodilation-further benefits, for example, on the mucociliary clearance. We assessed this in vitro by measuring the ciliary beating frequency (CBF) and the mucociliary transport rate (MCT) in nasal epithelial cells (NECs) of healthy volunteers and patients with CF. Aims: To investigate the effect of HS, salbutamol, and its combination on (muco)ciliary activity of NECs in vitro, and to assess potential differences between healthy controls and patients with CF. Methods: NECs obtained from 10 healthy volunteers and 5 patients with CF were differentiated at the air-liquid interface and aerosolized with 0.9% isotonic saline ([IS] control), 6% HS, 0.06% salbutamol, or combined HS and salbutamol. CBF and MCT were monitored over 48-72 hours. Results: In NECs of healthy controls, the absolute CBF increase was comparable for all substances, but CBF dynamics were different: HS increased CBF slowly and its effect lasted for an extended period, salbutamol and IS increased CBF rapidly and the effect subsided similarly fast, and HS and salbutamol resulted in a rapid and long-lasting CBF increase. Results for CF cells were comparable, but less pronounced. Similar to CBF, MCT increased after the application of all the tested substances. Conclusion: CBF and MCT of NECs of healthy participants and CBF of patients with CF increased upon treatment with aerosolized IS, HS, salbutamol, or HS and salbutamol, showing a relevant effect for all tested substances. The difference in the CBF dynamics can be explained by the fact that the properties of the mucus are changed differently by different saline concentrations.
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Affiliation(s)
- Anaïs Escher
- Division of Paediatric Respiratory Medicine and Allergology, Department of Paediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Elisabeth Kieninger
- Division of Paediatric Respiratory Medicine and Allergology, Department of Paediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Susan De Groof
- Division of Paediatric Respiratory Medicine and Allergology, Department of Paediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Sibel T Savas
- Division of Paediatric Respiratory Medicine and Allergology, Department of Paediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Martin Schneiter
- Institute of Applied Physics, University of Bern, Bern, Switzerland
- Institute of Anatomy, University of Bern, Bern, Switzerland
| | | | - Martin Frenz
- Institute of Applied Physics, University of Bern, Bern, Switzerland
| | - Philipp Latzin
- Division of Paediatric Respiratory Medicine and Allergology, Department of Paediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Carmen Casaulta
- Division of Paediatric Respiratory Medicine and Allergology, Department of Paediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Loretta Müller
- Division of Paediatric Respiratory Medicine and Allergology, Department of Paediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
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19
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Tosco A, Poli P, Casale A, De Gregorio F, Sepe A, Buonpensiero P, Di Pasqua A, Castaldo A, Cimbalo C, Buzzetti R, Raia V, Berlucchi M, Timpano S, Badolato R, Padoan R, Orlando C. The Role of Bronchoscopy in the Management of Children With Cystic Fibrosis. J Bronchology Interv Pulmonol 2023; 30:258-267. [PMID: 35698279 DOI: 10.1097/lbr.0000000000000874] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 04/25/2022] [Indexed: 11/25/2022]
Abstract
BACKGROUND Currently, no consensus guidelines recommend routine bronchoscopy procedure in cystic fibrosis (CF), as no evidence is available concerning its use as either a diagnostic or therapeutic tool. Its efficacy is controversial, and no randomized controlled prospective trials are available to check its effectiveness. The aims of the present study were to evaluate the effectiveness of bronchoscopy as a diagnostic/therapeutic tool in CF children and adolescents; and to verify the effect of serial bronchoscopy on lung disease progression in subjects with CF not responding to a single procedure. METHODS Data of patients who received bronchoscopy at 2 Italian CF centers were collected. Bronchoalveolar lavage was performed during the procedure including airway clearance with mucolytics, inhaled antibiotics, and/or surfactant instillation. RESULTS A total of 16 patients in center 1 and 17 in center 2 underwent, respectively, 28 and 23 bronchoscopic procedure in the study period. Five patients in each center underwent >1 procedure. All procedures were generally well tolerated. No patient required admission to the pediatric intensive therapy unit. In 19.6% of bronchoalveolar lavages, growth of Aspergillus fumigatus was evident, although not detected by sputum analyses. After the procedure, an increase in mean percent predicted forced expiratory volume in the 1 second >10% was observed, and a significant decrease in pulmonary exacerbations yearly was evident. CONCLUSION Based on the results, we suggest bronchoscopy is not to be considered an obsolete tool, and it remains useful in CF management, although in selected cases. We encourage to support longitudinal observational studies to standardize the procedure, focusing on the choice of drugs to be instilled, modalities and timing of serial bronchoscopy and subsequent follow-up in selected severe clinical conditions.
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Affiliation(s)
- Antonella Tosco
- Pediatric Unit, Department of Translational Medical Sciences, Regional Cystic Fibrosis Center, Federico II University
| | - Piercarlo Poli
- Paediatric Department, Cystic Fibrosis Support Centre, University of Brescia, ASST Spedali Civili Brescia
| | - Alida Casale
- Pediatric Unit, Department of Translational Medical Sciences, Regional Cystic Fibrosis Center, Federico II University
| | - Fabiola De Gregorio
- Pediatric Unit, Department of Translational Medical Sciences, Regional Cystic Fibrosis Center, Federico II University
| | - Angela Sepe
- Pediatric Unit, Department of Translational Medical Sciences, Regional Cystic Fibrosis Center, Federico II University
| | - Paolo Buonpensiero
- Pediatric Unit, Department of Translational Medical Sciences, Regional Cystic Fibrosis Center, Federico II University
| | - Antonio Di Pasqua
- Pediatric Unit, Department of Translational Medical Sciences, Regional Cystic Fibrosis Center, Federico II University
| | - Alice Castaldo
- Pediatric Unit, Department of Translational Medical Sciences, Regional Cystic Fibrosis Center, Federico II University
| | - Chiara Cimbalo
- Pediatric Unit, Department of Translational Medical Sciences, Regional Cystic Fibrosis Center, Federico II University
| | - Roberto Buzzetti
- Pediatric Unit, Department of Translational Medical Sciences, Regional Cystic Fibrosis Center, Federico II University
- Freelance Epidemiologist, Bergamo, Italy
| | - Valeria Raia
- Pediatric Unit, Department of Translational Medical Sciences, Regional Cystic Fibrosis Center, Federico II University
| | - Marco Berlucchi
- Unit of Pediatric Otorhinolaryngology, ASST Spedali Civili Brescia
| | - Silviana Timpano
- Paediatric Department, Cystic Fibrosis Support Centre, University of Brescia, ASST Spedali Civili Brescia
| | - Raffaele Badolato
- Paediatric Department, Cystic Fibrosis Support Centre, University of Brescia, ASST Spedali Civili Brescia
- Department of Molecular and Translational Medicine, Angelo Nocivelli Institute for Molecular Medicine, University of Brescia, Brescia
| | - Rita Padoan
- Paediatric Department, Cystic Fibrosis Support Centre, University of Brescia, ASST Spedali Civili Brescia
- Department of Molecular and Translational Medicine, Angelo Nocivelli Institute for Molecular Medicine, University of Brescia, Brescia
| | - Claudio Orlando
- Department of Pediatric Respiratory Endoscopy and Difficult Airways Management, Naples
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20
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Albers S, Allen EC, Bharti N, Davyt M, Joshi D, Perez-Garcia CG, Santos L, Mukthavaram R, Delgado-Toscano MA, Molina B, Kuakini K, Alayyoubi M, Park KJJ, Acharya G, Gonzalez JA, Sagi A, Birket SE, Tearney GJ, Rowe SM, Manfredi C, Hong JS, Tachikawa K, Karmali P, Matsuda D, Sorscher EJ, Chivukula P, Ignatova Z. Engineered tRNAs suppress nonsense mutations in cells and in vivo. Nature 2023; 618:842-848. [PMID: 37258671 PMCID: PMC10284701 DOI: 10.1038/s41586-023-06133-1] [Citation(s) in RCA: 57] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 04/25/2023] [Indexed: 06/02/2023]
Abstract
Nonsense mutations are the underlying cause of approximately 11% of all inherited genetic diseases1. Nonsense mutations convert a sense codon that is decoded by tRNA into a premature termination codon (PTC), resulting in an abrupt termination of translation. One strategy to suppress nonsense mutations is to use natural tRNAs with altered anticodons to base-pair to the newly emerged PTC and promote translation2-7. However, tRNA-based gene therapy has not yielded an optimal combination of clinical efficacy and safety and there is presently no treatment for individuals with nonsense mutations. Here we introduce a strategy based on altering native tRNAs into efficient suppressor tRNAs (sup-tRNAs) by individually fine-tuning their sequence to the physico-chemical properties of the amino acid that they carry. Intravenous and intratracheal lipid nanoparticle (LNP) administration of sup-tRNA in mice restored the production of functional proteins with nonsense mutations. LNP-sup-tRNA formulations caused no discernible readthrough at endogenous native stop codons, as determined by ribosome profiling. At clinically important PTCs in the cystic fibrosis transmembrane conductance regulator gene (CFTR), the sup-tRNAs re-established expression and function in cell systems and patient-derived nasal epithelia and restored airway volume homeostasis. These results provide a framework for the development of tRNA-based therapies with a high molecular safety profile and high efficacy in targeted PTC suppression.
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Affiliation(s)
- Suki Albers
- Institute of Biochemistry and Molecular Biology, University of Hamburg, Hamburg, Germany
| | | | - Nikhil Bharti
- Institute of Biochemistry and Molecular Biology, University of Hamburg, Hamburg, Germany
| | - Marcos Davyt
- Institute of Biochemistry and Molecular Biology, University of Hamburg, Hamburg, Germany
| | - Disha Joshi
- Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA, USA
- Children's Healthcare of Atlanta, Atlanta, GA, USA
| | | | - Leonardo Santos
- Institute of Biochemistry and Molecular Biology, University of Hamburg, Hamburg, Germany
| | | | | | | | | | | | | | | | | | - Amit Sagi
- Arcturus Therapeutics, San Diego, CA, USA
| | - Susan E Birket
- Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Guillermo J Tearney
- Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA, USA
- Harvard-MIT Health Sciences and Technology, MA, Cambridge, USA
| | - Steven M Rowe
- Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Candela Manfredi
- Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA, USA
- Children's Healthcare of Atlanta, Atlanta, GA, USA
| | - Jeong S Hong
- Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA, USA
- Children's Healthcare of Atlanta, Atlanta, GA, USA
| | | | | | | | - Eric J Sorscher
- Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA, USA.
- Children's Healthcare of Atlanta, Atlanta, GA, USA.
| | | | - Zoya Ignatova
- Institute of Biochemistry and Molecular Biology, University of Hamburg, Hamburg, Germany.
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21
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Myszor IT, Gudmundsson GH. Modulation of innate immunity in airway epithelium for host-directed therapy. Front Immunol 2023; 14:1197908. [PMID: 37251385 PMCID: PMC10213533 DOI: 10.3389/fimmu.2023.1197908] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Accepted: 04/24/2023] [Indexed: 05/31/2023] Open
Abstract
Innate immunity of the mucosal surfaces provides the first-line defense from invading pathogens and pollutants conferring protection from the external environment. Innate immune system of the airway epithelium consists of several components including the mucus layer, mucociliary clearance of beating cilia, production of host defense peptides, epithelial barrier integrity provided by tight and adherens junctions, pathogen recognition receptors, receptors for chemokines and cytokines, production of reactive oxygen species, and autophagy. Therefore, multiple components interplay with each other for efficient protection from pathogens that still can subvert host innate immune defenses. Hence, the modulation of innate immune responses with different inducers to boost host endogenous front-line defenses in the lung epithelium to fend off pathogens and to enhance epithelial innate immune responses in the immunocompromised individuals is of interest for host-directed therapy. Herein, we reviewed possibilities of modulation innate immune responses in the airway epithelium for host-directed therapy presenting an alternative approach to standard antibiotics.
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Affiliation(s)
- Iwona T. Myszor
- Faculty of Life and Environmental Sciences, Biomedical Center, University of Iceland, Reykjavik, Iceland
| | - Gudmundur Hrafn Gudmundsson
- Faculty of Life and Environmental Sciences, Biomedical Center, University of Iceland, Reykjavik, Iceland
- Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
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22
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Lemmens-Gruber R, Tzotzos S. The Epithelial Sodium Channel-An Underestimated Drug Target. Int J Mol Sci 2023; 24:ijms24097775. [PMID: 37175488 PMCID: PMC10178586 DOI: 10.3390/ijms24097775] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 04/14/2023] [Accepted: 04/15/2023] [Indexed: 05/15/2023] Open
Abstract
Epithelial sodium channels (ENaC) are part of a complex network of interacting biochemical pathways and as such are involved in several disease states. Dependent on site and type of mutation, gain- or loss-of-function generated symptoms occur which span from asymptomatic to life-threatening disorders such as Liddle syndrome, cystic fibrosis or generalized pseudohypoaldosteronism type 1. Variants of ENaC which are implicated in disease assist further understanding of their molecular mechanisms in order to create models for specific pharmacological targeting. Identification and characterization of ENaC modifiers not only furthers our basic understanding of how these regulatory processes interact, but also enables discovery of new therapeutic targets for the disease conditions caused by ENaC dysfunction. Numerous test compounds have revealed encouraging results in vitro and in animal models but less in clinical settings. The EMA- and FDA-designated orphan drug solnatide is currently being tested in phase 2 clinical trials in the setting of acute respiratory distress syndrome, and the NOX1/ NOX4 inhibitor setanaxib is undergoing clinical phase 2 and 3 trials for therapy of primary biliary cholangitis, liver stiffness, and carcinoma. The established ENaC blocker amiloride is mainly used as an add-on drug in the therapy of resistant hypertension and is being studied in ongoing clinical phase 3 and 4 trials for special applications. This review focuses on discussing some recent developments in the search for novel therapeutic agents.
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Affiliation(s)
- Rosa Lemmens-Gruber
- Department of Pharmaceutical Sciences, Division of Pharmacology and Toxicology, University of Vienna, A-1090 Vienna, Austria
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23
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Pellielo G, Agyapong ED, Pinton P, Rimessi A. Control of mitochondrial functions by Pseudomonas aeruginosa in cystic fibrosis. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2023; 377:19-43. [PMID: 37268349 DOI: 10.1016/bs.ircmb.2023.03.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Cystic fibrosis (CF) is a genetic disease characterized by mutations of cystic fibrosis transmembrane conductance regulator (CFTR) gene, which lead to a dysfunctional chloride and bicarbonate channel. Abnormal mucus viscosity, persistent infections and hyperinflammation that preferentially affect the airways, referred to the pathogenesis of CF lung disease. It has largely demonstrated that Pseudomonas aeruginosa (P. aeruginosa) represents the most important pathogen that affect CF patients, leading to worsen inflammation by stimulating pro-inflammatory mediators release and tissue destruction. The conversion to mucoid phenotype and formation of biofilms, together with the increased frequency of mutations, are only few changes that characterize the P. aeruginosa's evolution during CF lung chronic infection. Recently, mitochondria received increasing attention due to their involvement in inflammatory-related diseases, including in CF. Alteration of mitochondrial homeostasis is sufficient to stimulate immune response. Exogenous or endogenous stimuli that perturb mitochondrial activity are used by cells, which, through the mitochondrial stress, potentiate immunity programs. Studies show the relationship between mitochondria and CF, supporting the idea that mitochondrial dysfunction endorses the exacerbation of inflammatory responses in CF lung. In particular, evidences suggest that mitochondria in CF airway cells are more susceptible to P. aeruginosa infection, with consequent detrimental effects that lead to amplify the inflammatory signals. This review discusses the evolution of P. aeruginosa in relationship with the pathogenesis of CF, a fundamental step to establish chronic infection in CF lung disease. Specifically, we focus on the role of P. aeruginosa in the exacerbation of inflammatory response, by triggering mitochondria in CF.
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Affiliation(s)
- Giulia Pellielo
- Department of Medical Sciences, Section of Experimental Medicine, Laboratory for Technologies of Advanced Therapies, University of Ferrara, Ferrara, Italy
| | - Esther Densu Agyapong
- Department of Medical Sciences, Section of Experimental Medicine, Laboratory for Technologies of Advanced Therapies, University of Ferrara, Ferrara, Italy
| | - Paolo Pinton
- Department of Medical Sciences, Section of Experimental Medicine, Laboratory for Technologies of Advanced Therapies, University of Ferrara, Ferrara, Italy; Center of research for innovative therapies in cystic fibrosis, University of Ferrara, Ferrara, Italy
| | - Alessandro Rimessi
- Department of Medical Sciences, Section of Experimental Medicine, Laboratory for Technologies of Advanced Therapies, University of Ferrara, Ferrara, Italy; Center of research for innovative therapies in cystic fibrosis, University of Ferrara, Ferrara, Italy.
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24
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Rehman T, Welsh MJ. Inflammation as a Regulator of the Airway Surface Liquid pH in Cystic Fibrosis. Cells 2023; 12:1104. [PMID: 37190013 PMCID: PMC10137218 DOI: 10.3390/cells12081104] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 04/05/2023] [Accepted: 04/06/2023] [Indexed: 05/17/2023] Open
Abstract
The airway surface liquid (ASL) is a thin sheet of fluid that covers the luminal aspect of the airway epithelium. The ASL is a site of several first-line host defenses, and its composition is a key factor that determines respiratory fitness. Specifically, the acid-base balance of ASL has a major influence on the vital respiratory defense processes of mucociliary clearance and antimicrobial peptide activity against inhaled pathogens. In the inherited disorder cystic fibrosis (CF), loss of cystic fibrosis transmembrane conductance regulator (CFTR) anion channel function reduces HCO3- secretion, lowers the pH of ASL (pHASL), and impairs host defenses. These abnormalities initiate a pathologic process whose hallmarks are chronic infection, inflammation, mucus obstruction, and bronchiectasis. Inflammation is particularly relevant as it develops early in CF and persists despite highly effective CFTR modulator therapy. Recent studies show that inflammation may alter HCO3- and H+ secretion across the airway epithelia and thus regulate pHASL. Moreover, inflammation may enhance the restoration of CFTR channel function in CF epithelia exposed to clinically approved modulators. This review focuses on the complex relationships between acid-base secretion, airway inflammation, pHASL regulation, and therapeutic responses to CFTR modulators. These factors have important implications for defining optimal ways of tackling CF airway inflammation in the post-modulator era.
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Affiliation(s)
- Tayyab Rehman
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
| | - Michael J. Welsh
- Departments of Internal Medicine and Molecular Physiology and Biophysics, Pappajohn Biomedical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
- Howard Hughes Medical Institute, University of Iowa, Iowa City, IA 52242, USA
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25
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Ribeiro CMP, Higgs MG, Muhlebach MS, Wolfgang MC, Borgatti M, Lampronti I, Cabrini G. Revisiting Host-Pathogen Interactions in Cystic Fibrosis Lungs in the Era of CFTR Modulators. Int J Mol Sci 2023; 24:ijms24055010. [PMID: 36902441 PMCID: PMC10003689 DOI: 10.3390/ijms24055010] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 02/25/2023] [Accepted: 03/02/2023] [Indexed: 03/08/2023] Open
Abstract
Cystic fibrosis transmembrane conductance regulator (CFTR) modulators, a new series of therapeutics that correct and potentiate some classes of mutations of the CFTR, have provided a great therapeutic advantage to people with cystic fibrosis (pwCF). The main hindrances of the present CFTR modulators are related to their limitations in reducing chronic lung bacterial infection and inflammation, the main causes of pulmonary tissue damage and progressive respiratory insufficiency, particularly in adults with CF. Here, the most debated issues of the pulmonary bacterial infection and inflammatory processes in pwCF are revisited. Special attention is given to the mechanisms favoring the bacterial infection of pwCF, the progressive adaptation of Pseudomonas aeruginosa and its interplay with Staphylococcus aureus, the cross-talk among bacteria, the bronchial epithelial cells and the phagocytes of the host immune defenses. The most recent findings of the effect of CFTR modulators on bacterial infection and the inflammatory process are also presented to provide critical hints towards the identification of relevant therapeutic targets to overcome the respiratory pathology of pwCF.
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Affiliation(s)
- Carla M. P. Ribeiro
- Marsico Lung Institute/Cystic Fibrosis Research Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Correspondence: (C.M.P.R.); (G.C.)
| | - Matthew G. Higgs
- Marsico Lung Institute/Cystic Fibrosis Research Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Marianne S. Muhlebach
- Marsico Lung Institute/Cystic Fibrosis Research Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Department of Pediatrics, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Matthew C. Wolfgang
- Marsico Lung Institute/Cystic Fibrosis Research Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Monica Borgatti
- Department of Life Sciences and Biotechnology, University of Ferrara, 44121 Ferrara, Italy
- Innthera4CF, Center on Innovative Therapies for Cystic Fibrosis, University of Ferrara, 44121 Ferrara, Italy
| | - Ilaria Lampronti
- Department of Life Sciences and Biotechnology, University of Ferrara, 44121 Ferrara, Italy
- Innthera4CF, Center on Innovative Therapies for Cystic Fibrosis, University of Ferrara, 44121 Ferrara, Italy
| | - Giulio Cabrini
- Department of Life Sciences and Biotechnology, University of Ferrara, 44121 Ferrara, Italy
- Innthera4CF, Center on Innovative Therapies for Cystic Fibrosis, University of Ferrara, 44121 Ferrara, Italy
- Correspondence: (C.M.P.R.); (G.C.)
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26
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The Role of MMPs in the Era of CFTR Modulators: An Additional Target for Cystic Fibrosis Patients? Biomolecules 2023; 13:biom13020350. [PMID: 36830719 PMCID: PMC9952876 DOI: 10.3390/biom13020350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 01/27/2023] [Accepted: 02/08/2023] [Indexed: 02/15/2023] Open
Abstract
Cystic fibrosis (CF) is a high-prevalence disease characterized by significant lung remodeling, responsible for high morbidity and mortality worldwide. The lung structural changes are partly due to proteolytic activity associated with inflammatory cells such as neutrophils and macrophages. Matrix metalloproteases (MMPs) are the major proteases involved in CF, and recent literature data focused on their potential role in the pathogenesis of the disease. In fact, an imbalance of proteases and antiproteases was observed in CF patients, resulting in dysfunction of protease activity and loss of lung homeostasis. Currently, many steps forward have been moved in the field of pharmacological treatment with the recent introduction of triple-combination therapy targeting the CFTR channel. Despite CFTR modulator therapy potentially being effective in up to 90% of patients with CF, there are still patients who are not eligible for the available therapies. Here, we introduce experimental drugs to provide updates on therapy evolution regarding a proportion of CF non-responder patients to current treatment, and we summarize the role of MMPs in pathogenesis and as future therapeutic targets of CF.
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27
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Baines DL, Vasiljevs S, Kalsi KK. Getting sweeter: new evidence for glucose transporters in specific cell types of the airway? Am J Physiol Cell Physiol 2023; 324:C153-C166. [PMID: 36409177 PMCID: PMC9829484 DOI: 10.1152/ajpcell.00140.2022] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
New technologies such as single-cell RNA sequencing (scRNAseq) has enabled identification of the mRNA transcripts expressed by individual cells. This review provides insight from recent scRNAseq studies on the expression of glucose transporters in the epithelial cells of the airway epithelium from trachea to alveolus. The number of studies analyzed was limited, not all reported the full range of glucose transporters and there were differences between cells freshly isolated from the airways and those grown in vitro. Furthermore, glucose transporter mRNA transcripts were expressed at lower levels than other epithelial marker genes. Nevertheless, these studies highlighted that there were differences in cellular expression of glucose transporters. GLUT1 was the most abundant of the broadly expressed transporters that included GLUT8, 10, and 13. GLUT9 transcripts were more common in basal cells and GLUT12 in ionocytes/ciliated cells. In addition to alveolar cells, SGLT1 transcripts were present in secretory cells. GLUT3 mRNA transcripts were expressed in a cell cluster that expressed monocarboxylate (MCT2) transporters. Such distributions likely underlie cell-specific metabolic requirements to support proliferation, ion transport, mucous secretion, environment sensing, and airway glucose homeostasis. These studies have also highlighted the role of glucose transporters in the movement of dehydroascorbic acid/vitamin C/myoinositol/urate, which are factors important to the innate immune properties of the airways. Discrepancies remain between detection of mRNAs, protein, and function of glucose transporters in the lungs. However, collation of the data from further scRNAseq studies may provide a better consensus and understanding, supported by qPCR, immunohistochemistry, and functional experiments.
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Affiliation(s)
- Deborah L. Baines
- Institute for Infection and Immunity, St George’s, University of London, London, United Kingdom
| | - Stanislavs Vasiljevs
- Institute for Infection and Immunity, St George’s, University of London, London, United Kingdom
| | - Kameljit K. Kalsi
- Institute for Infection and Immunity, St George’s, University of London, London, United Kingdom
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28
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Meoli A, Eickmeier O, Pisi G, Fainardi V, Zielen S, Esposito S. Impact of CFTR Modulators on the Impaired Function of Phagocytes in Cystic Fibrosis Lung Disease. Int J Mol Sci 2022; 23:12421. [PMID: 36293274 PMCID: PMC9604330 DOI: 10.3390/ijms232012421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 10/13/2022] [Accepted: 10/14/2022] [Indexed: 11/17/2022] Open
Abstract
Cystic fibrosis (CF), the most common genetically inherited disease in Caucasian populations, is a multi-systemic life-threatening autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. In 2012, the arrival of CFTR modulators (potentiators, correctors, amplifiers, stabilizers, and read-through agents) revolutionized the therapeutic approach to CF. In this review, we examined the physiopathological mechanism of chronic dysregulated innate immune response in the lungs of CF patients with pulmonary involvement with particular reference to phagocytes, critically analyzing the role of CFTR modulators in influencing and eventually restoring their function. Our literature review highlighted that the role of CFTR in the lungs is crucial not only for the epithelial function but also for host defense, with particular reference to phagocytes. In macrophages and neutrophils, the CFTR dysfunction compromises both the intricate process of phagocytosis and the mechanisms of initiation and control of inflammation which then reverberates on the epithelial environment already burdened by the chronic colonization of pathogens leading to irreversible tissue damage. In this context, investigating the impact of CFTR modulators on phagocytic functions is therefore crucial not only for explaining the underlying mechanisms of pleiotropic effects of these molecules but also to better understand the physiopathological basis of this disease, still partly unexplored, and to develop new complementary or alternative therapeutic approaches.
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Affiliation(s)
- Aniello Meoli
- Pediatric Clinic, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
- Division of Allergy, Pulmonology and Cystic Fibrosis, Department for Children and Adolescents, University Hospital, 60431 Frankfurt, Germany
| | - Olaf Eickmeier
- Division of Allergy, Pulmonology and Cystic Fibrosis, Department for Children and Adolescents, University Hospital, 60431 Frankfurt, Germany
| | - Giovanna Pisi
- Pediatric Clinic, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
| | - Valentina Fainardi
- Pediatric Clinic, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
| | - Stefan Zielen
- Division of Allergy, Pulmonology and Cystic Fibrosis, Department for Children and Adolescents, University Hospital, 60431 Frankfurt, Germany
| | - Susanna Esposito
- Pediatric Clinic, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
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29
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Almulhem M, Harnett N, Graham S, Haq I, Visram S, Ward C, Brodlie M. Exploring the impact of elexacaftor-tezacaftor-ivacaftor treatment on opinions regarding airway clearance techniques and nebulisers: TEMPO a qualitative study in children with cystic fibrosis, their families and healthcare professionals. BMJ Open Respir Res 2022; 9:9/1/e001420. [PMID: 36207030 PMCID: PMC9557266 DOI: 10.1136/bmjresp-2022-001420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 09/24/2022] [Indexed: 11/05/2022] Open
Abstract
Background Cystic fibrosis (CF) is a genetic condition caused by variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that primarily impacts the lungs. Treatments historically have been symptomatic to improve airway clearance and treat infection. However, CFTR modulator drugs have recently been developed that target the underlying defect. The triple combination of elexacaftor-tezacaftor-ivacaftor (ETI) was approved in 2020 in England for over 80% of people with CF aged over 12 years and in 2022 extended to those over 6 years. ETI treatment is associated with substantial improvements in lung function. The experience of children with CF starting on ETI or their views regarding future treatments have not been well studied. This study aimed to explore the opinions of children with CF, their parents/carers and healthcare professionals (HCPs) on the impact of ETI, airway clearance techniques (ACTs) and nebulised treatments. Methods Semistructured qualitative interviews were performed with 10 children with CF, 7 parents/carers and 10 HCPs. Audio recordings were transcribed and analysed using reflexive thematic analysis. Results Four main themes were identified: ‘Kaftrio changed my life’, ‘Your entire life is dictated by the CF timetable’, ‘Simplifying treatment-hopes and fears’ and ‘Kaftrio is a game-changer’ along with several subthemes and an overarching theme of ‘I still can’t get my head around how three tablets can do what Kaftrio done’. Conclusions Despite the highly positive impact of ETI on the health of children with CF some concerns remain about the longer-term outcomes of reducing ACTs or nebulised treatments. ETI has prompted a shift in treatment for many and offers an opportunity to personalise approaches.
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Affiliation(s)
- Maryam Almulhem
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK,College of Applied Medical Sciences, King Faisal University, Al-Ahsa, Saudi Arabia
| | - Nuala Harnett
- Physiotherapy, Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Stephanie Graham
- Physiotherapy, Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Iram Haq
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK,Paediatric Respiratory Medicine, Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Shelina Visram
- Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Christopher Ward
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Malcolm Brodlie
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK,Paediatric Respiratory Medicine, Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
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30
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Rehman T, Karp PH, Thurman AL, Mather SE, Jain A, Cooney AL, Sinn PL, Pezzulo AA, Duffey ME, Welsh MJ. WNK Inhibition Increases Surface Liquid pH and Host Defense in Cystic Fibrosis Airway Epithelia. Am J Respir Cell Mol Biol 2022; 67:491-502. [PMID: 35849656 PMCID: PMC9564924 DOI: 10.1165/rcmb.2022-0172oc] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 07/18/2022] [Indexed: 02/05/2023] Open
Abstract
In cystic fibrosis (CF), reduced HCO3- secretion acidifies the airway surface liquid (ASL), and the acidic pH disrupts host defenses. Thus, understanding the control of ASL pH (pHASL) in CF may help identify novel targets and facilitate therapeutic development. In diverse epithelia, the WNK (with-no-lysine [K]) kinases coordinate HCO3- and Cl- transport, but their functions in airway epithelia are poorly understood. Here, we tested the hypothesis that WNK kinases regulate CF pHASL. In primary cultures of differentiated human airway epithelia, inhibiting WNK kinases acutely increased both CF and non-CF pHASL. This response was HCO3- dependent and involved downstream SPAK/OSR1 (Ste20/SPS1-related proline-alanine-rich protein kinase/oxidative stress responsive 1 kinase). Importantly, WNK inhibition enhanced key host defenses otherwise impaired in CF. Human airway epithelia expressed two WNK isoforms in secretory cells and ionocytes, and knockdown of either WNK1 or WNK2 increased CF pHASL. WNK inhibition decreased Cl- secretion and the response to bumetanide, an NKCC1 (sodium-potassium-chloride cotransporter 1) inhibitor. Surprisingly, bumetanide alone or basolateral Cl- substitution also alkalinized CF pHASL. These data suggest that WNK kinases influence the balance between transepithelial Cl- versus HCO3- secretion. Moreover, reducing basolateral Cl- entry may increase HCO3- secretion and raise pHASL, thereby improving CF host defenses.
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Affiliation(s)
| | - Philip H. Karp
- Department of Internal Medicine and
- Howard Hughes Medical Institute, University of Iowa, Iowa City, Iowa; and
| | | | | | | | | | | | | | - Michael E. Duffey
- Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York
| | - Michael J. Welsh
- Department of Internal Medicine and
- Department of Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, and
- Howard Hughes Medical Institute, University of Iowa, Iowa City, Iowa; and
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31
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The CFTR Amplifier Nesolicaftor Rescues TGF-β1 Inhibition of Modulator-Corrected F508del CFTR Function. Int J Mol Sci 2022; 23:ijms231810956. [PMID: 36142862 PMCID: PMC9504033 DOI: 10.3390/ijms231810956] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 09/13/2022] [Accepted: 09/15/2022] [Indexed: 11/16/2022] Open
Abstract
Highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulators have led to dramatic improvements in lung function in many people with cystic fibrosis (PwCF). However, the efficacy of CFTR modulators may be hindered by persistent airway inflammation. The cytokine transforming growth factor-beta1 (TGF-β1) is associated with worse pulmonary disease in PwCF and can diminish modulator efficacy. Thus, strategies to augment the CFTR response to modulators in an inflammatory environment are needed. Here, we tested whether the CFTR amplifier nesolicaftor (or PTI-428) could rescue the effects of TGF-β1 on CFTR function and ciliary beating in primary human CF bronchial epithelial (CFBE) cells. CFBE cells homozygous for F508del were treated with the combination of elexacaftor/tezacaftor/ivacaftor (ETI) and TGF-β1 in the presence and absence of nesolicaftor. Nesolicaftor augmented the F508del CFTR response to ETI and reversed TGF-β1-induced reductions in CFTR conductance by increasing the expression of CFTR mRNA. Nesolicaftor further rescued the reduced ciliary beating and increased expression of the cytokines IL-6 and IL-8 caused by TGF-β1. Finally, nesolicaftor augmented the F508del CFTR response to ETI in CFBE cells overexpressing miR-145, a negative regulator of CFTR expression. Thus, CFTR amplifiers, but only when used with highly effective modulators, may provide benefit in an inflamed environment.
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32
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Wrigley-Carr HE, van Dorst JM, Ooi CY. Intestinal dysbiosis and inflammation in cystic fibrosis impacts gut and multi-organ axes. MEDICINE IN MICROECOLOGY 2022. [DOI: 10.1016/j.medmic.2022.100057] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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33
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Schwarz C, Procaccianti C, Costa L, Brini R, Friend R, Caivano G, Sadafi H, Mussche C, Schwenck N, Hahn M, Murgia X, Bianco F. Differential Performance and Lung Deposition of Levofloxacin with Different Nebulisers Used in Cystic Fibrosis. Int J Mol Sci 2022; 23:ijms23179597. [PMID: 36076992 PMCID: PMC9455972 DOI: 10.3390/ijms23179597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 08/15/2022] [Accepted: 08/19/2022] [Indexed: 11/16/2022] Open
Abstract
We compared the performance and levofloxacin (Quinsair) lung deposition of three nebulisers commonly used in CF (I-Neb Advance, eFlow rapid, and LC Plus) with the approved nebuliser Zirela. The delivered dose, delivery rate, and aerosol particle size distribution (APSD) for each device were determined using the methods described in the Pharmacopeia. High-resolution computed tomography scans obtained from seven adult patients with mild CF were used to generate computer-aided, three-dimensional models of their airway tree to assess lung deposition using functional respiratory imaging (FRI). The eFlow rapid and the LC Plus showed poor delivery efficiencies due to their high residual volumes. The I-Neb, which only delivers aerosols during the inspiratory phase, achieved the highest aerosol delivery efficiency. However, the I-Neb showed the largest particle size and lowest delivery rate (2.9 mg/min), which were respectively associated with a high extrathoracic deposition and extremely long nebulisation times (>20 min). Zirela showed the best performance considering delivery efficiency (159.6 mg out of a nominal dose of 240 mg), delivery rate (43.5 mg/min), and lung deposition (20% of the nominal dose), requiring less than 5 min to deliver a full dose of levofloxacin. The present study supports the use of drug-specific nebulisers and discourages the off-label use of general-purpose devices with the present levofloxacin formulation since subtherapeutic lung doses and long nebulisation times may compromise treatment efficacy and adherence.
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Affiliation(s)
- Carsten Schwarz
- Division Cystic Fibrosis, CF Center Westbrandenburg, Campus Potsdam, Clinic Westbrandenburg, 14467 Potsdam, Germany
| | | | - Laura Costa
- Global Medical Affairs, Chiesi Farmaceutici S.p.A., 43122 Parma, Italy
| | - Riccardo Brini
- Global Technical Development, Chiesi Ltd., Chippenham SN14 0AB, UK
| | - Richard Friend
- Global Technical Development, Chiesi Ltd., Chippenham SN14 0AB, UK
| | - Grazia Caivano
- Global Technical Development, Chiesi Farmaceutici S.p.A., 43122 Parma, Italy
| | | | | | | | | | | | - Federico Bianco
- Global Medical Affairs, Chiesi Farmaceutici S.p.A., 43122 Parma, Italy
- Correspondence:
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34
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Philp AR, Miranda F, Gianotti A, Mansilla A, Scudieri P, Musante I, Vega G, Figueroa CD, Galietta LJV, Sarmiento JM, Flores CA. KCa3.1 differentially regulates trachea and bronchi epithelial gene expression in a chronic-asthma mouse model. Physiol Genomics 2022; 54:273-282. [PMID: 35658672 DOI: 10.1152/physiolgenomics.00134.2021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Ion channels are potentially exploitable as pharmacological targets to treat asthma. This study evaluated the role of KCa3.1 channels, encoded by Kcnn4, in regulating the gene expression of mouse airway epithelium and the development of asthma traits. We used the ovalbumin (OVA) challenge as an asthma model in wild type and Kcnn4-/- mice, performed histological analysis, and measured serum IgE to evaluate asthma traits. We analyzed gene expression of isolated epithelial cells of trachea or bronchi using mRNA sequencing and gene ontology and performed Ussing chamber experiments in mouse trachea to evaluate anion secretion. Gene expression of epithelial cells from mouse airways differed between trachea and bronchi, indicating regional differences in the inflammatory and transepithelial transport properties of proximal and distal airways. We found that Kcnn4 silencing reduced mast cell numbers, mucus, and collagen in the airways, and reduced the amount of epithelial anion secretion in the OVA-challenged animals. Additionally, gene expression was differentially modified in the trachea and bronchi, with Kcnn4 genetic silencing significantly altering the expression of genes involved in the TNF pathway, supporting the potential of KCa3.1 as a therapeutic target for asthma.
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Affiliation(s)
- Amber R Philp
- Centro de Estudios Científicos, Valdivia, Los Rios, Chile.,Austral University of Chile, Valdivia, Chile
| | - Fernando Miranda
- Departamento de Fisiología, Austral University of Chile, Valdivia, Chile
| | | | - Agustín Mansilla
- Centro de Estudios Científicos, Valdivia, Los Rios, Chile.,Austral University of Chile, Valdivia, Chile
| | | | | | - Génesis Vega
- Centro de Estudios Científicos, Valdivia, Los Rios, Chile
| | | | - Luis J V Galietta
- TIGEM, Pozzuoli, Italia.,Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
| | - José M Sarmiento
- Departamento de Fisiología, Austral University of Chile, Valdivia, Chile
| | - Carlos A Flores
- Centro de Estudios Científicos, Valdivia, Los Rios, Chile.,Universidad San Sebastián, Valdivia, Chile
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35
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Jackson CL, Bottier M. Methods for the assessment of human airway ciliary function. Eur Respir J 2022; 60:13993003.02300-2021. [PMID: 35595315 DOI: 10.1183/13993003.02300-2021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 04/19/2022] [Indexed: 11/05/2022]
Affiliation(s)
- Claire L Jackson
- Primary Ciliary Dyskinesia Centre, NIHR Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK .,School of Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton, UK
| | - Mathieu Bottier
- Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK
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36
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Cabrini G, Rimessi A, Borgatti M, Pinton P, Gambari R. Overview of CF lung pathophysiology. Curr Opin Pharmacol 2022; 64:102214. [PMID: 35453033 DOI: 10.1016/j.coph.2022.102214] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Revised: 03/02/2022] [Accepted: 03/16/2022] [Indexed: 12/21/2022]
Abstract
Defects of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein affect the homeostasis of chloride, bicarbonate, sodium, and water in the airway surface liquid, influencing the mucus composition and viscosity, which induces a severe condition of infection and inflammation along the whole life of CF patients. The introduction of CFTR modulators, novel drugs directly intervening to rescue the function of CFTR protein, opens a new era of experimental research. The review summarizes the most recent advancements to understand the characteristics of the infective and inflammatory pathology of CF lungs.
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Affiliation(s)
- Giulio Cabrini
- Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy; Center of Innovative Therapies for Cystic Fibrosis, University of Ferrara, Ferrara, Italy.
| | - Alessandro Rimessi
- Department of Medical Sciences, University of Ferrara, Ferrara, Italy; Center of Innovative Therapies for Cystic Fibrosis, University of Ferrara, Ferrara, Italy
| | - Monica Borgatti
- Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy; Center of Innovative Therapies for Cystic Fibrosis, University of Ferrara, Ferrara, Italy
| | - Paolo Pinton
- Department of Medical Sciences, University of Ferrara, Ferrara, Italy; Center of Innovative Therapies for Cystic Fibrosis, University of Ferrara, Ferrara, Italy
| | - Roberto Gambari
- Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy; Center of Innovative Therapies for Cystic Fibrosis, University of Ferrara, Ferrara, Italy
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37
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Gong J, He G, Wang C, Bartlett C, Panjwani N, Mastromatteo S, Lin F, Keenan K, Avolio J, Halevy A, Shaw M, Esmaeili M, Côté-Maurais G, Adam D, Bégin S, Bjornson C, Chilvers M, Reisman J, Price A, Parkins M, van Wylick R, Berthiaume Y, Bilodeau L, Mateos-Corral D, Hughes D, Smith MJ, Morrison N, Brusky J, Tullis E, Stephenson AL, Quon BS, Wilcox P, Leung WM, Solomon M, Sun L, Brochiero E, Moraes TJ, Gonska T, Ratjen F, Rommens JM, Strug LJ. Genetic evidence supports the development of SLC26A9 targeting therapies for the treatment of lung disease. NPJ Genom Med 2022; 7:28. [PMID: 35396391 PMCID: PMC8993824 DOI: 10.1038/s41525-022-00299-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Accepted: 03/04/2022] [Indexed: 12/19/2022] Open
Abstract
Over 400 variants in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) are CF-causing. CFTR modulators target variants to improve lung function, but marked variability in response exists and current therapies do not address all CF-causing variants highlighting unmet needs. Alternative epithelial ion channel/transporters such as SLC26A9 could compensate for CFTR dysfunction, providing therapeutic targets that may benefit all individuals with CF. We investigate the relationship between rs7512462, a marker of SLC26A9 activity, and lung function pre- and post-treatment with CFTR modulators in Canadian and US CF cohorts, in the general population, and in those with chronic obstructive pulmonary disease (COPD). Rs7512462 CC genotype is associated with greater lung function in CF individuals with minimal function variants (for which there are currently no approved therapies; p = 0.008); and for gating (p = 0.033) and p.Phe508del/ p.Phe508del (p = 0.006) genotypes upon treatment with CFTR modulators. In parallel, human nasal epithelia with CC and p.Phe508del/p.Phe508del after Ussing chamber analysis of a combination of approved and experimental modulator treatments show greater CFTR function (p = 0.0022). Beyond CF, rs7512462 is associated with peak expiratory flow in a meta-analysis of the UK Biobank and Spirometa Consortium (p = 2.74 × 10-44) and provides p = 0.0891 in an analysis of COPD case-control status in the UK Biobank defined by spirometry. These findings support SLC26A9 as a therapeutic target to improve lung function for all people with CF and in individuals with other obstructive lung diseases.
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Affiliation(s)
- Jiafen Gong
- Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada
| | - Gengming He
- Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada
- Biostatistics Division, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
| | - Cheng Wang
- Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada
| | - Claire Bartlett
- Program in Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada
| | - Naim Panjwani
- Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada
| | - Scott Mastromatteo
- Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada
| | - Fan Lin
- Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada
| | - Katherine Keenan
- Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada
- Program in Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada
| | - Julie Avolio
- Program in Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada
| | - Anat Halevy
- Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada
| | - Michelle Shaw
- Program in Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada
| | - Mohsen Esmaeili
- Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada
| | - Guillaume Côté-Maurais
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada
| | - Damien Adam
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada
- Department of Medicine, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada
| | - Stéphanie Bégin
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada
| | | | - Mark Chilvers
- British Columbia Children's Hospital, Vancouver, BC, Canada
| | - Joe Reisman
- The Children's Hospital of Eastern Ontario, Ottawa, ON, Canada
| | - April Price
- The Children's Hospital, London Health Science Centre, London, ON, Canada
| | | | | | - Yves Berthiaume
- Department of Medicine, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada
| | - Lara Bilodeau
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval, Québec City, QC, Canada
| | | | | | - Mary J Smith
- Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, Canada
| | - Nancy Morrison
- Queen Elizabeth II Health Sciences Centre, Halifax, NS, Canada
| | - Janna Brusky
- Department of Pediatrics, University of Saskatchewan, Saskatoon, SK, Canada
| | | | | | | | | | | | - Melinda Solomon
- Respiratory Medicine, Hospital for Sick Children, Toronto, ON, Canada
- Department of Paediatrics, University of Toronto, Toronto, ON, Canada
| | - Lei Sun
- Biostatistics Division, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
- Department of Statistical Sciences, University of Toronto, Toronto, ON, Canada
| | - Emmanuelle Brochiero
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada
- Department of Medicine, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada
| | - Theo J Moraes
- Program in Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada
- Respiratory Medicine, Hospital for Sick Children, Toronto, ON, Canada
| | - Tanja Gonska
- Program in Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada
- Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, ON, Canada
| | - Felix Ratjen
- Program in Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada
- Department of Paediatrics, University of Toronto, Toronto, ON, Canada
| | - Johanna M Rommens
- Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Lisa J Strug
- Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
- Biostatistics Division, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
- Department of Statistical Sciences, University of Toronto, Toronto, ON, Canada.
- The Centre for Applied Genomics, Hospital for Sick Children, Toronto, ON, Canada.
- Department of Computer Science, University of Toronto, Toronto, ON, Canada.
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38
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Jiang X, Wu K, Bai R, Zhang P, Zhang Y. Functionalized quinoxalinones as privileged structures with broad-ranging pharmacological activities. Eur J Med Chem 2022; 229:114085. [PMID: 34998058 DOI: 10.1016/j.ejmech.2021.114085] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 12/16/2021] [Accepted: 12/24/2021] [Indexed: 02/08/2023]
Abstract
Quinoxalinones are a class of heterocyclic compounds which attract extensive attention owing to their potential in the field of organic synthesis and medicinal chemistry. During the past few decades, many new synthetic strategies toward the functionalization of quinoxalinone based scaffolds have been witnessed. Regrettably, there are only a few reports on the pharmacological activities of quinoxalinone scaffolds from a medicinal chemistry perspective. Therefore, herein we intend to outline the applications of multifunctional quinoxalinones as privileged structures possessing various biological activities, including anticancer, neuroprotective, antibacterial, antiviral, antiparasitic, anti-inflammatory, antiallergic, anti-cardiovascular, anti-diabetes, antioxidation, etc. We hope that this review will facilitate the development of quinoxalinone derivatives in medicinal chemistry.
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Affiliation(s)
- Xiaoying Jiang
- Hunan Provincial Key Laboratory of Micro & Nano Materials Interface Science, College of Chemistry and Chemical Engineering, Central South University, Changsha, 410083, PR China; College of Material, Chemistry and Chemical Engineering, Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education, Hangzhou Normal University, Hangzhou, 311121, PR China
| | - Kaiyu Wu
- College of Material, Chemistry and Chemical Engineering, Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education, Hangzhou Normal University, Hangzhou, 311121, PR China
| | - Renren Bai
- School of Pharmacy, Hangzhou Normal University, Hangzhou, 311121, PR China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, 311121, PR China.
| | - Pengfei Zhang
- College of Material, Chemistry and Chemical Engineering, Key Laboratory of Organosilicon Chemistry and Material Technology, Ministry of Education, Hangzhou Normal University, Hangzhou, 311121, PR China.
| | - Yi Zhang
- Hunan Provincial Key Laboratory of Micro & Nano Materials Interface Science, College of Chemistry and Chemical Engineering, Central South University, Changsha, 410083, PR China.
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39
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Haq I, Almulhem M, Soars S, Poulton D, Brodlie M. Precision Medicine Based on CFTR Genotype for People with Cystic Fibrosis. Pharmgenomics Pers Med 2022; 15:91-104. [PMID: 35153502 PMCID: PMC8828078 DOI: 10.2147/pgpm.s245603] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 01/24/2022] [Indexed: 12/22/2022] Open
Abstract
Cystic fibrosis (CF) is an autosomal recessive genetic condition that is caused by variants in the cystic fibrosis transmembrane conductance regulator gene. This causes multisystem disease due to dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel at the apical surface of epithelia. Until recently, treatment was directed at managing the downstream effects in affected organs, principally improving airway clearance and treating infection in the lungs and improving malabsorption in the gastrointestinal tract. Care delivered by multidisciplinary teams has yielded incremental improvements in outcomes. However, the development of small-molecule CFTR modulator drugs over the last decade has heralded a new era of CF therapeutics. Modulators target the underlying defect and improve CFTR function. Either monotherapy or a combination of modulators is used depending on the specific genotype and class of CFTR disease-causing variants that an individual has. Both ivacaftor and the ivacaftor/tezacaftor/elexacaftor combination have been demonstrated to be associated with clinically very significant benefits in randomised trials and have rapidly been made available as part of standard care in many countries. CFTR modulators represent one of the best examples of precision medicine to date. They are expensive, however, and equity of access to them worldwide remains an issue. Studies and approvals are also ongoing for children under the age of 6 years for ivacaftor/tezacaftor/elexacaftor. Furthermore, no modulators are available for around 10% of the people with CF. In this review, we firstly summarise the genetics, pathophysiology and clinical problems associated with CF. We then discuss the development of CFTR modulators and key clinical trials to support their use along with other potential future therapeutic approaches.
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Affiliation(s)
- Iram Haq
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- Paediatric Respiratory Medicine, Great North Children’s Hospital, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Maryam Almulhem
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Simone Soars
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - David Poulton
- Paediatric Respiratory Medicine, Great North Children’s Hospital, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
- Paediatrics, Ninewells Hospital, NHS Tayside, Dundee, UK
| | - Malcolm Brodlie
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- Paediatric Respiratory Medicine, Great North Children’s Hospital, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
- Correspondence: Malcolm Brodlie, Paediatric Respiratory Medicine, Level 3, Clinical Resource Building, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK, Tel +44 191 2336161, Email
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40
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Wang XP, Balchak DM, Gentilcore C, Clark NL, Kashlan OB. Activation by cleavage of the epithelial Na + channel α and γ subunits independently coevolved with the vertebrate terrestrial migration. eLife 2022; 11:75796. [PMID: 34984981 PMCID: PMC8791634 DOI: 10.7554/elife.75796] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 12/28/2021] [Indexed: 12/17/2022] Open
Abstract
Vertebrates evolved mechanisms for sodium conservation and gas exchange in conjunction with migration from aquatic to terrestrial habitats. Epithelial Na+ channel (ENaC) function is critical to systems responsible for extracellular fluid homeostasis and gas exchange. ENaC is activated by cleavage at multiple specific extracellular polybasic sites, releasing inhibitory tracts from the channel’s α and γ subunits. We found that proximal and distal polybasic tracts in ENaC subunits coevolved, consistent with the dual cleavage requirement for activation observed in mammals. Polybasic tract pairs evolved with the terrestrial migration and the appearance of lungs, coincident with the ENaC activator aldosterone, and appeared independently in the α and γ subunits. In summary, sites within ENaC for protease activation developed in vertebrates when renal Na+ conservation and alveolar gas exchange were required for terrestrial survival.
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Affiliation(s)
- Xue-Ping Wang
- Department of Medicine, University of Pittsburgh, Pittsburgh, United States
| | - Deidra M Balchak
- Department of Medicine, University of Pittsburgh, Pittsburgh, United States
| | - Clayton Gentilcore
- Department of Medicine, University of Pittsburgh, Pittsburgh, United States
| | - Nathan L Clark
- Department of Human Genetics, University of Utah, Salt Lake City, United States
| | - Ossama B Kashlan
- Department of Medicine, University of Pittsburgh, Pittsburgh, United States.,Computational and Systems Biology, University of Pittsburgh, Pittsburgh, United States
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41
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Faulkner AL, Grayling M, Shillitoe B, Brodlie M, Michaelis LJ. Characterising the allergic profile of children with cystic fibrosis. Immun Inflamm Dis 2022; 10:60-69. [PMID: 34570951 PMCID: PMC8669696 DOI: 10.1002/iid3.540] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Revised: 08/17/2021] [Accepted: 09/01/2021] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Cystic fibrosis (CF) is a genetic condition that affects multiple organ systems. Allergic bronchopulmonary aspergillosis (ABPA) is a well-recognised problem but other allergic conditions are less well documented in CF. OBJECTIVE To characterise the allergic profile of a cohort of children with CF, with a focus on those with ABPA. METHODS A cohort of children with CF were interviewed and retrospective data were collected regarding their allergic histories and other relevant clinical features. RESULTS The cohort included 37 children with median age of 9 years (interquartile range: 6-12). There was a history of ≥1 allergic condition(s) in 28/37 children (76%). The most common allergic condition was allergic rhinitis (AR) in 21/37 (57%) and 16 of these 21 children (76%) had another allergic condition. All children with ABPA (8) had another allergic condition. In some children ABPA exacerbations appeared to be seasonal, suggesting possible cross-sensitisation between Aspergillus fumigatus and aeroallergens associated with seasonal AR. Allergic conditions were also common in children with Pseudomonas aeruginosa infection.
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Affiliation(s)
- Amy L. Faulkner
- Faculty of Medical SciencesNewcastle UniversityNewcastle upon TyneUK
| | - Michael Grayling
- Population Health Sciences Institute, Faculty of Medical SciencesNewcastle UniversityNewcastle upon TyneUK
| | - Benjamin Shillitoe
- Department of Immunology, Allergy, and Infectious Diseases, Great North Children's HospitalNewcastle upon Tyne Hospitals NHS Foundation TrustNewcastle upon TyneUK
| | - Malcolm Brodlie
- Translational and Clinical Research Institute, Faculty of Medical SciencesNewcastle UniversityNewcastle upon TyneUK
- Paediatric Respiratory Medicine, Great North Children's HospitalNewcastle upon Tyne Hospitals NHS Foundation TrustNewcastle upon TyneUK
| | - Louise J. Michaelis
- Population Health Sciences Institute, Faculty of Medical SciencesNewcastle UniversityNewcastle upon TyneUK
- Department of Immunology, Allergy, and Infectious Diseases, Great North Children's HospitalNewcastle upon Tyne Hospitals NHS Foundation TrustNewcastle upon TyneUK
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42
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Alhajj N, O'Reilly NJ, Cathcart H. Developing ciprofloxacin dry powder for inhalation: A story of challenges and rational design in the treatment of cystic fibrosis lung infection. Int J Pharm 2021; 613:121388. [PMID: 34923051 DOI: 10.1016/j.ijpharm.2021.121388] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Revised: 12/08/2021] [Accepted: 12/12/2021] [Indexed: 12/11/2022]
Abstract
Cystic fibrosis (CF) is an inherited multisystem disease affecting the lung which leads to a progressive decline in lung function as a result of malfunctioning mucociliary clearance and subsequent chronic bacterial infections. Pseudomonas aeruginosa is the predominant cause of lung infection in CF patients and is associated with significant morbidity and mortality. Thus, antibiotic therapy remains the cornerstone of the treatment of CF. Pulmonary delivery of antibiotics for lung infections significantly reduces the required dose and the associated systemic side effects while improving therapeutic outcomes. Ciprofloxacin is one of the most widely used antibiotics against P. aeruginosa and the most effective fluoroquinolone. However, in spite of the substantial amount of research aimed at developing ciprofloxacin powder for inhalation, none of these formulations has been commercialized. Here, we present an integrated view of the diverse challenges associated with delivering ciprofloxacin dry particles to the lungs of CF patients and the rationales behind recent formulations of ciprofloxacin dry powder for inhalation. This review will discuss the challenges in developing ciprofloxacin powder for inhalation along with the physiological and pathophysiological challenges such as ciprofloxacin lung permeability, overproduction of viscous mucus and bacterial biofilms. The review will also discuss the current and emerging particle engineering approaches to overcoming these challenges. By doing so, we believe the review will help the reader to understand the current limitations in developing an inhalable ciprofloxacin powder and explore new opportunities of rational design strategies.
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Affiliation(s)
- Nasser Alhajj
- Pharmaceutical and Molecular Biotechnology Research Centre (PMBRC), Waterford Institute of Technology, Waterford, Ireland.
| | - Niall J O'Reilly
- Pharmaceutical and Molecular Biotechnology Research Centre (PMBRC), Waterford Institute of Technology, Waterford, Ireland; SSPC - The Science Foundation Ireland Research Centre for Pharmaceuticals, Ireland
| | - Helen Cathcart
- Pharmaceutical and Molecular Biotechnology Research Centre (PMBRC), Waterford Institute of Technology, Waterford, Ireland
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43
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Infield DT, Strickland KM, Gaggar A, McCarty NA. The molecular evolution of function in the CFTR chloride channel. J Gen Physiol 2021; 153:212705. [PMID: 34647973 PMCID: PMC8640958 DOI: 10.1085/jgp.202012625] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 08/11/2021] [Accepted: 09/09/2021] [Indexed: 12/13/2022] Open
Abstract
The ATP-binding cassette (ABC) transporter superfamily includes many proteins of clinical relevance, with genes expressed in all domains of life. Although most members use the energy of ATP binding and hydrolysis to accomplish the active import or export of various substrates across membranes, the cystic fibrosis transmembrane conductance regulator (CFTR) is the only known animal ABC transporter that functions primarily as an ion channel. Defects in CFTR, which is closely related to ABCC subfamily members that bear function as bona fide transporters, underlie the lethal genetic disease cystic fibrosis. This article seeks to integrate structural, functional, and genomic data to begin to answer the critical question of how the function of CFTR evolved to exhibit regulated channel activity. We highlight several examples wherein preexisting features in ABCC transporters were functionally leveraged as is, or altered by molecular evolution, to ultimately support channel function. This includes features that may underlie (1) construction of an anionic channel pore from an anionic substrate transport pathway, (2) establishment and tuning of phosphoregulation, and (3) optimization of channel function by specialized ligand–channel interactions. We also discuss how divergence and conservation may help elucidate the pharmacology of important CFTR modulators.
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Affiliation(s)
- Daniel T Infield
- Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA
| | | | - Amit Gaggar
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL.,Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL.,Program in Protease and Matrix Biology, University of Alabama at Birmingham, Birmingham, AL.,Birmingham Veterans Administration Medical Center, Birmingham, AL
| | - Nael A McCarty
- Department of Pediatrics, Emory University, Atlanta, GA.,Children's Healthcare of Atlanta Center for Cystic Fibrosis and Airways Disease Research, Emory University, Atlanta, GA
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Laselva O, Guerra L, Castellani S, Favia M, Di Gioia S, Conese M. Small-molecule drugs for cystic fibrosis: Where are we now? Pulm Pharmacol Ther 2021; 72:102098. [PMID: 34793977 DOI: 10.1016/j.pupt.2021.102098] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Revised: 10/24/2021] [Accepted: 11/12/2021] [Indexed: 01/05/2023]
Abstract
The cystic fibrosis (CF) lung disease is due to the lack/dysfunction of the CF Transmembrane Conductance Regulator (CFTR), a chloride channel expressed by epithelial cells as the main regulator of ion and fluid homeostasis. More than 2000 genetic variation in the CFTR gene are known, among which those with identified pathomechanism have been divided into six VI mutation classes. A major advancement in the pharmacotherapy of CF has been the development of small-molecule drugs hitting the root of the disease, i.e. the altered ion and fluid transport through the airway epithelium. These drugs, called CFTR modulators, have been advanced to the clinics to treat nearly 90% of CF patients, including the CFTR potentiator ivacaftor, approved for residual function mutations (Classes III and IV), and combinations of correctors (lumacaftor, tezacaftor, elexacaftor) and ivacaftor for patients bearing at least one the F508del mutation, the most frequent mutation belonging to class II. To cover the 10% of CF patients without etiological therapies, other novel small-molecule CFTR modulators are in evaluation of their effectiveness in all the CFTR mutation classes: read-through agents for Class I, correctors, potentiators and amplifiers from different companies for Class II-V, stabilizers for Class VI. In alternative, other solute carriers, such as SLC26A9 and SLC6A14, are the focus of intensive investigation. Finally, other molecular targets are being evaluated for patients with no approved CFTR modulator therapy or as means of enhancing CFTR modulatory therapy, including small molecules forming ion channels, inhibitors of the ENaC sodium channel and potentiators of the calcium-activated chloride channel TMEM16A. This paper aims to give an up-to-date overview of old and novel CFTR modulators as well as of novel strategies based on small-molecule drugs. Further investigations in in-vivo and cell-based models as well as carrying out large prospective studies will be required to determine if novel CFTR modulators, stabilizers, amplifiers, and the ENaC inhibitors or TMEM16A potentiators will further improve the clinical outcomes in CF management.
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Affiliation(s)
- Onofrio Laselva
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Lorenzo Guerra
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy
| | - Stefano Castellani
- Department of Medical Sciences and Human Oncology, University of Bari, Bari, Italy
| | - Maria Favia
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy
| | - Sante Di Gioia
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Massimo Conese
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
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Pereira C, Mazein A, Farinha CM, Gray MA, Kunzelmann K, Ostaszewski M, Balaur I, Amaral MD, Falcao AO. CyFi-MAP: an interactive pathway-based resource for cystic fibrosis. Sci Rep 2021; 11:22223. [PMID: 34782688 PMCID: PMC8592983 DOI: 10.1038/s41598-021-01618-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 10/27/2021] [Indexed: 12/11/2022] Open
Abstract
Cystic fibrosis (CF) is a life-threatening autosomal recessive disease caused by more than 2100 mutations in the CF transmembrane conductance regulator (CFTR) gene, generating variability in disease severity among individuals with CF sharing the same CFTR genotype. Systems biology can assist in the collection and visualization of CF data to extract additional biological significance and find novel therapeutic targets. Here, we present the CyFi-MAP-a disease map repository of CFTR molecular mechanisms and pathways involved in CF. Specifically, we represented the wild-type (wt-CFTR) and the F508del associated processes (F508del-CFTR) in separate submaps, with pathways related to protein biosynthesis, endoplasmic reticulum retention, export, activation/inactivation of channel function, and recycling/degradation after endocytosis. CyFi-MAP is an open-access resource with specific, curated and continuously updated information on CFTR-related pathways available online at https://cysticfibrosismap.github.io/ . This tool was developed as a reference CF pathway data repository to be continuously updated and used worldwide in CF research.
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Affiliation(s)
- Catarina Pereira
- Faculty of Sciences, BioISI-Biosystems Integrative Sciences Institute, University of Lisboa, Campo Grande, 1749-016, Lisbon, Portugal
- LASIGE, Faculty of Sciences, University of Lisboa, Campo Grande, 1749-016, Lisbon, Portugal
| | - Alexander Mazein
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 6 Avenue du Swing, 4367, Belvaux, Luxembourg
- CIRI UMR5308, CNRS-ENS-UCBL-INSERM, European Institute for Systems Biology and Medicine, Université de Lyon, 50 Avenue Tony Garnier, 69007, Lyon, France
| | - Carlos M Farinha
- Faculty of Sciences, BioISI-Biosystems Integrative Sciences Institute, University of Lisboa, Campo Grande, 1749-016, Lisbon, Portugal
| | - Michael A Gray
- Biosciences Institute, University Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK
| | | | - Marek Ostaszewski
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 6 Avenue du Swing, 4367, Belvaux, Luxembourg
| | - Irina Balaur
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 6 Avenue du Swing, 4367, Belvaux, Luxembourg
- CIRI UMR5308, CNRS-ENS-UCBL-INSERM, European Institute for Systems Biology and Medicine, Université de Lyon, 50 Avenue Tony Garnier, 69007, Lyon, France
| | - Margarida D Amaral
- Faculty of Sciences, BioISI-Biosystems Integrative Sciences Institute, University of Lisboa, Campo Grande, 1749-016, Lisbon, Portugal
| | - Andre O Falcao
- Faculty of Sciences, BioISI-Biosystems Integrative Sciences Institute, University of Lisboa, Campo Grande, 1749-016, Lisbon, Portugal.
- LASIGE, Faculty of Sciences, University of Lisboa, Campo Grande, 1749-016, Lisbon, Portugal.
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Hanssens LS, Duchateau J, Casimir GJ. CFTR Protein: Not Just a Chloride Channel? Cells 2021; 10:2844. [PMID: 34831067 PMCID: PMC8616376 DOI: 10.3390/cells10112844] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 10/15/2021] [Accepted: 10/19/2021] [Indexed: 12/17/2022] Open
Abstract
Cystic fibrosis (CF) is a recessive genetic disease caused by mutations in a gene encoding a protein called Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). The CFTR protein is known to acts as a chloride (Cl-) channel expressed in the exocrine glands of several body systems where it also regulates other ion channels, including the epithelial sodium (Na+) channel (ENaC) that plays a key role in salt absorption. This function is crucial to the osmotic balance of the mucus and its viscosity. However, the pathophysiology of CF is more challenging than a mere dysregulation of epithelial ion transport, mainly resulting in impaired mucociliary clearance (MCC) with consecutive bronchiectasis and in exocrine pancreatic insufficiency. This review shows that the CFTR protein is not just a chloride channel. For a long time, research in CF has focused on abnormal Cl- and Na+ transport. Yet, the CFTR protein also regulates numerous other pathways, such as the transport of HCO3-, glutathione and thiocyanate, immune cells, and the metabolism of lipids. It influences the pH homeostasis of airway surface liquid and thus the MCC as well as innate immunity leading to chronic infection and inflammation, all of which are considered as key pathophysiological characteristics of CF.
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Affiliation(s)
- Laurence S. Hanssens
- Department of Pediatric Pulmonology and Cystic Fibrosis Clinic, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles (ULB), Avenue J.J. Crocq 15, 1020 Brussels, Belgium;
| | - Jean Duchateau
- Laboratoire Académique de Pédiatrie, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles (ULB), Avenue J.J. Crocq 15, 1020 Brussels, Belgium;
| | - Georges J. Casimir
- Department of Pediatric Pulmonology and Cystic Fibrosis Clinic, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles (ULB), Avenue J.J. Crocq 15, 1020 Brussels, Belgium;
- Laboratoire Académique de Pédiatrie, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles (ULB), Avenue J.J. Crocq 15, 1020 Brussels, Belgium;
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Luan X, Le Y, Jagadeeshan S, Murray B, Carmalt JL, Duke T, Beazley S, Fujiyama M, Swekla K, Gray B, Burmester M, Campanucci VA, Shipley A, Machen TE, Tam JS, Ianowski JP. cAMP triggers Na + absorption by distal airway surface epithelium in cystic fibrosis swine. Cell Rep 2021; 37:109795. [PMID: 34610318 DOI: 10.1016/j.celrep.2021.109795] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 07/05/2021] [Accepted: 09/13/2021] [Indexed: 10/20/2022] Open
Abstract
A controversial hypothesis pertaining to cystic fibrosis (CF) lung disease is that the CF transmembrane conductance regulator (CFTR) channel fails to inhibit the epithelial Na+ channel (ENaC), yielding increased Na+ reabsorption and airway dehydration. We use a non-invasive self-referencing Na+-selective microelectrode technique to measure Na+ transport across individual folds of distal airway surface epithelium preparations from CFTR-/- (CF) and wild-type (WT) swine. We show that, under unstimulated control conditions, WT and CF epithelia exhibit similar, low rates of Na+ transport that are unaffected by the ENaC blocker amiloride. However, in the presence of the cyclic AMP (cAMP)-elevating agents forskolin+IBMX (isobutylmethylxanthine), folds of WT tissues secrete large amounts of Na+, while CFTR-/- tissues absorb small, but potentially important, amounts of Na+. In cAMP-stimulated conditions, amiloride inhibits Na+ absorption in CFTR-/- tissues but does not affect secretion in WT tissues. Our results are consistent with the hypothesis that ENaC-mediated Na+ absorption may contribute to dehydration of CF distal airways.
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Affiliation(s)
- Xiaojie Luan
- Department of Anatomy Physiology and Pharmacology, University of Saskatchewan, Saskatoon, SK, Canada
| | - Yen Le
- Department of Anatomy Physiology and Pharmacology, University of Saskatchewan, Saskatoon, SK, Canada
| | - Santosh Jagadeeshan
- Department of Anatomy Physiology and Pharmacology, University of Saskatchewan, Saskatoon, SK, Canada
| | - Brendan Murray
- Department of Anatomy Physiology and Pharmacology, University of Saskatchewan, Saskatoon, SK, Canada
| | - James L Carmalt
- Department of Large Animal Clinical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK, Canada
| | - Tanya Duke
- Department of Small Animal Clinical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK, Canada
| | - Shannon Beazley
- Department of Small Animal Clinical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK, Canada
| | - Masako Fujiyama
- Department of Small Animal Clinical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK, Canada
| | - Kurtis Swekla
- Animal Care and Research Support, Research Excellence and Innovation, University of Saskatchewan, Saskatoon, SK, Canada
| | - Bridget Gray
- Animal Care and Research Support, Research Excellence and Innovation, University of Saskatchewan, Saskatoon, SK, Canada
| | - Monique Burmester
- Animal Care Unit, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK, Canada
| | - Veronica A Campanucci
- Department of Anatomy Physiology and Pharmacology, University of Saskatchewan, Saskatoon, SK, Canada; Respiratory Research Centre, University of Saskatchewan, Saskatoon, SK, Canada
| | | | - Terry E Machen
- Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA
| | - Julian S Tam
- Department of Medicine, Division of Respirology, Critical Care, and Sleep Medicine, Royal University Hospital, University of Saskatchewan, Saskatoon, SK, Canada; Respiratory Research Centre, University of Saskatchewan, Saskatoon, SK, Canada
| | - Juan P Ianowski
- Department of Anatomy Physiology and Pharmacology, University of Saskatchewan, Saskatoon, SK, Canada; Respiratory Research Centre, University of Saskatchewan, Saskatoon, SK, Canada.
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Soares VEM, do Carmo TIT, Dos Anjos F, Wruck J, de Oliveira Maciel SFV, Bagatini MD, de Resende E Silva DT. Role of inflammation and oxidative stress in tissue damage associated with cystic fibrosis: CAPE as a future therapeutic strategy. Mol Cell Biochem 2021; 477:39-51. [PMID: 34529223 DOI: 10.1007/s11010-021-04263-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 09/08/2021] [Indexed: 10/20/2022]
Abstract
Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, responsible for the synthesis of the CFTR protein, a chloride channel. The gene has approximately 2000 known mutations and all of them affect in some degree the protein function, which makes the pathophysiological manifestations to be multisystemic, mainly affecting the respiratory, gastrointestinal, endocrine, and reproductive tracts. Currently, the treatment of the disease is restricted to controlling symptoms and, more recently, a group of drugs that act directly on the defective protein, known as CFTR modulators, was developed. However, their high cost and difficult access mean that their use is still very restricted. It is important to search for safe and low-cost alternative therapies for CF and, in this context, natural compounds and, mainly, caffeic acid phenethyl ester (CAPE) appear as promising strategies to assist in the treatment of the disease. CAPE is a compound derived from propolis extracts that has antioxidant and anti-inflammatory activities, covering important aspects of the pathophysiology of CF, which points to the possible benefit of its use in the disease treatment. To date, no studies have effectively tested CAPE for CF and, therefore, we intend with this review to elucidate the role of inflammation and oxidative stress for tissue damage seen in CF, associating them with CAPE actions and its pharmacologically active derivatives. In this way, we offer a theoretical basis for conducting preclinical and clinical studies relating the use of this molecule to CF.
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Affiliation(s)
- Victor Emanuel Miranda Soares
- Medical School, Federal University of Fronteira Sul, Rodovia SC 484 - Km 02, Fronteira Sul, Chapecó, SC, 89815-899, Brazil
| | | | - Fernanda Dos Anjos
- Medical School, Federal University of Fronteira Sul, Rodovia SC 484 - Km 02, Fronteira Sul, Chapecó, SC, 89815-899, Brazil
| | - Jonatha Wruck
- Medical School, Federal University of Fronteira Sul, Rodovia SC 484 - Km 02, Fronteira Sul, Chapecó, SC, 89815-899, Brazil
| | | | - Margarete Dulce Bagatini
- Graduate Program in Biomedical Sciences, Federal University of Fronteira Sul, Rodovia SC 484 - Km 02, Fronteira Sul, Chapecó, SC, 89815-899, Brazil
| | - Débora Tavares de Resende E Silva
- Graduate Program in Biomedical Sciences, Federal University of Fronteira Sul, Rodovia SC 484 - Km 02, Fronteira Sul, Chapecó, SC, 89815-899, Brazil.
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Bush A, Pavord ID. Challenging the paradigm: moving from umbrella labels to treatable traits in airway disease. Breathe (Sheff) 2021; 17:210053. [PMID: 35035544 PMCID: PMC8753662 DOI: 10.1183/20734735.0053-2021] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 05/11/2021] [Indexed: 12/15/2022] Open
Abstract
Airway diseases were initially described by nonspecific patterns of symptoms, for example "dry and wheezy" and "wet and crackly". The model airway disease is cystic fibrosis, which has progressed from nonspecific reactive treatments such as antibiotics for airway infection to molecular sub-endotype, proactive therapies with an unequivocal evidence base, early diagnosis, and biomarkers of treatment efficacy. Unfortunately, other airway diseases lag behind, not least because nonspecific umbrella labels such as "asthma" are considered to be diagnoses not mere descriptions. Pending the delineation of molecular sub-endotypes in other airway disease the concept of treatable traits, and consideration of airway disease in a wider context is preferable. A treatable trait is a characteristic amenable to therapy, with measurable benefits of treatment. This approach determines what pathology is actually present and treatable, rather than using umbrella labels. We determine if airway inflammation is present, and whether there is airway eosinophilia which will likely respond to inhaled corticosteroids; whether there is variable airflow obstruction due to bronchoconstriction which will respond to β2-agonists; and whether there is unsuspected underlying airway infection which should be treated with antibiotics unless there is an underlying endotype which can be addressed, as for example an immunodeficiency. The context of airway disease should also be extrapulmonary comorbidities, social and environmental factors, and a developmental perspective, particularly this last aspect if preventive strategies are being contemplated. This approach allows targeted treatment for maximal patient benefit, as well as preventing the discarding of therapies which are useful for appropriate subgroups of patients. Failure to appreciate this almost led to the discarding of valuable treatments such as prednisolone. EDUCATIONAL AIMS To use cystic fibrosis as a paradigm to show the benefits of the journey from nonspecific umbrella terms to specific endotypes and sub-endotypes, as a road map for other airway diseases to follow.Demonstrate that nonspecific labels to describe airway disease can and should be abandoned in favour of treatable traits to ensure diagnostic and therapeutic precision.Begin to learn to see airway disease in the context of extrapulmonary comorbidities, and social and environmental factors, as well as with a developmental perspective.
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Affiliation(s)
- Andrew Bush
- Paediatrics and Paediatric Respirology, Imperial Centre for Paediatrics and Child Health, Imperial College London, London, UK
- Royal Brompton and Harefield NHS Foundation Trust, London, UK
| | - Ian D. Pavord
- Respiratory Medicine, Respiratory Medicine Unit and Oxford Respiratory NIHR BRC, Nuffield Dept of Medicine, University of Oxford, Oxford, UK
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Yimnual C, Satitsri S, Ningsih BNS, Rukachaisirikul V, Muanprasat C. A fungus-derived purpactin A as an inhibitor of TMEM16A chloride channels and mucin secretion in airway epithelial cells. Biomed Pharmacother 2021; 139:111583. [PMID: 33901875 DOI: 10.1016/j.biopha.2021.111583] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 03/31/2021] [Accepted: 04/02/2021] [Indexed: 12/20/2022] Open
Abstract
TMEM16A is a Ca2+-activated Cl- channel involved in mucus secretion in inflamed airways and proposed as a drug target for diseases associated with mucus hypersecretion including asthma. This study aimed to identify novel inhibitors of TMEM16A-mediated Cl- secretion in airway epithelial cells from a collection of compounds isolated from fungi indigenous in Thailand and examine its potential utility in mitigating airway mucus secretion using Calu-3 cells as a study model. Screening of > 400 fungal metabolites revealed purpactin A isolated from a soil-derived fungus Penicillium aculeatum PSU-RSPG105 as an inhibitor of TMEM16A-mediated Cl- transport with an IC50 value of ~2 µM. A consistent inhibitory effect of purpactin A on TMEM16A were observed regardless of TMEM16A activators or in the presence of an inhibitor of Ca2+/calmodulin-dependent protein kinase II (CaMKII), a negative regulator of TMEM16A. In addition, purpactin A did not affect cell viability, epithelial barrier integrity and activities of membrane transport proteins essential for maintaining airway hydration including CFTR Cl- channels and apical BK K+ channels. Intriguingly, purpactin A prevented a Ca2+-induced mucin release in cytokine-treated airway cells. Taken together, purpactin A represents the first class of TMEM16A inhibitor derived from fungus, which may be beneficial for the treatment of diseases associated with mucus hypersecretion.
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Affiliation(s)
- Chantapol Yimnual
- Department of Physiology, Faculty of Science, Mahidol University, Rajathevi, Bangkok 10400, Thailand; Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bang Phli, Samut Prakarn 10540, Thailand
| | - Saravut Satitsri
- Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bang Phli, Samut Prakarn 10540, Thailand
| | - Baiq Nila Sari Ningsih
- Division of Physical Science and Center of Excellence for Innovation in Chemistry, Faculty of Science, Prince of Songkla University, Hat Yai, Songkhla 90112, Thailand
| | - Vatcharin Rukachaisirikul
- Division of Physical Science and Center of Excellence for Innovation in Chemistry, Faculty of Science, Prince of Songkla University, Hat Yai, Songkhla 90112, Thailand
| | - Chatchai Muanprasat
- Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bang Phli, Samut Prakarn 10540, Thailand.
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