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1
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Cohen‐Cymberknoh M. Infection and Inflammation in the Cystic fibrosis (CF) airway. Pediatr Pulmonol 2025; 60 Suppl 1:S82-S83. [PMID: 39465651 PMCID: PMC11921074 DOI: 10.1002/ppul.27355] [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: 10/07/2024] [Accepted: 10/13/2024] [Indexed: 10/29/2024]
Abstract
Cystic fibrosis (CF) airway disease is characterized by chronic infection and neutrophil-driven inflammation, leading to progressive airway damage and early mortality. Infection with Pseudomonas aeruginosa significantly impacts morbidity and mortality, requiring early detection and aggressive antibiotic treatment. Controlling inflammation remains difficult due to the limited availability of effective anti-inflammatory treatments. CFTR modulators show potential in reducing inflammation, but further research is needed. Effective management of CF lung disease requires a comprehensive approach addressing both infection and inflammation.
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Affiliation(s)
- Malena Cohen‐Cymberknoh
- Pediatric Pulmonology Unit and Cystic fibrosis Center, Hadassah Medical Center and Faculty of MedicineHebrew University of JerusalemJerusalemIsrael
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2
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Cohen‐Cymberknoh M. Advances in the restoration of CFTR in children and pwCF with "mild disease". Pediatr Pulmonol 2025; 60 Suppl 1:S84-S85. [PMID: 39526579 PMCID: PMC11921122 DOI: 10.1002/ppul.27359] [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: 09/20/2024] [Accepted: 09/30/2024] [Indexed: 11/16/2024]
Abstract
Cystic fibrosis (CF) is a progressive genetic disorder, with lung disease being the main cause of morbidity and mortality. While advances in treatment have extended life expectancy, lung function still declines over time. Early inflammation and chronic infection, particularly with pseudomonas, worsen outcomes. Current management focuses on nutrition, airway clearance and infection control, but CFTR modulators directly target the genetic defect, improving lung function and reducing pulmonary exacerbations. Early use of CFTR modulators can alter the course of the disease.
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Affiliation(s)
- Malena Cohen‐Cymberknoh
- Pediatric Pulmonology Unit and Cystic fibrosis Center, Hadassah‐Hebrew University Medical CenterJerusalemIsrael
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3
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Finotti A, Gambari R. Perspectives in MicroRNA Therapeutics for Cystic Fibrosis. Noncoding RNA 2025; 11:3. [PMID: 39846681 PMCID: PMC11755495 DOI: 10.3390/ncrna11010003] [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: 11/10/2024] [Revised: 12/23/2024] [Accepted: 01/06/2025] [Indexed: 01/24/2025] Open
Abstract
The discovery of the involvement of microRNAs (miRNAs) in cystic fibrosis (CF) has generated increasing interest in the past years, due to their possible employment as a novel class of drugs to be studied in pre-clinical settings of therapeutic protocols for cystic fibrosis. In this narrative review article, consider and comparatively evaluate published laboratory information of possible interest for the development of miRNA-based therapeutic protocols for cystic fibrosis. We consider miRNAs involved in the upregulation of CFTR, miRNAs involved in the inhibition of inflammation and, finally, miRNAs exhibiting antibacterial activity. We suggest that antago-miRNAs and ago-miRNAs (miRNA mimics) can be proposed for possible validation of therapeutic protocols in pre-clinical settings.
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Affiliation(s)
- Alessia Finotti
- Department of Life Sciences and Biotechnology, Section of Biochemistry and Molecular Biology, University of Ferrara, 44121 Ferrara, Italy
- Research Center on Innovative Therapies for Cystic Fibrosis, University of Ferrara, 44121 Ferrara, Italy
| | - Roberto Gambari
- Department of Life Sciences and Biotechnology, Section of Biochemistry and Molecular Biology, University of Ferrara, 44121 Ferrara, Italy
- Research Center on Innovative Therapies for Cystic Fibrosis, University of Ferrara, 44121 Ferrara, Italy
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Jeyaraman S, Sankar J, Wong LS, Muthusamy K. E-pharmacophore based virtual screening of potent lead molecules against Cystic Fibrosis: An in silico study. Comput Biol Chem 2024; 113:108249. [PMID: 39427605 DOI: 10.1016/j.compbiolchem.2024.108249] [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: 06/29/2024] [Revised: 09/20/2024] [Accepted: 10/09/2024] [Indexed: 10/22/2024]
Abstract
Cystic fibrosis is an autosomal recessive condition caused by mutations in the CFTR gene, which encodes the CFTR protein. Currently, CF is a life-limiting illness that has a limited cure. The present study aimed to identify top leads against CFTR protein with F508del in comparison with Lumacaftor. In this study, a homology model of the NBD domain of CFTR protein was developed using the available NBD domain crystal structure. The protein model was refined through apo dynamics. Energy-optimized pharmacophore mapping was carried out to identify essential features for CFTR, resulting in a model with a hydrogen-bond donor, two hydrogen-bond acceptors, and three aromatic ring sites. A screening of a compound from the NPASS database using these DAARRR six-point-pharmacophore features led to the identification of potential ligands that could act against CFTR protein. Further studies such as ADME/T, molecular dynamics, MM_GBSA, and DFT were performed to identify the top-hit compound from the NPASS database. The compound Anguibactin (NPC41982) has been identified as a top lead that exhibits higher binding affinity and stability than the reference compound Lumacaftor, suggesting their potential to bind to the active site of the CFTR protein. These compounds could serve as starting points for the development of drug-like molecules for treating cystic fibrosis.
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Affiliation(s)
- Sabareeswari Jeyaraman
- Department of Bioinformatics, Pharmacogenomics and CADD Lab, Alagappa University, Karaikudi, Tamil Nadu, India
| | - Jeyanthi Sankar
- Department of Bioinformatics, Pharmacogenomics and CADD Lab, Alagappa University, Karaikudi, Tamil Nadu, India
| | - Ling Shing Wong
- Faculty of Health and Life Sciences, INTI International University, Nilai, Negeri Sembilan 71800, Malaysia
| | - Karthikeyan Muthusamy
- Department of Bioinformatics, Pharmacogenomics and CADD Lab, Alagappa University, Karaikudi, Tamil Nadu, India.
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Lin B, Gong J, Keenan K, Lin F, Lin YC, Mésinèle J, Calmel C, Mohand Oumoussa B, Boëlle PY, Guillot L, Corvol H, Waters V, Sun L, Strug LJ. Genome-wide association study of susceptibility to Pseudomonas aeruginosa infection in cystic fibrosis. Eur Respir J 2024; 64:2400062. [PMID: 39117430 PMCID: PMC11540985 DOI: 10.1183/13993003.00062-2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 07/10/2024] [Indexed: 08/10/2024]
Abstract
BACKGROUND Pseudomonas aeruginosa is a common pathogen that contributes to progressive lung disease in cystic fibrosis (CF). Genetic factors other than CF-causing CFTR (CF transmembrane conductance regulator) variations contribute ∼85% of the variation in chronic P. aeruginosa infection age in CF according to twin studies, but the susceptibility loci remain unknown. Our objective is to advance understanding of the genetic basis of host susceptibility to P. aeruginosa infection. MATERIALS AND METHODS We conducted a genome-wide association study of chronic P. aeruginosa infection age in 1037 Canadians with CF. We subsequently assessed the genetic correlation between chronic P. aeruginosa infection age and lung function through polygenic risk score (PRS) analysis and inferred their causal relationship through bidirectional Mendelian randomisation analysis. RESULTS Two novel genome-wide significant loci with lead single nucleotide polymorphisms (SNPs) rs62369766 (chr5p12; p=1.98×10-8) and rs927553 (chr13q12.12; p=1.91×10-8) were associated with chronic P. aeruginosa infection age. The rs62369766 locus was validated using an independent French cohort (n=501). Furthermore, the PRS constructed from CF lung function-associated SNPs was significantly associated with chronic P. aeruginosa infection age (p=0.002). Finally, our analysis presented evidence for a causal effect of lung function on chronic P. aeruginosa infection age (β=0.782 years, p=4.24×10-4). In the reverse direction, we observed a moderate effect (β=0.002, p=0.012). CONCLUSIONS We identified two novel loci that are associated with chronic P. aeruginosa infection age in individuals with CF. Additionally, we provided evidence of common genetic contributors and a potential causal relationship between P. aeruginosa infection susceptibility and lung function in CF. Therapeutics targeting these genetic factors may delay the onset of chronic infections, which account for significant remaining morbidity in CF.
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Affiliation(s)
- Boxi Lin
- Biostatistics Division, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
- Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada
| | - Jiafen Gong
- 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
| | - Fan Lin
- Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada
| | - Yu-Chung Lin
- Biostatistics Division, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
- Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada
| | - Julie Mésinèle
- Sorbonne Université, Inserm U938, Centre de Recherche Saint-Antoine (CRSA), Paris, France
- Inovarion, Paris, France
| | - Claire Calmel
- Sorbonne Université, Inserm U938, Centre de Recherche Saint-Antoine (CRSA), Paris, France
| | - Badreddine Mohand Oumoussa
- Sorbonne Université, Inserm, UMS Production et Analyse des données en Sciences de la vie et en Santé (PASS), Plateforme Post-génomique de la Pitié-Salpêtrière, Paris, France
| | - Pierre-Yves Boëlle
- Sorbonne Université, Inserm, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), AP-HP, Hôpital Saint-Antoine, Paris, France
| | - Loïc Guillot
- Sorbonne Université, Inserm U938, Centre de Recherche Saint-Antoine (CRSA), Paris, France
| | - Harriet Corvol
- Sorbonne Université, Inserm U938, Centre de Recherche Saint-Antoine (CRSA), Paris, France
- Sorbonne Université, AP-HP, Hôpital Trousseau, Service de Pneumologie Pédiatrique, Paris, France
| | - Valerie Waters
- Division of Infectious Diseases, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
- Translational Medicine Research Program, The Hospital for Sick Children, 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
| | - Lisa J Strug
- Biostatistics Division, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
- Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada
- Department of Statistical Sciences, University of Toronto, Toronto, ON, Canada
- Department of Computer Science, University of Toronto, Toronto, ON, Canada
- The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada
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Carbone A, Vitullo P, Di Gioia S, Castellani S, Conese M. A New Frontier in Cystic Fibrosis Pathophysiology: How and When Clock Genes Can Affect the Inflammatory/Immune Response in a Genetic Disease Model. Curr Issues Mol Biol 2024; 46:10396-10410. [PMID: 39329970 PMCID: PMC11430433 DOI: 10.3390/cimb46090618] [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: 08/26/2024] [Revised: 09/13/2024] [Accepted: 09/15/2024] [Indexed: 09/28/2024] Open
Abstract
Cystic fibrosis (CF) is a monogenic syndrome caused by variants in the CF Transmembrane Conductance Regulator (CFTR) gene, affecting various organ and systems, in particular the lung, pancreas, sweat glands, liver, gastrointestinal tract, vas deferens, and vascular system. While for some organs, e.g., the pancreas, a strict genotype-phenotype occurs, others, such as the lung, display a different pathophysiologic outcome in the presence of the same mutational asset, arguing for genetic and environmental modifiers influencing severity and clinical trajectory. CFTR variants trigger a pathophysiological cascade of events responsible for chronic inflammatory responses, many aspects of which, especially related to immunity, are not ascertained yet. Although clock genes expression and function are known modulators of the innate and adaptive immunity, their involvement in CF has been only observed in relation to sleep abnormalities. The aim of this review is to present current evidence on the clock genes role in immune-inflammatory responses at the lung level. While information on this topic is known in other chronic airway diseases (chronic obstructive pulmonary disease and asthma), CF lung disease (CFLD) is lacking in this knowledge. We will present the bidirectional effect between clock genes and inflammatory factors that could possibly be implicated in the CFLD. It must be stressed that besides sleep disturbance and its mechanisms, there are not studies directly addressing the exact nature of clock genes' involvement in inflammation and immunity in CF, pointing out the directions of new and deepened studies in this monogenic affection. Importantly, clock genes have been found to be druggable by means of genetic tools or pharmacological agents, and this could have therapeutic implications in CFLD.
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Affiliation(s)
- Annalucia Carbone
- Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy; (A.C.); (S.D.G.)
| | - Pamela Vitullo
- Cystic Fibrosis Support Center, Ospedale “G. Tatarella”, 71042 Cerignola, Italy;
| | - Sante Di Gioia
- Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy; (A.C.); (S.D.G.)
| | - Stefano Castellani
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari “Aldo Moro”, 70125 Bari, Italy;
| | - Massimo Conese
- Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy; (A.C.); (S.D.G.)
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Luo J, Wang J, Liu H, Jiang W, Pan L, Huang W, Liu C, Qu X, Liu C, Qin X, Xiang Y. Chloride intracellular channel 4 participates in the regulation of lipopolysaccharide-induced inflammatory responses in human bronchial epithelial cells. Respir Physiol Neurobiol 2024; 327:104303. [PMID: 39029565 DOI: 10.1016/j.resp.2024.104303] [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: 03/19/2024] [Revised: 07/11/2024] [Accepted: 07/15/2024] [Indexed: 07/21/2024]
Abstract
The airway epithelium is located at the interactional boundary between the external and internal environments of the organism and is often exposed to harmful environmental stimuli. Inflammatory response that occurs after airway epithelial stress is the basis of many lung and systemic diseases. Chloride intracellular channel 4 (CLIC4) is abundantly expressed in epithelial cells. The purpose of this study was to investigate whether CLIC4 is involved in the regulation of lipopolysaccharide (LPS)-induced inflammatory response in airway epithelial cells and to clarify its potential mechanism. Our results showed that LPS induced inflammatory response and decreased CLIC4 levels in vivo and in vitro. CLIC4 silencing aggravated the inflammatory response in epithelial cells, while overexpression of CLIC4 combined with LPS exposure significantly decreased the inflammatory response compared with cells exposed to LPS without CLIC4 overexpression. By labeling intracellular chloride ions with chloride fluorescent probe MQAE, we showed that CLIC4 mediated intracellular chloride ion-regulated LPS-induced cellular inflammatory response.
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Affiliation(s)
- Jinhua Luo
- Department of Physiology, School of Basic Medicine, Central South University, Changsha 410000, China
| | - Jia Wang
- Department of Physiology, School of Basic Medicine, Central South University, Changsha 410000, China; Hunan Provincial People's Hospital, The First-affiliated Hospital of Hunan Normal University, Changsha 410016, China
| | - Huijun Liu
- Department of Physiology, School of Basic Medicine, Central South University, Changsha 410000, China
| | - Wang Jiang
- Department of Physiology, School of Basic Medicine, Central South University, Changsha 410000, China
| | - Lang Pan
- Department of Physiology, School of Basic Medicine, Central South University, Changsha 410000, China; Department of Microbiology and Immunology, School of Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Wenjie Huang
- Department of Physiology, School of Basic Medicine, Central South University, Changsha 410000, China; Department of Reproductive Medicine, Liuzhou maternity and Child Healthcare Hospital, Liuzhou, Guangxi 545001, China
| | - Caixia Liu
- Department of Physiology, School of Basic Medicine, Central South University, Changsha 410000, China; Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Xiangping Qu
- Department of Physiology, School of Basic Medicine, Central South University, Changsha 410000, China
| | - Chi Liu
- Department of Physiology, School of Basic Medicine, Central South University, Changsha 410000, China
| | - Xiaoqun Qin
- Department of Physiology, School of Basic Medicine, Central South University, Changsha 410000, China
| | - Yang Xiang
- Department of Physiology, School of Basic Medicine, Central South University, Changsha 410000, China.
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8
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Gil HI, Han K, Hong S, Park CY. Incidence of bronchiectasis in patients with acromegaly: a cohort study. Front Endocrinol (Lausanne) 2024; 15:1362950. [PMID: 39220366 PMCID: PMC11361995 DOI: 10.3389/fendo.2024.1362950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Accepted: 08/01/2024] [Indexed: 09/04/2024] Open
Abstract
Objective Associations between acromegaly and several respiratory diseases, such as obstructive lung disease or sleep apnea, have been suggested, but the relationship between bronchiectasis and acromegaly is unclear. We investigated whether acromegaly is related to the development of bronchiectasis. Materials and methods Using the Korean National Health Insurance System database between 2006 and 2016, we studied the relationship between acromegaly and bronchiectasis in patients with acromegaly (n=2593) and controls (1:5 age- and sex-matched subjects without acromegaly, n=12965) with a mean follow-up period of 8.9 years. Cox proportional hazards regression analysis was used to assess the risk of bronchiectasis in patients with acromegaly compared with controls after adjusting for age, sex, household income, place, type 2 diabetes, hypertension, and dyslipidemia. Results The mean age of the participants was 47.65 years, and male subjects comprised 45.62% of the cohort. The incidence rate of bronchiectasis in patients with acromegaly was 3.64 per 1,000 person-years and was significantly higher than that in controls (2.47 per 1,000 person-years) (log-rank test p = 0.002). In multivariable Cox proportional hazards regression modeling, the risk of bronchiectasis was significantly higher in patients with acromegaly than that in controls (HR: 1.49; 95% CI: 1.15-1.94, p = 0.0025) after adjusting for age, sex, household income, place, type 2 diabetes, hypertension, and dyslipidemia. Conclusions Our results suggest that acromegaly may be associated with bronchiectasis.
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Affiliation(s)
- Hyun-Il Gil
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Kyungdo Han
- Department of Statistics and Actuarial Science, Soongsil University, Seoul, Republic of Korea
| | - Sangmo Hong
- Department of Internal Medicine, Guri Hospital, College of Medicine, Hanyang University, Guri-si, Republic of Korea
| | - Cheol-Young Park
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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9
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Malekahmadi M, Soltani S, Pahlavani N, Sharifi Zahabi E, Kazemizadeh H, Hadavi S, Farsani GM. Zinc status in cystic fibrosis patients; a systematic review and meta-analysis. Heliyon 2024; 10:e33686. [PMID: 39027558 PMCID: PMC11255513 DOI: 10.1016/j.heliyon.2024.e33686] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 06/20/2024] [Accepted: 06/25/2024] [Indexed: 07/20/2024] Open
Abstract
Background Cystic fibrosis (CF) is an autosomal recessive hereditary disease causes concentration of secretions and this affects the lungs and digestive system. These patients are exposed to zinc (zn) deficiency. In this review, we decided to investigate the status of zn in CF patients compared to control group. Also, the clinical trials that have so far performed zinc supplementation in these patients are examined. Method ISI Web of Science, Scopus, PubMed/Medline, and Cochrane database were searched, up to December 2023, for studies that reported the association between zn levels of CF patients compared to a healthy control group. A random-effect model was used to compute the pooled weighted mean difference (WMD) with 95 % confidence intervals (CI). Subgroup analysis was done for region, sample and method of measurement, zinc supplementation and age. Result Overall, meta-analysis of 9 studies (n = 383 participants) revealed that the zn levels were significantly lower in children and adolescents with CF compared with healthy subjects (WMD = -11.97 μg/dL, 95 % CI: -22.57 to -1.37; I2 = 92.83 %). Meta-analysis of 8 studies (n = 320 participants) revealed that the serum and plasma level of zn was significantly lower in CF patients compared with healthy subjects (WMD = -14.31 μg/dL, 95 % CI: -25.09 to -3.53; I2 = 88.14 %, P-heterogeneity <0.001) While the zn level in saliva and sputum was significantly higher in CF patients. Conclusion CF patients have decreased zn levels in circulatory reservoirs. zn may effective for the diminish the respiratory and gastrointestinal symptoms in CF patients, further well-designed clinical trial studies is required to prove these effects.
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Affiliation(s)
- Mahsa Malekahmadi
- Imam Khomaini hospital complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Sepideh Soltani
- Yazd Cardiovascular Research Center, Non-communicable Diseases Research Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Naseh Pahlavani
- Social Determinants of Health Research Center, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran
- Health Sciences Research Center, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran
| | - Elham Sharifi Zahabi
- School of nutrition sciences and food technology, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Hossein Kazemizadeh
- Advanced Thoracic Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Shima Hadavi
- Treatment Department of Tehran University of Medical Sciences, Tehran, Iran
| | - Gholamreza Mohammadi Farsani
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
- Minimally Invasive Surgery Research Center, Iran University of Medical Sciences, Tehran, Iran
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10
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Nickerson R, Thornton CS, Johnston B, Lee AHY, Cheng Z. Pseudomonas aeruginosa in chronic lung disease: untangling the dysregulated host immune response. Front Immunol 2024; 15:1405376. [PMID: 39015565 PMCID: PMC11250099 DOI: 10.3389/fimmu.2024.1405376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 06/14/2024] [Indexed: 07/18/2024] Open
Abstract
Pseudomonas aeruginosa is a highly adaptable opportunistic pathogen capable of exploiting barriers and immune defects to cause chronic lung infections in conditions such as cystic fibrosis. In these contexts, host immune responses are ineffective at clearing persistent bacterial infection, instead driving a cycle of inflammatory lung damage. This review outlines key components of the host immune response to chronic P. aeruginosa infection within the lung, beginning with initial pathogen recognition, followed by a robust yet maladaptive innate immune response, and an ineffective adaptive immune response that propagates lung damage while permitting bacterial persistence. Untangling the interplay between host immunity and chronic P. aeruginosa infection will allow for the development and refinement of strategies to modulate immune-associated lung damage and potentiate the immune system to combat chronic infection more effectively.
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Affiliation(s)
- Rhea Nickerson
- Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada
| | - Christina S. Thornton
- Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Brent Johnston
- Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada
| | - Amy H. Y. Lee
- Department of Molecular Biology and Biochemistry, Faculty of Science, Simon Fraser University, Burnaby, BC, Canada
| | - Zhenyu Cheng
- Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada
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11
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Loske J, Völler M, Lukassen S, Stahl M, Thürmann L, Seegebarth A, Röhmel J, Wisniewski S, Messingschlager M, Lorenz S, Klages S, Eils R, Lehmann I, Mall MA, Graeber SY, Trump S. Pharmacological Improvement of Cystic Fibrosis Transmembrane Conductance Regulator Function Rescues Airway Epithelial Homeostasis and Host Defense in Children with Cystic Fibrosis. Am J Respir Crit Care Med 2024; 209:1338-1350. [PMID: 38259174 PMCID: PMC11146576 DOI: 10.1164/rccm.202310-1836oc] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Accepted: 01/19/2024] [Indexed: 01/24/2024] Open
Abstract
Rationale: Pharmacological improvement of cystic fibrosis transmembrane conductance regulator (CFTR) function with elexacaftor/tezacaftor/ivacaftor (ETI) provides unprecedented improvements in lung function and other clinical outcomes in patients with cystic fibrosis (CF). However, ETI effects on impaired mucosal homeostasis and host defense at the molecular and cellular levels in the airways of patients with CF remain unknown. Objectives: To investigate effects of ETI on the transcriptome of nasal epithelial and immune cells from children with CF at the single-cell level. Methods: Nasal swabs from 13 children with CF and at least one F508del allele aged 6 to 11 years were collected at baseline and 3 months after initiation of ETI, subjected to single-cell RNA sequencing, and compared with swabs from 12 age-matched healthy children. Measurements and Main Results: Proportions of CFTR-positive cells were decreased in epithelial basal, club, and goblet cells, but not in ionocytes, from children with CF at baseline and were restored by ETI therapy to nearly healthy levels. Single-cell transcriptomics revealed an impaired IFN signaling and reduced expression of major histocompatibility complex classes I and II encoding genes in epithelial cells of children with CF at baseline, which was partially restored by ETI. In addition, ETI therapy markedly reduced the inflammatory phenotype of immune cells, particularly of neutrophils and macrophages. Conclusions: Pharmacological improvement of CFTR function improves innate mucosal immunity and reduces immune cell inflammatory responses in the upper airways of children with CF at the single-cell level, highlighting the potential to restore epithelial homeostasis and host defense in CF airways by early initiation of ETI therapy.
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Affiliation(s)
- Jennifer Loske
- Center of Digital Health, Molecular Epidemiology Unit, Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, Germany
- Department of Biology and
| | - Mirjam Völler
- Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Sören Lukassen
- Center of Digital Health, Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Mirjam Stahl
- Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, Germany
- German Center for Lung Research, Associated Partner Site, Berlin, Germany
| | - Loreen Thürmann
- Center of Digital Health, Molecular Epidemiology Unit, Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Anke Seegebarth
- Center of Digital Health, Molecular Epidemiology Unit, Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Jobst Röhmel
- Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, Germany
- German Center for Lung Research, Associated Partner Site, Berlin, Germany
| | - Sebastian Wisniewski
- Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Marey Messingschlager
- Center of Digital Health, Molecular Epidemiology Unit, Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, Germany
- Department of Biology and
| | - Stephan Lorenz
- Max Planck Institute for Molecular Genetics, Berlin, Germany
| | - Sven Klages
- Max Planck Institute for Molecular Genetics, Berlin, Germany
| | - Roland Eils
- Department of Mathematics and Computer Science, Freie Universität Berlin, Berlin, Germany
- Center of Digital Health, Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, Germany
- German Center for Lung Research, Associated Partner Site, Berlin, Germany
- Health Data Science Unit, BioQuant, Medical Faculty, University of Heidelberg, Heidelberg, Germany
| | - Irina Lehmann
- Center of Digital Health, Molecular Epidemiology Unit, Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, Germany
- German Center for Lung Research, Associated Partner Site, Berlin, Germany
| | - Marcus A. Mall
- Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, Germany
- German Center for Lung Research, Associated Partner Site, Berlin, Germany
| | - Simon Y. Graeber
- Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, Germany
- German Center for Lung Research, Associated Partner Site, Berlin, Germany
| | - Saskia Trump
- Center of Digital Health, Molecular Epidemiology Unit, Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, Germany
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12
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Azoicai AN, Lupu A, Trandafir LM, Alexoae MM, Alecsa M, Starcea IM, Cuciureanu M, Knieling A, Salaru DL, Hanganu E, Mocanu A, Lupu VV, Ioniuc I. Cystic fibrosis management in pediatric population-from clinical features to personalized therapy. Front Pediatr 2024; 12:1393193. [PMID: 38798310 PMCID: PMC11116730 DOI: 10.3389/fped.2024.1393193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 04/24/2024] [Indexed: 05/29/2024] Open
Abstract
Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations of the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). In 1949, it's been identified as a monogenic disease and was thought to primarily affect individuals of Northern European descent. It was the most prevalent autosomal recessive disease that shortens life. With the availability of multiple testing methodologies nowadays, there is a chance to create novel and enhanced treatment options. Even in the absence of a high sweat chloride test (SCT) result, the discovery of two causal mutations is diagnostic for cystic fibrosis (CF). For a CF diagnosis, however, at least two positive E sweat chloride tests are still required. In order to achieve early and active intervention to manage cystic fibrosis (CF) and its comorbidities, treatment regimens for pediatric patients should be evaluated, improved, and closely monitored. New developments in the treatment of cystic fibrosis (CF) have led to the development of medications derived from molecules that target the pathogenetic pathway of the illness. These options are very efficient and allow pediatric patients to receive individualized care. However, in order to better direct patient care and enhance patient outcomes, it is crucial to research uncommon CF mutations, which can provide crucial information about the prognosis of the disease and the relationships between genotype and phenotype. To ensure the success of creating novel, safer, and more efficient treatment approaches, a deeper understanding of the pathogeny of the illness is required. In the age of customized medicine, genetic research will be essential to improving patient care and quality of life for those with uncommon mutations.
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Affiliation(s)
| | - Ancuta Lupu
- Pediatrics, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi, Romania
| | | | | | - Mirabela Alecsa
- Pediatrics, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi, Romania
| | | | - Magdalena Cuciureanu
- Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi, Romania
| | - Anton Knieling
- Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi, Romania
| | - Delia Lidia Salaru
- Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi, Romania
| | - Elena Hanganu
- Department of Biomedical Sciences, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi, Romania
| | - Adriana Mocanu
- Pediatrics, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi, Romania
| | - Vasile Valeriu Lupu
- Pediatrics, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi, Romania
| | - Ileana Ioniuc
- Pediatrics, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi, Romania
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13
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Santinelli R, Benz N, Guellec J, Quinquis F, Kocas E, Thomas J, Montier T, Ka C, Luczka-Majérus E, Sage E, Férec C, Coraux C, Trouvé P. The Inhibition of the Membrane-Bound Transcription Factor Site-1 Protease (MBTP1) Alleviates the p.Phe508del-Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Defects in Cystic Fibrosis Cells. Cells 2024; 13:185. [PMID: 38247876 PMCID: PMC10814821 DOI: 10.3390/cells13020185] [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: 12/01/2023] [Revised: 12/27/2023] [Accepted: 01/11/2024] [Indexed: 01/23/2024] Open
Abstract
Cystic Fibrosis (CF) is present due to mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene, the most frequent variant being p.phe508del. The CFTR protein is a chloride (Cl-) channel which is defective and almost absent of cell membranes when the p.Phe508del mutation is present. The p.Phe508del-CFTR protein is retained in the endoplasmic reticulum (ER) and together with inflammation and infection triggers the Unfolded Protein Response (UPR). During the UPR, the Activating Transcription Factor 6 (ATF6) is activated with cleavage and then decreases the expression of p.Phe508del-CFTR. We have previously shown that the inhibition of the activation of ATF6 alleviates the p.Phe508del-CFTR defects in cells overexpressing the mutated protein. In the present paper, our aim was to inhibit the cleavage of ATF6, and thus its activation in a human bronchial cell line with endogenous p.Phe508del-CFTR expression and in bronchial cells from patients, to be more relevant to CF. This was achieved by inhibiting the protease MBTP1 which is responsible for the cleavage of ATF6. We show here that this inhibition leads to increased mRNA and p.Phe508del-CFTR expression and, consequently, to increased Cl-efflux. We also explain the mechanisms linked to these increases with the modulation of genes when MBTP1 is inhibited. Indeed, RT-qPCR assays show that genes such as HSPA1B, CEBPB, VIMP, PFND2, MAPK8, XBP1, INSIG1, and CALR are modulated. In conclusion, we show that the inhibition of MBTP1 has a beneficial effect in relevant models to CF and that this is due to the modulation of genes involved in the disease.
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Affiliation(s)
- Raphaël Santinelli
- Univ Brest, Inserm, EFS, UMR 1078, 22 Avenue Camille Desmoulins, F-29200 Brest, France; (R.S.); (N.B.); (J.G.); (F.Q.); (E.K.); (J.T.); (T.M.); (C.K.); (C.F.)
| | - Nathalie Benz
- Univ Brest, Inserm, EFS, UMR 1078, 22 Avenue Camille Desmoulins, F-29200 Brest, France; (R.S.); (N.B.); (J.G.); (F.Q.); (E.K.); (J.T.); (T.M.); (C.K.); (C.F.)
| | - Julie Guellec
- Univ Brest, Inserm, EFS, UMR 1078, 22 Avenue Camille Desmoulins, F-29200 Brest, France; (R.S.); (N.B.); (J.G.); (F.Q.); (E.K.); (J.T.); (T.M.); (C.K.); (C.F.)
| | - Fabien Quinquis
- Univ Brest, Inserm, EFS, UMR 1078, 22 Avenue Camille Desmoulins, F-29200 Brest, France; (R.S.); (N.B.); (J.G.); (F.Q.); (E.K.); (J.T.); (T.M.); (C.K.); (C.F.)
| | - Ervin Kocas
- Univ Brest, Inserm, EFS, UMR 1078, 22 Avenue Camille Desmoulins, F-29200 Brest, France; (R.S.); (N.B.); (J.G.); (F.Q.); (E.K.); (J.T.); (T.M.); (C.K.); (C.F.)
| | - Johan Thomas
- Univ Brest, Inserm, EFS, UMR 1078, 22 Avenue Camille Desmoulins, F-29200 Brest, France; (R.S.); (N.B.); (J.G.); (F.Q.); (E.K.); (J.T.); (T.M.); (C.K.); (C.F.)
| | - Tristan Montier
- Univ Brest, Inserm, EFS, UMR 1078, 22 Avenue Camille Desmoulins, F-29200 Brest, France; (R.S.); (N.B.); (J.G.); (F.Q.); (E.K.); (J.T.); (T.M.); (C.K.); (C.F.)
| | - Chandran Ka
- Univ Brest, Inserm, EFS, UMR 1078, 22 Avenue Camille Desmoulins, F-29200 Brest, France; (R.S.); (N.B.); (J.G.); (F.Q.); (E.K.); (J.T.); (T.M.); (C.K.); (C.F.)
| | - Emilie Luczka-Majérus
- Inserm UMR-S 1250, University of Reims Champagne-Ardenne (URCA), SFR Cap-Santé, F-51100 Reims, France; (E.L.-M.); (C.C.)
| | - Edouard Sage
- Université Paris-Saclay, INRAE, UVSQ, VIM, F-78350 Jouy-en-Josas, France;
| | - Claude Férec
- Univ Brest, Inserm, EFS, UMR 1078, 22 Avenue Camille Desmoulins, F-29200 Brest, France; (R.S.); (N.B.); (J.G.); (F.Q.); (E.K.); (J.T.); (T.M.); (C.K.); (C.F.)
| | - Christelle Coraux
- Inserm UMR-S 1250, University of Reims Champagne-Ardenne (URCA), SFR Cap-Santé, F-51100 Reims, France; (E.L.-M.); (C.C.)
| | - Pascal Trouvé
- Univ Brest, Inserm, EFS, UMR 1078, 22 Avenue Camille Desmoulins, F-29200 Brest, France; (R.S.); (N.B.); (J.G.); (F.Q.); (E.K.); (J.T.); (T.M.); (C.K.); (C.F.)
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14
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Pabary R, Jaffe A, Bush A. Macrolides and Cystic Fibrosis. PROGRESS IN INFLAMMATION RESEARCH 2024:59-92. [DOI: 10.1007/978-3-031-42859-3_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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15
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Diab Cáceres L, Zamarrón de Lucas E. [Cystic fibrosis: Epidemiology, clinical manifestations, diagnosis and treatment]. Med Clin (Barc) 2023; 161:389-396. [PMID: 37558605 DOI: 10.1016/j.medcli.2023.06.006] [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: 02/23/2023] [Revised: 06/19/2023] [Accepted: 06/21/2023] [Indexed: 08/11/2023]
Abstract
Cystic fibrosis is a genetic and multisystemic disease. The main comorbidity in adulthood is respiratory involvement, with the presence of bronchiectasis, chronic bronchial infection and airflow obstruction. Until a decade ago, treatments were aimed at favoring secretion drainage, reducing respiratory exacerbations, controlling chronic bronchial infection and slowing functional deterioration, but with the advent of cystic fibrosis transmembrane conductance regulator (CFTR) modulators, the cystic fibrosis paradigm has changed. This novel treatment goes a step further in the management of this disease, it is able to improve the production of defective CFTR protein and increase its expression on the cell surface, thus achieving a better functioning of ion exchange, fluidizing respiratory secretions and reducing airflow obstruction. In addition, there are currently different lines of research aimed at correcting the genetic defect that causes cystic fibrosis.
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Affiliation(s)
- Layla Diab Cáceres
- Unidad de Fibrosis Quística, Servicio de Neumología, Hospital Universitario 12 de Octubre, Madrid, España.
| | - Ester Zamarrón de Lucas
- Unidad de Fibrosis Quística, Servicio de de Neumología, Hospital Universitario La Paz, Madrid
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16
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Holz F, Can E, Grehn C, Klotsche J, Materne B, Kruppa J, Kallinich T, Schwarz C. Manifestation and staging of arthropathy in cystic fibrosis. Defining different stages of cystic fibrosis arthropathy using ultrasound imaging and clinical scoring. J Cyst Fibros 2023; 22:980-988. [PMID: 37150649 DOI: 10.1016/j.jcf.2023.04.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Revised: 03/24/2023] [Accepted: 04/17/2023] [Indexed: 05/09/2023]
Abstract
BACKGROUND The true prevalence of cystic fibrosis arthropathy (CFA) remains unclear and may be significantly higher than previously reported. In recent studies, joint symptoms have been reported in up to 30% of adults with CF. This underlines the importance of CFA as a rising and clinically relevant co-morbidity. A clear definition of CFA is yet missing and its pathogenesis remains unclear. We investigated the clinical manifestation of CFA particularly via ultrasound (US) examination to define and implement a staging for clinical assessment. METHODS In a prospective cohort study between March 2018 and February 2020 a total of 98 consecutively recruited, adult cystic fibrosis (CF) patients underwent joint-US examination according to a newly developed ultrasound score (US-CFA). A clinical assessment including rheumatological scores (DAS28, HAQ) has been conducted as well as a specially designed questionnaire. Investigation on clinical and microbiological data, as well as a comprehensive laboratory analysis, were carried out. Cluster analysis has been performed to detect patterns defining different CFA stages based on disease activity. RESULTS US imaging has shown a considerable incidence of mild to moderate effusion as sign of joint inflammation/(teno-)synovitis. K-means clustering was used to distinguish 3 different stages of CFA based on the intensity of the detected effusion. These stages showed a significant association with disease activity (DAS28, p = 0.0004) as well as with patient-reported symptoms such as total weeks of CFA per year (p = 0.004), acute CFA (p = 0.015), chronic CFA (p = 0.016), disease burden (p = 0.04). Based on the US-CFA, 16% of patients suffered from severe CFA (II), 51% from intermediate CFA (I) and 33% did not present detectable arthritis. Positive serology for Chlamydophilia pneumoniae (IgA, IgG) and Chlamydia trachomatis (IgA, IgG) significantly correlated with the US-CFA. CONCLUSIONS The results of this study show that a definition and categorization for the clinical manifestation of CFA can be described through US examination, which is able to detect disease activity concordant with the DAS28 as a validated clinical score on arthritis. Defining these stages will lead to a better understanding of the clinical phenotype of the disease and will optimize diagnosis, therapy and research on CFA in the future.
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Affiliation(s)
- F Holz
- Department of Pediatric Pneumology, Immunology and Intensive Care Medicine, Division of Cystic Fibrosis, Charité - Universitätsmedizin, Berlin, Germany.
| | - E Can
- Department of Radiology including Pediatric Radiology, Charité - Universitätsmedizin, Berlin, Germany
| | - C Grehn
- Department of Pediatric Pneumology, Immunology and Intensive Care Medicine, Division of Cystic Fibrosis, Charité - Universitätsmedizin, Berlin, Germany
| | - J Klotsche
- German Rheumatism Research Centre, Berlin, Germany
| | - B Materne
- Department of Biostatistics and Clinical Epidemiology, Charité - Universitätsmedizin, Berlin, Germany
| | - J Kruppa
- Hochschule Osnabrück, University of Applied Sciences, Germany
| | - T Kallinich
- German Rheumatism Research Centre, Berlin, Germany; Department of Pediatric Pneumology, Immunology and Intensive Care Medicine, Division of Rheumatology, Charité - Universitätsmedizin, Berlin, Germany
| | - C Schwarz
- Division Cystic Fibrosis, CF Center Westbrandenburg, Clinic Westbrandenburg, Potsdam, Germany; HMU Health and Medical University, Potsdam, Germany
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17
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Şişmanlar Eyuboglu T, Aslan AT, Asfuroglu P, Kunt N, Ersoy A, Kose M, Unal G, Pekcan S. Neutrophil lymphocyte ratio, mean platelet volume, and immunoreactive trypsinogen as early inflammatory biomarkers for cystic fibrosis in infancy: A retrospective cohort study. Pediatr Pulmonol 2023; 58:3106-3112. [PMID: 37530491 DOI: 10.1002/ppul.26628] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 06/27/2023] [Accepted: 07/24/2023] [Indexed: 08/03/2023]
Abstract
BACKGROUND Airway inflammation starts in early life in cystic fibrosis (CF) and limited, objective markers are available to help identify infants with increased inflammation. We aimed to investigate neutrophil, lymphocyte ratio (NLR), mean platelet volume (MPV) and immunoreactive trypsinogen (IRT) to be a possible inflammatory biomarker for CF in infancy. METHODS This was a retrospective cohort study in three centers. Between January 2015 and December 2022, children with CF newborn screening (NBS) positivity and diagnosed as CF were included in the study. Correlation analysis were performed with NLR, MPV, IRT and follow-up parameters such as z-scores, modified Shwachman-Kulczycki score (mSKS) at the first, second, third and sixth ages and pulmonary function test (PFT) at the sixth age. RESULTS A total of 92 children with CF included in the study and 47.8% of them were female. There were no correlations between NLR, MPV and weight and height z-scores for all ages (p > 0.05), a negative correlation was found between MPV and body mass indexes (BMI) z-score at the age of 6 (r = -0.443, p = 0.038). No correlation was found between NLR, MPV and PFT parameters and mSKS at all ages (p > 0.05). There was a negative correlation between first IRT and BMI z-score at 6 years of age (r = -0.381, p = 0.046) and negative correlations between second IRT and weight and BMI z-score at the age of 6 (r = -0.462, p = 0.010; r = -0.437, p = 0.016, respectively). CONCLUSION Higher MPV and IRT levels during NBS period are associated with worse nutritional outcome which may reflect chronic inflammation. Children with higher MPV and IRT should be followed up closely in terms of chronic inflammation and nutritional status.
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Affiliation(s)
| | - Ayse Tana Aslan
- Department of Pediatric Pulmonology, Gazi University Faculty of Medicine, Ankara, Turkey
| | - Pelin Asfuroglu
- Department of Pediatric Pulmonology, Gazi University Faculty of Medicine, Ankara, Turkey
| | - Nursima Kunt
- Department of Pediatrics, Gazi University Faculty of Medicine, Ankara, Turkey
| | - Ali Ersoy
- Department of Pediatric Pulmonology, Erciyes University Faculty of Medicine, Kayseri, Turkey
| | - Mehmet Kose
- Department of Pediatric Pulmonology, Erciyes University Faculty of Medicine, Kayseri, Turkey
| | - Gokcen Unal
- Department of Pediatric Pulmonology, Necmettin Erbakan University Meram Medicine Faculty, Konya, Turkey
| | - Sevgi Pekcan
- Department of Pediatric Pulmonology, Necmettin Erbakan University Meram Medicine Faculty, Konya, Turkey
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18
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Carbone A, Vitullo P, Di Gioia S, Conese M. Lung Inflammatory Genes in Cystic Fibrosis and Their Relevance to Cystic Fibrosis Transmembrane Conductance Regulator Modulator Therapies. Genes (Basel) 2023; 14:1966. [PMID: 37895314 PMCID: PMC10606852 DOI: 10.3390/genes14101966] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 10/16/2023] [Accepted: 10/17/2023] [Indexed: 10/29/2023] Open
Abstract
Cystic fibrosis (CF) is a monogenic syndrome determined by over 2000 mutations in the CF Transmembrane Conductance Regulator (CFTR) gene harbored on chromosome 7. In people with CF (PWCF), lung disease is the major determinant of morbidity and mortality and is characterized by a clinical phenotype which differs in the presence of equal mutational assets, indicating that genetic and environmental modifiers play an important role in this variability. Airway inflammation determines the pathophysiology of CF lung disease (CFLD) both at its onset and progression. In this narrative review, we aim to depict the inflammatory process in CF lung, with a particular emphasis on those genetic polymorphisms that could modify the clinical outcome of the respiratory disease in PWCF. The natural history of CF has been changed since the introduction of CFTR modulator therapies in the clinical arena. However, also in this case, there is a patient-to-patient variable response. We provide an overview on inflammatory/immunity gene variants that affect CFLD severity and an appraisal of the effects of CFTR modulator therapies on the inflammatory process in lung disease and how this knowledge may advance the optimization of the management of PWCF.
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Affiliation(s)
- Annalucia Carbone
- Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy; (A.C.); (S.D.G.)
| | - Pamela Vitullo
- Cystic Fibrosis Support Center, Ospedale “G. Tatarella”, 71042 Cerignola, Italy;
| | - Sante Di Gioia
- Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy; (A.C.); (S.D.G.)
| | - Massimo Conese
- Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy; (A.C.); (S.D.G.)
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19
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Cohen-Cymberknoh M, Dimand I, Tanny T, Blau H, Mussaffi H, Kadosh D, Gartner S, Bentur L, Nir V, Gur M, Reiter J, Kerem E, Berger I. The association between Attention-Deficit-Hyperactivity-Disorder (ADHD) symptoms and disease severity in people with Cystic Fibrosis (pwCF). J Cyst Fibros 2023; 22:772-776. [PMID: 37061352 DOI: 10.1016/j.jcf.2023.04.004] [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: 11/26/2022] [Revised: 04/05/2023] [Accepted: 04/09/2023] [Indexed: 04/17/2023]
Abstract
BACKGROUND The hallmarks of Cystic fibrosis (CF), chronic infection and inflammation, require intensive daily treatment to maintain and improve quality of life and outcome. The incidence of Attention Deficit/Hyperactivity Disorder (ADHD) is increased in chronic inflammatory diseases. Previous studies suggested that the prevalence of ADHD in people with CF (pwCF) is higher than in the general population. The objective of this study was to evaluate the association between ADHD symptoms and parameters of CF disease severity, measured by demographic and clinical data. METHODS Based on our previous study, the results of ADHD questionnaires and the MOXOCPT (continuous performance task) from 143 pwCF (7-68 years old) were analyzed and linked to patient data such as forced expiratory volume in 1 second (FEV1)%predicted, body mass index (BMI), number of pulmonary exacerbations, days of antibiotic (Abx) treatment and serum inflammatory markers. RESULTS A positive correlation between FEV1 and ADHD questionnaire's score (p = 0.046) was observed in the children's group. Furthermore, BMI, white blood cells (WBC) count, and days of Abx treatment showed a positive correlation with some of the MOXOCPT parameters. CONCLUSION There is an association between ADHD symptoms and some parameters of CF disease severity. These results highlight the need for an early diagnosis of ADHD in pwCF, which have the potential to improve their ability to deal with the burden of their disease and consequently their quality of life. Additional research is needed to understand the full spectrum of ADHD pathophysiology and the relationship with chronic inflammatory diseases such as CF.
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Affiliation(s)
- Malena Cohen-Cymberknoh
- Pediatric Pulmonary Unit and Cystic fibrosis Center, Hadassah Medical Center, Jerusalem, Israel; Faculty of Medicine, Hebrew University of Jerusalem, Israel.
| | - Inon Dimand
- Pediatric Pulmonary Unit and Cystic fibrosis Center, Hadassah Medical Center, Jerusalem, Israel
| | - Tzlil Tanny
- Pediatric Department, Pediatric Division, Meir Medical Center, Kfar-Saba, Israel
| | - Hannah Blau
- Graub CF Center Schneider Children's Medical Center, Petach-Tikva and Sackler School of Medicine, Tel-Aviv University, Israel
| | - Huda Mussaffi
- Graub CF Center Schneider Children's Medical Center, Petach-Tikva and Sackler School of Medicine, Tel-Aviv University, Israel
| | - Diana Kadosh
- Graub CF Center Schneider Children's Medical Center, Petach-Tikva and Sackler School of Medicine, Tel-Aviv University, Israel
| | - Silvia Gartner
- CF Center, Hospital Universitari Vall d' Hebron, Barcelona, Spain
| | - Lea Bentur
- CF Center, Ruth Rappaport Children's Hospital, Rambam Medical Center, Haifa, Israel
| | - Vered Nir
- CF Center, Ruth Rappaport Children's Hospital, Rambam Medical Center, Haifa, Israel
| | - Michal Gur
- CF Center, Ruth Rappaport Children's Hospital, Rambam Medical Center, Haifa, Israel
| | - Joel Reiter
- Pediatric Pulmonary Unit and Cystic fibrosis Center, Hadassah Medical Center, Jerusalem, Israel; Faculty of Medicine, Hebrew University of Jerusalem, Israel
| | - Eitan Kerem
- Pediatric Pulmonary Unit and Cystic fibrosis Center, Hadassah Medical Center, Jerusalem, Israel; Faculty of Medicine, Hebrew University of Jerusalem, Israel
| | - Itai Berger
- Assuta-Ashdod University Hospital, Faculty of Health Sciences, Ben-Gurion University of the Negev, Israel; School of Social Work and Social Welfare, Hebrew University, Jerusalem, Israel
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20
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Ruzycki CA, Montoya D, Irshad H, Cox J, Zhou Y, McDonald JD, Kuehl PJ. Inhalation delivery of nucleic acid gene therapies in preclinical drug development. Expert Opin Drug Deliv 2023; 20:1097-1113. [PMID: 37732957 DOI: 10.1080/17425247.2023.2261369] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 09/18/2023] [Indexed: 09/22/2023]
Abstract
INTRODUCTION Inhaled gene therapy programs targeting diseases of the lung have seen increasing interest in recent years, though as of yet no product has successfully entered the market. Preclinical research to support such programs is critically important in maximizing the chances of developing successful candidates. AREAS COVERED Aspects of inhalation delivery of gene therapies are reviewed, with a focus on preclinical research in animal models. Various barriers to inhalation delivery of gene therapies are discussed, including aerosolization stresses, aerosol behavior in the respiratory tract, and disposition processes post-deposition. Important aspects of animal models are considered, including determinations of biologically relevant determinations of dose and issues related to translatability. EXPERT OPINION Development of clinically-efficacious inhaled gene therapies has proven difficult owing to numerous challenges. Fit-for-purpose experimental and analytical methods are necessary for determinations of biologically relevant doses in preclinical animal models. Further developments in disease-specific animal models may aid in improving the translatability of results in future work, and we expect to see accelerated interests in inhalation gene therapies for various diseases. Sponsors, researchers, and regulators are encouraged to engage in early and frequent discussion regarding candidate therapies, and additional dissemination of preclinical methodologies would be of immense value in avoiding common pitfalls.
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Affiliation(s)
- Conor A Ruzycki
- Lovelace Biomedical Research Institute, Albuquerque, NM, USA
| | - Derek Montoya
- Lovelace Biomedical Research Institute, Albuquerque, NM, USA
| | - Hammad Irshad
- Lovelace Biomedical Research Institute, Albuquerque, NM, USA
| | - Jason Cox
- Lovelace Biomedical Research Institute, Albuquerque, NM, USA
| | - Yue Zhou
- Lovelace Biomedical Research Institute, Albuquerque, NM, USA
| | | | - Philip J Kuehl
- Lovelace Biomedical Research Institute, Albuquerque, NM, USA
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21
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Ho PM, Nazeer RR, Welch M. Therapeutic interventions alter ecological interactions among cystic fibrosis airway microbiota. Front Microbiol 2023; 14:1178131. [PMID: 37323900 PMCID: PMC10265647 DOI: 10.3389/fmicb.2023.1178131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 04/28/2023] [Indexed: 06/17/2023] Open
Abstract
The airways of people with cystic fibrosis (CF) often harbor a diverse microbiota and in recent years, much effort has been invested in cataloguing these. In spite of providing a wealth of insight, this cataloguing tells us little about how the organisms interact with one another in the CF airways. However, such relationships can be inferred using the theoretical framework of the Lotka-Volterra (LV) model. In the current work, we use a generalized Lotka-Volterra model to interrogate the nationwide data collected and curated by the UK CF Registry. This longitudinal dataset (covering the period 2008-2020) contains annual depositions that record the presence/absence of microbial taxa in each patient, their medication, and their CF genotype. Specifically, we wanted to identify trends in ecological relationships between the CF microbiota at a nationwide level, and whether these are potentially affected by medication. Our results show that some medications have a distinct influence on the microbial interactome, especially those that potentially influence the "gut-lung axis" or mucus viscosity. In particular, we found that patients treated with a combination of antimicrobial agents (targeting the airway microbiota), digestive enzymes (assisting in the assimilation of dietary fats and carbohydrates), and DNase (to reduce mucus viscosity) displayed a distinctly different airway interactome compared with patients treated separately with these medications.
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Affiliation(s)
| | | | - Martin Welch
- Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
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22
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Zhuang Y, Wang L, Ji C, Sun Y, Shao F. Construction of a novel pyrotosis-related prognostic model of esophageal square cell carcinoma and determination of the anti-tumor effect of WFDC12. Funct Integr Genomics 2023; 23:177. [PMID: 37225895 DOI: 10.1007/s10142-023-01103-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 05/05/2023] [Accepted: 05/15/2023] [Indexed: 05/26/2023]
Abstract
Esophageal squamous cell carcinoma (ESCC) is a prevalent cancer type with a poor prognosis. As a form of programmed cell death, pyroptosis has been implicated in cancer growth, invasion, and metastasis. To investigate the relationship between pyroptosis and the prognosis of ESCC, we analyzed the expression profiles and clinical data of patients with ESCC, obtained from the Gene Expression Omnibus and The Cancer Genome Atlas databases, using bioinformatics analysis. Univariate Cox, multivariate Cox, and LASSO Cox regression analyses were conducted to develop a pyroptosis-related prognostic model (riskScore). CIBERSORT and MCPcounter algorithm evaluated the proportion of various immune infiltrating cells. Tissues from 16 patients were collected to verify the expression of key pyroptosis-related genes (PRGs) using real-time quantitative PCR (RT-qPCR), western blot, and immunohistochemical assays. Additionally, functional assays were performed in ESCC cell lines KYSE-150 and ECA-109 to examine the role of key PRGs. Among 25 pyroptosis-related regulators, 12 genes exhibited differential expression between tumor and normal tissues. Based on the differential expression of PRGs, we identified two subgroups with distinct clinical and molecular features. We further established a pyroptosis-related model with high prognostic value. In addition, we found a significant association of PRGs and riskScore with immune cell infiltration and the response rate of immunotherapy. Furthermore, we confirmed the low expression of WFDC12 in ESCC. Cellular assays demonstrated that the knockdown of WFDC12 in ESCC cell lines promoted cell proliferation and migration. Collectively, our findings highlight the critical role of PRGs in the development and prognosis of ESCC, while our riskScore could accurately predict the prognosis and immunogenicity of ESCC. Finally, our preliminary evidence suggests a protective role of WFDC12 in ESCC in vitro.
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Affiliation(s)
- Yu Zhuang
- Department of thoracic surgery, Nanjing Chest Hospital, Nanjing, China
- Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, China
| | - Lan Wang
- Digestive Endoscopy Center, Affiliated Hospital of Nanjing University of Chinese Medicine (Jiangsu Provincial Hospital of Chinese Medicine), Nanjing, 210029, China
| | - Chengjian Ji
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, 210029, China
| | - Yungang Sun
- Department of thoracic surgery, Nanjing Chest Hospital, Nanjing, China.
- Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, China.
| | - Feng Shao
- Department of thoracic surgery, Nanjing Chest Hospital, Nanjing, China.
- Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, China.
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23
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Lepissier A, Bonnel AS, Wizla N, Weiss L, Mittaine M, Bessaci K, Kerem E, Houdouin V, Reix P, Marguet C, Sermet-Gaudelus I. Moving the Dial on Airway Inflammation in Response to Trikafta in Adolescents with Cystic Fibrosis. Am J Respir Crit Care Med 2023; 207:792-795. [PMID: 36599047 PMCID: PMC10037474 DOI: 10.1164/rccm.202210-1938le] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Affiliation(s)
| | - Anne Sophie Bonnel
- Hôpital Necker Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris, France
- Hôpital André Mignot, Le Chesnay, France
| | | | | | | | | | - Eitan Kerem
- Hadassah Hebrew University Medical Center, Jerusalem, Israel
| | | | - Philippe Reix
- Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France
- UMR 5558 CNRS Equipe EMET Université Claude Bernard Lyon 1, Lyon, France
| | - Christophe Marguet
- CHU de Rouen, Rouen, France
- UMR 1311, Université de Normandie, Rouen, France
| | - Isabelle Sermet-Gaudelus
- INSERM U1151, Institut Necker Enfants Malades, Paris, France
- Hôpital Necker Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris, France
- Université Paris Cité, Paris, France
- European Respiratory Network-Lung, Frankfurt, Germany
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24
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Inflammation and Infection in Cystic Fibrosis: Update for the Clinician. CHILDREN (BASEL, SWITZERLAND) 2022; 9:children9121898. [PMID: 36553341 PMCID: PMC9777099 DOI: 10.3390/children9121898] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 11/29/2022] [Accepted: 11/30/2022] [Indexed: 12/09/2022]
Abstract
Inflammation and infection play an important role in the pathophysiology of cystic fibrosis, and they are significant causes of morbidity and mortality in CF. The presence of thick mucus in the CF airways predisposes to local hypoxia and promotes infection and inflammation. A vicious cycle of airway obstruction, inflammation, and infection is of critical importance for the progression of the disease, and new data elucidate the different factors that influence it. Recent research has been focused on improving infection and inflammation in addition to correcting the basic gene defect. This review aims to summarize important advances in infection and inflammation as well as the effect of new treatments modulating the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein. New approaches to target infection and inflammation are being studied, including gallium, nitric oxide, and phage therapy for infection, along with retinoids and neutrophil elastase inhibitors for inflammation.
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25
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Britto CJ, Ratjen F, Clancy JP. Emerging Approaches to Monitor and Modify Care in the Era of Cystic Fibrosis Transmembrane Conductance Regulators. Clin Chest Med 2022; 43:631-646. [PMID: 36344071 DOI: 10.1016/j.ccm.2022.06.006] [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: 11/06/2022]
Abstract
As we characterize the clinical benefits of highly effective modulator therapy (HEMT) in the cystic fibrosis (CF) population, our paradigm for treating and monitoring disease continues to evolve. More sensitive approaches are necessary to detect early disease and clinical progression. This article reviews evolving strategies to assess disease control and progression in the HEMT era. This article also explores developments in pulmonary function monitoring, advanced respiratory imaging, tools for the collection of patient-reported outcomes, and their application to profile individual responses, guide therapeutic decisions, and improve the quality of life of people with CF.
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Affiliation(s)
- Clemente J Britto
- Yale Adult Cystic Fibrosis Program, Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, Yale University School of Medicine.
| | - Felix Ratjen
- Division of Respiratory Medicine, Translational Medicine, University of Toronto Hospital for Sick Children, 555 University Avenue, Toronto Ontario M5G 1X8, Canada
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26
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Hill DB, Button B, Rubinstein M, Boucher RC. Physiology and pathophysiology of human airway mucus. Physiol Rev 2022; 102:1757-1836. [PMID: 35001665 PMCID: PMC9665957 DOI: 10.1152/physrev.00004.2021] [Citation(s) in RCA: 137] [Impact Index Per Article: 45.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 12/13/2021] [Accepted: 12/19/2021] [Indexed: 01/27/2023] Open
Abstract
The mucus clearance system is the dominant mechanical host defense system of the human lung. Mucus is cleared from the lung by cilia and airflow, including both two-phase gas-liquid pumping and cough-dependent mechanisms, and mucus transport rates are heavily dependent on mucus concentration. Importantly, mucus transport rates are accurately predicted by the gel-on-brush model of the mucociliary apparatus from the relative osmotic moduli of the mucus and periciliary-glycocalyceal (PCL-G) layers. The fluid available to hydrate mucus is generated by transepithelial fluid transport. Feedback interactions between mucus concentrations and cilia beating, via purinergic signaling, coordinate Na+ absorptive vs Cl- secretory rates to maintain mucus hydration in health. In disease, mucus becomes hyperconcentrated (dehydrated). Multiple mechanisms derange the ion transport pathways that normally hydrate mucus in muco-obstructive lung diseases, e.g., cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), non-CF bronchiectasis (NCFB), and primary ciliary dyskinesia (PCD). A key step in muco-obstructive disease pathogenesis is the osmotic compression of the mucus layer onto the airway surface with the formation of adherent mucus plaques and plugs, particularly in distal airways. Mucus plaques create locally hypoxic conditions and produce airflow obstruction, inflammation, infection, and, ultimately, airway wall damage. Therapies to clear adherent mucus with hydrating and mucolytic agents are rational, and strategies to develop these agents are reviewed.
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Affiliation(s)
- David B Hill
- Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
- Joint Department of Biomedical Engineering, The University of North Carolina and North Carolina State University, Chapel Hill, North Carolina
| | - Brian Button
- Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Michael Rubinstein
- Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
- Department of Mechanical Engineering and Materials Science, Biomedical Engineering, Physics, and Chemistry, Duke University, Durham, North Carolina
| | - Richard C Boucher
- Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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27
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Blanchard AC, Waters VJ. Opportunistic Pathogens in Cystic Fibrosis: Epidemiology and Pathogenesis of Lung Infection. J Pediatric Infect Dis Soc 2022; 11:S3-S12. [PMID: 36069904 DOI: 10.1093/jpids/piac052] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 06/20/2022] [Indexed: 11/13/2022]
Abstract
Cystic fibrosis (CF) is one of the most common life-shortening genetic diseases in Caucasians. Due to abnormal accumulation of mucus, respiratory failure caused by chronic infections is the leading cause of mortality in this patient population. The microbiology of these respiratory infections includes a distinct set of opportunistic pathogens, including Pseudomonas aeruginosa, Burkholderia spp., Achromobacter spp., Stenotrophomonas maltophilia, anaerobes, nontuberculous mycobacteria, and fungi. In recent years, culture-independent methods have shown the polymicrobial nature of lung infections, and the dynamics of microbial communities. The unique environment of the CF airway predisposes to infections caused by opportunistic pathogens. In this review, we will highlight how the epidemiology and role in disease of these pathogens in CF differ from that in individuals with other medical conditions. Infectious diseases (ID) physicians should be aware of these differences and the specific characteristics of infections associated with CF.
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Affiliation(s)
- Ana C Blanchard
- Department of Pediatrics, Division of Infectious Diseases, CHU Sainte-Justine, Université de Montréal, 3175 Chemin de la Côte-Sainte-Catherine, Montreal, Quebec, H3T 1C5, Canada
| | - Valerie J Waters
- Department of Pediatrics, Division of Infectious Diseases, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada
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28
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Ruhluel D, O'Brien S, Fothergill JL, Neill DR. Development of liquid culture media mimicking the conditions of sinuses and lungs in cystic fibrosis and health. F1000Res 2022; 11:1007. [PMID: 36519007 PMCID: PMC9718992 DOI: 10.12688/f1000research.125074.1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/26/2022] [Indexed: 11/25/2023] Open
Abstract
The respiratory tract is a compartmentalised and heterogenous environment. The nasopharynx and sinuses of the upper airways have distinct properties from the lungs and these differences may shape bacterial adaptation and evolution. Upper airway niches act as early colonisation sites for respiratory bacterial pathogens, including those, such as Pseudomonas aeruginosa, that can go on to establish chronic infection of the lungs in people with cystic fibrosis (CF). Despite the importance of upper airway environments in facilitating early adaptation to host environments, currently available in vitro models for study of respiratory infection in CF focus exclusively on the lungs. Furthermore, animal models, widely used to bridge the gap between in vitro systems and the clinical scenario, do not allow the upper and lower airways to be studied in isolation. We have developed a suite of culture media reproducing key features of the upper and lower airways, for the study of bacterial adaptation and evolution in different respiratory environments. For both upper and lower airway-mimicking media, we have developed formulations that reflect airway conditions in health and those that reflect the altered environment of the CF respiratory tract. Here, we describe the development and validation of these media and their use for study of genetic and phenotypic adaptations in P. aeruginosa during growth under upper or lower airway conditions in health and in CF.
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Affiliation(s)
- Dilem Ruhluel
- University of Liverpool, Institute of Infection, Veterinary and Ecological Sciences,, Liverpool, L69 7BE, UK
| | - Siobhan O'Brien
- Department of Microbiology, Moyne Institute of Preventive Medicine, Trinity College, Dublin, 2, Ireland
| | - Joanne L Fothergill
- University of Liverpool, Institute of Infection, Veterinary and Ecological Sciences,, Liverpool, L69 7BE, UK
| | - Daniel R Neill
- University of Liverpool, Institute of Infection, Veterinary and Ecological Sciences,, Liverpool, L69 7BE, UK
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29
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Ruhluel D, O'Brien S, Fothergill JL, Neill DR. Development of liquid culture media mimicking the conditions of sinuses and lungs in cystic fibrosis and health. F1000Res 2022; 11:1007. [PMID: 36519007 PMCID: PMC9718992 DOI: 10.12688/f1000research.125074.2] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/18/2022] [Indexed: 12/05/2022] Open
Abstract
The respiratory tract is a compartmentalised and heterogenous environment. The nasopharynx and sinuses of the upper airways have distinct properties from the lungs and these differences may shape bacterial adaptation and evolution. Upper airway niches act as early colonisation sites for respiratory bacterial pathogens, including those, such as Pseudomonas aeruginosa, that can go on to establish chronic infection of the lungs in people with cystic fibrosis (CF). Despite the importance of upper airway environments in facilitating early adaptation to host environments, currently available in vitro models for study of respiratory infection in CF focus exclusively on the lungs. Furthermore, animal models, widely used to bridge the gap between in vitro systems and the clinical scenario, do not allow the upper and lower airways to be studied in isolation. We have developed a suite of culture media reproducing key features of the upper and lower airways, for the study of bacterial adaptation and evolution in different respiratory environments. For both upper and lower airway-mimicking media, we have developed formulations that reflect airway conditions in health and those that reflect the altered environment of the CF respiratory tract. Here, we describe the development and validation of these media and their use for study of genetic and phenotypic adaptations in P. aeruginosa during growth under upper or lower airway conditions in health and in CF.
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Affiliation(s)
- Dilem Ruhluel
- University of Liverpool, Institute of Infection, Veterinary and Ecological Sciences,, Liverpool, L69 7BE, UK
| | - Siobhan O'Brien
- Department of Microbiology, Moyne Institute of Preventive Medicine, Trinity College, Dublin, 2, Ireland
| | - Joanne L Fothergill
- University of Liverpool, Institute of Infection, Veterinary and Ecological Sciences,, Liverpool, L69 7BE, UK
| | - Daniel R Neill
- University of Liverpool, Institute of Infection, Veterinary and Ecological Sciences,, Liverpool, L69 7BE, UK
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30
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Bitossi C, Viscido A, Prezioso C, Brazzini G, Trancassini M, Borrazzo C, Passerini S, Frasca F, Scordio M, Sorrentino L, Oliveto G, Fracella M, D'Auria A, Selvaggi C, Cimino G, Midulla F, Pierangeli A, Antonelli G, Moens U, Pietropaolo V, Scagnolari C. High prevalence of Merkel cell polyomavirus is associated with dysregulation in transcript levels of TLR9 and type I IFNs in a large cohort of CF patients from the Italian (Lazio) reference center for cystic fibrosis. Microb Pathog 2022; 169:105644. [PMID: 35752381 DOI: 10.1016/j.micpath.2022.105644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 04/14/2022] [Accepted: 06/13/2022] [Indexed: 11/21/2022]
Abstract
Merkel cell polyomavirus (MCPyV) has been detected in respiratory specimens including those from Cystic Fibrosis (CF) patients, raising questions about its immunological and clinical relevance in the respiratory tract. MCPyV might promote an inappropriate antiviral response contributing to a chronic inflammatory response and resulting in detrimental effects in CF. Respiratory samples (n = 1138) were randomly collected from respiratory tract of CF patients (n = 539) during July 2018-October 2019. MCPyV-DNA detection was performed by real time PCR and positive samples were characterized by sequencing of the NCCR genomic region. The transcript levels of Toll-like receptor 9 (TLR9) and type I interferon (IFN-I) genes (IFNα, IFNβ and IFNε) were examined by real-time RT-PCR assays. MCPyV-DNA was detected in 268 out of 1138 respiratory specimens (23.5%) without any difference in the prevalence of MCPyV-DNA according to age, gender or bacteriological status of CF individuals. Thirteen out of 137 CF patients remained positive for MCPyV-DNA over the time (a median follow-up period of 8.8 months). Detection of MCPyV-DNA in respiratory specimens was not associated with the occurrence of exacerbation events. Both MCPyV positive adolescents (11-24 years) and adults (≥25 years) had lower mRNA levels of TLR9, IFNβ, IFNε and IFNα than the negative patients of the same age group, while MCPyV positive children produced increased levels of TLR9 and IFN-I genes (p < 0.05 for TLR9, IFNβ, IFNε) with respect to the negative ones. There were significant differences in TLR9 levels (p < 0.01), but not in those of IFNs, between MCPyV-DNA positive and negative patients with S. aureus, P. aeruginosa or both. Overall, these results indicate that MCPyV-DNA is frequently detected in the respiratory samples of CF patients and might influence the expression levels of IFN-related genes in an age dependent manner. The concomitant detection of MCPyV together with S. aureus and/or P. aeruginosa correlated with alterations in TLR9 levels suggesting that virus-bacteria coinfections might contribute to affect antiviral immunity in CF patients.
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Affiliation(s)
- Camilla Bitossi
- Laboratory of Virology, Department of Molecular Medicine, Sapienza University of Rome, Affiliated to Istituto Pasteur Italia, 00185, Rome, Italy
| | - Agnese Viscido
- Laboratory of Virology, Department of Molecular Medicine, Sapienza University of Rome, Affiliated to Istituto Pasteur Italia, 00185, Rome, Italy
| | - Carla Prezioso
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00185, Rome, Italy; IRCSS San Raffaele Roma, Microbiology of Chronic Neuro-degenerative Pathologies, 00163, Rome, Italy
| | - Gabriele Brazzini
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00185, Rome, Italy
| | - Maria Trancassini
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00185, Rome, Italy
| | - Cristian Borrazzo
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00185, Rome, Italy
| | - Sara Passerini
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00185, Rome, Italy
| | - Federica Frasca
- Laboratory of Virology, Department of Molecular Medicine, Sapienza University of Rome, Affiliated to Istituto Pasteur Italia, 00185, Rome, Italy
| | - Mirko Scordio
- Laboratory of Virology, Department of Molecular Medicine, Sapienza University of Rome, Affiliated to Istituto Pasteur Italia, 00185, Rome, Italy
| | - Leonardo Sorrentino
- Laboratory of Virology, Department of Molecular Medicine, Sapienza University of Rome, Affiliated to Istituto Pasteur Italia, 00185, Rome, Italy
| | - Giuseppe Oliveto
- Laboratory of Virology, Department of Molecular Medicine, Sapienza University of Rome, Affiliated to Istituto Pasteur Italia, 00185, Rome, Italy
| | - Matteo Fracella
- Laboratory of Virology, Department of Molecular Medicine, Sapienza University of Rome, Affiliated to Istituto Pasteur Italia, 00185, Rome, Italy
| | - Alessandra D'Auria
- Laboratory of Virology, Department of Molecular Medicine, Sapienza University of Rome, Affiliated to Istituto Pasteur Italia, 00185, Rome, Italy
| | - Carla Selvaggi
- Laboratory of Virology, Department of Molecular Medicine, Sapienza University of Rome, Affiliated to Istituto Pasteur Italia, 00185, Rome, Italy
| | - Giuseppe Cimino
- Lazio Reference Center for Cystic Fibrosis, Policlinico Umberto I University Hospital, 00185, Rome, Italy
| | - Fabio Midulla
- Department of Pediatric Emergency, University La Sapienza of Rome, 00185, Rome, Italy
| | - Alessandra Pierangeli
- Laboratory of Virology, Department of Molecular Medicine, Sapienza University of Rome, Affiliated to Istituto Pasteur Italia, 00185, Rome, Italy
| | - Guido Antonelli
- Laboratory of Virology, Department of Molecular Medicine, Sapienza University of Rome, Affiliated to Istituto Pasteur Italia, 00185, Rome, Italy; Microbiology and Virology Unit, Hospital "Policlinico Umberto I", Sapienza University, 00185, Rome, Italy
| | - Ugo Moens
- Department of Medical Biology, Faculty of Health Sciences, University of Tromsø-The Arctic University of Norway, 9037, Tromsø, Norway
| | - Valeria Pietropaolo
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00185, Rome, Italy
| | - Carolina Scagnolari
- Laboratory of Virology, Department of Molecular Medicine, Sapienza University of Rome, Affiliated to Istituto Pasteur Italia, 00185, Rome, Italy.
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31
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Lepissier A, Addy C, Hayes K, Noel S, Bui S, Burgel PR, Dupont L, Eickmeier O, Fayon M, Leal T, Lopes C, Downey DG, Sermet-Gaudelus I. Inflammation biomarkers in sputum for clinical trials in cystic fibrosis: current understanding and gaps in knowledge. J Cyst Fibros 2022; 21:691-706. [PMID: 34772643 DOI: 10.1016/j.jcf.2021.10.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 10/25/2021] [Accepted: 10/25/2021] [Indexed: 12/12/2022]
Abstract
RATIONALE Sputum biomarkers hold promise as a direct measure of inflammation within the cystic fibrosis (CF) lung, but variability in study design and sampling methodology have limited their use. A full evaluation of the reliability, validity and clinical relevance of individual biomarkers is required to optimise their use within CF clinical research. OBJECTIVES A biomarker Special Interest Working Group was established within the European Cystic Fibrosis Society-Clinical Trials Network Standardisation Committee, to perform a review of the evidence regarding sputum biomarkers in CF. METHODS From the 139 included articles, we identified 71 sputum biomarkers to undergo evaluation of their clinimetric properties, responsiveness, discriminant, concurrent and convergent validity. RESULTS Current evidence confirms the potential of sputum biomarkers as outcome measures in clinical trials. Inconsistency in responsiveness, concurrent and convergent validity require further research into these markers and processing standardisation before translation into wider use. Of the 71 biomarkers identified, Neutrophil Elastase (NE), IL-8, TNF-α and IL-1β, demonstrated validity and responsiveness to be currently considered for use in clinical trials. Other biomarkers show future promise, including IL-6, calprotectin, HMGB-1 and YKL-40. CONCLUSION A concerted international effort across the cystic fibrosis community is needed to promote high quality biomarker trial design, establish large population-based biomarker studies, and work together to create standards for collection, storage and analysis of sputum biomarkers.
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Affiliation(s)
- Agathe Lepissier
- Paediatric Center for Cystic Fibrosis, Centre de Référence Maladies Rares, Mucoviscidose et Maladies Apparentées, Hôpital Necker Enfants Malades 149 rue de Sévres, Paris 75743, France; INSERM U1151, Institut Necker Enfants Malades, 160 rue de Vaugirard, Paris 75743, France; European Reference Network (ERN Lung)
| | - Charlotte Addy
- Northern Ireland Clinical Research Facility, Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL; All Wales Adult Cystic Fibrosis Centre, University Hopsital Llandough, Penlan Road, CF64 2XX
| | - Kate Hayes
- Northern Ireland Clinical Research Facility, Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL
| | - Sabrina Noel
- INSERM U1151, Institut Necker Enfants Malades, 160 rue de Vaugirard, Paris 75743, France
| | - Stéphanie Bui
- Université de Bordeaux (INSERM U1045), CHU de Bordeaux, (CIC1401), F-33000 Bordeaux, France
| | - Pierre-Régis Burgel
- European Reference Network (ERN Lung); National Reference Cystic Fibrosis Center and Department of Respiratory Medicine, Cochin Hospital, Assistance Publique Hôpitaux de Paris, Paris, 75014, France; Institut Cochin, INSERM U1016 and Université de Paris; Paris 75014, France
| | - Lieven Dupont
- University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium
| | - Olaf Eickmeier
- Facharzt für Kinder- und Jugendmedizin, Universitätsklinikum Frankfurt a.M., Johann Wolfgang-Goethe-Universität, Allergologie, Pneumologie & Mukoviszidose, Theodor-Stern-Kai 7, 60590 Frankfurt/Main
| | - Michael Fayon
- Université de Bordeaux (INSERM U1045), CHU de Bordeaux, (CIC1401), F-33000 Bordeaux, France
| | - Teresinha Leal
- Louvain Toxicology and Applied Pharmacology, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
| | - Carlos Lopes
- Departamento do Tórax, Hospital de Santa Maria, Lisbon
| | - Damian G Downey
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL
| | - Isabelle Sermet-Gaudelus
- Paediatric Center for Cystic Fibrosis, Centre de Référence Maladies Rares, Mucoviscidose et Maladies Apparentées, Hôpital Necker Enfants Malades 149 rue de Sévres, Paris 75743, France; INSERM U1151, Institut Necker Enfants Malades, 160 rue de Vaugirard, Paris 75743, France; European Reference Network (ERN Lung); Service de Pneumologie et Allergologie Pédiatriques, Centre de Ressources et de Compétence de la Mucoviscidose, Hôpital Necker Enfants Malades 149 rue de Sévres, INSERM U1151, Institut Necker Enfants Malades, Université Paris Sorbonne, Paris 75743, France.
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32
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Albedewi H, Bindayel I, Albarrag A, Banjar H. Correlation of Gut Microbiota, Vitamin D Status, and Pulmonary Function Tests in Children With Cystic Fibrosis. Front Nutr 2022; 9:884104. [PMID: 35757256 PMCID: PMC9218790 DOI: 10.3389/fnut.2022.884104] [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: 02/25/2022] [Accepted: 05/05/2022] [Indexed: 11/26/2022] Open
Abstract
Background Children with cystic fibrosis (CF) are expected to have suboptimal serum vitamin D status and altered gut microbiota. The altered gut microbiota is hypothesized to have a pro-inflammatory effect that further complicates the existing respiratory inflammation. Emerging evidence suggests an association between vitamin D and gut microbiota. The aim of this study was to assess the relationships between 25-hydroxyvitamin D [25(OH)D] status, pulmonary function, and fecal bacteria in children with CF. Methods In this cross-sectional study, a total of 35 children with CF (8.7 ± 2.83 years) and 24 controls without CF (9 ± 2.7 years) were included in this study. Serum 25(OH)D status was measured using the Elecsys vitamin D total II assay. In the CF group, gut microbiota composition was assessed using real-time PCR analysis. Pulmonary function tests (PFTs) were measured using spirometry. Comparisons between the CF and non-CF controls were conducted using the independent sample t-test. In the CF group, one-way analysis of variance (ANOVA) was used to assess differences in PFTs and gut microbiota composition across the three vitamin D subgroups. The correlations between 25(OH)D status and PFTs, or gut microbiota composition, and PFTs with gut microbiota composition were analyzed using the Pearson's correlation coefficient test. Results Children with CF had significantly lower serum 25(OH)D levels compared with children without CF (44.3 ± 22.4 vs. 59 ± 25.5, respectively, P = 0.026). Children with CF with optimal serum 25(OH)D level had significantly higher levels of Bacteroidetes, Firmicutes, and total bacteria (P = 0.007, P = 0.007, and P = 0.022, respectively). The level of Firmicutes was found to be significantly higher in mild forced expiratory volume in 1 s (FEV1) compared with moderate FEV1 (P = 0.032), whereas the level of the other bacteria species was comparable across FEV1 severity groups. Conclusion Our findings may encourage studies that target and modify gut microbiota to potentially achieve better outcomes in terms of respiratory function in CF.
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Affiliation(s)
- Hadeel Albedewi
- Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Iman Bindayel
- Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Ahmed Albarrag
- Department of Pathology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Hanaa Banjar
- Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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33
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Evaluation of aminopyrrolidine amide to improve chloride transport in CFTR-defective cells. Bioorg Med Chem Lett 2022; 72:128866. [PMID: 35752380 DOI: 10.1016/j.bmcl.2022.128866] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 06/14/2022] [Accepted: 06/20/2022] [Indexed: 11/22/2022]
Abstract
The aminopyrrolidine amide PF-429242 is a specific inhibitor of the Site-1 Protease which is responsible for the cleavage, and thus the activation of the Activating Transcription Factor6 that down regulates many genes, during the Unfolded Protein Response. We hypothesized that PF-429242 could be used to prevent the ATF6-dependent down regulation of some genes. We chose the CFTR gene encoding the CFTR chloride channel as a model because it is down-regulated by ATF6 in Cystic Fibrosis. We evaluated the action of PF-429242 in human bronchial cells expressing the most frequent mutation of CFTR (p.Phe508del) found in patients. We observed that PF-429242 increases the synthesis of the mRNA and the protein encoded by the CFTR gene harbouring the mutation. We also observed that PF-429242 alleviates the defects of the p.Phe508del-CFTR channel in human Cystic Fibrosis cells. Our results suggest that aminopyrrolidine amide is a potential therapeutic target for Cystic Fibrosis that could also have beneficial effects in other diseases involving CFTR, such as the Chronic Obstructive Pulmonary Disease.
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34
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Zhang X, Moore CM, Harmacek LD, Domenico J, Rangaraj VR, Ideozu JE, Knapp JR, Woods KJ, Jump S, Jia S, Prokop JW, Bowler R, Hessner MJ, Gelfand EW, Levy H. CFTR-mediated monocyte/macrophage dysfunction revealed by cystic fibrosis proband-parent comparisons. JCI Insight 2022; 7:152186. [PMID: 35315363 PMCID: PMC8986072 DOI: 10.1172/jci.insight.152186] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 02/02/2022] [Indexed: 12/23/2022] Open
Abstract
Cystic fibrosis (CF) is an inherited disorder caused by biallelic mutations of the CF transmembrane conductance regulator (CFTR) gene. Converging evidence suggests that CF carriers with only 1 defective CFTR copy are at increased risk for CF-related conditions and pulmonary infections, but the molecular mechanisms underpinning this effect remain unknown. We performed transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) of CF child-parent trios (proband, father, and mother) and healthy control (HC) PBMCs or THP-1 cells incubated with the plasma of these participants. Transcriptomic analyses revealed suppression of cytokine-enriched immune-related genes (IL-1β, CXCL8, CREM), implicating lipopolysaccharide tolerance in innate immune cells (monocytes) of CF probands and their parents. These data suggest that a homozygous as well as a heterozygous CFTR mutation can modulate the immune/inflammatory system. This conclusion is further supported by the finding of lower numbers of circulating monocytes in CF probands and their parents, compared with HCs, and the abundance of mononuclear phagocyte subsets, which correlated with Pseudomonas aeruginosa infection, lung disease severity, and CF progression in the probands. This study provides insight into demonstrated CFTR-related innate immune dysfunction in individuals with CF and carriers of a CFTR mutation that may serve as a target for personalized therapy.
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Affiliation(s)
- Xi Zhang
- Data Science program, Weinberg College of Arts and Sciences, Northwestern University, Evanston, Illinois, USA.,Division of Pediatric Pulmonary Medicine, Department of Pediatrics, and
| | - Camille M Moore
- Center for Genes, Environment and Health, National Jewish Health, Denver, Colorado, USA
| | - Laura D Harmacek
- Center for Genes, Environment and Health, National Jewish Health, Denver, Colorado, USA
| | - Joanne Domenico
- Division of Pediatric Pulmonary Medicine, Department of Pediatrics, and
| | - Vittobai Rashika Rangaraj
- Division of Pulmonary & Sleep Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA
| | - Justin E Ideozu
- Genomic Medicine, Genomics Research Center, AbbVie, North Chicago, Illinois, USA
| | - Jennifer R Knapp
- Center for Genes, Environment and Health, National Jewish Health, Denver, Colorado, USA
| | - Katherine J Woods
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Stephanie Jump
- Department of Pediatrics, National Jewish Health, Denver, Colorado, USA
| | - Shuang Jia
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.,Max McGee Center for Juvenile Diabetes, Children's Research Institute, Children's Hospital of Wisconsin, Milwaukee, Wisconsin, USA
| | - Jeremy W Prokop
- Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, Michigan, USA
| | - Russell Bowler
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, and
| | - Martin J Hessner
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.,Max McGee Center for Juvenile Diabetes, Children's Research Institute, Children's Hospital of Wisconsin, Milwaukee, Wisconsin, USA
| | - Erwin W Gelfand
- Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado, USA.,Division of Immunology, Microbiology and Pediatrics, Department of Pediatrics, University of Colorado School of Medicine, Denver, Colorado, USA
| | - Hara Levy
- Division of Pediatric Pulmonary Medicine, Department of Pediatrics, and
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35
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Mir M, Chen J, Pinezich MR, O'Neill JD, Huang SXL, Vunjak-Novakovic G, Kim J. Imaging-guided bioreactor for de-epithelialization and long-term cultivation of ex vivo rat trachea. LAB ON A CHIP 2022; 22:1018-1031. [PMID: 35166739 PMCID: PMC8942046 DOI: 10.1039/d1lc01105g] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/14/2023]
Abstract
Recent synergistic advances in organ-on-chip and tissue engineering technologies offer opportunities to create in vitro-grown tissue or organ constructs that can faithfully recapitulate their in vivo counterparts. Such in vitro tissue or organ constructs can be utilized in multiple applications, including rapid drug screening, high-fidelity disease modeling, and precision medicine. Here, we report an imaging-guided bioreactor that allows in situ monitoring of the lumen of ex vivo airway tissues during controlled in vitro tissue manipulation and cultivation of isolated rat trachea. Using this platform, we demonstrated partial removal of the rat tracheal epithelium (i.e., de-epithelialization) without disrupting the underlying subepithelial cells and extracellular matrix. Through different tissue evaluation assays, such as immunofluorescent staining, DNA/protein quantification, and electron beam microscopy, we showed that the epithelium of the tracheal lumen can be effectively removed with negligible disruption in the underlying tissue layers, such as cartilage and blood vessel. Notably, using a custom-built micro-optical imaging device integrated with the bioreactor, the trachea lumen was visualized at the cellular level, and removal of the endogenous epithelium and distribution of locally delivered exogenous cells were demonstrated in situ. Moreover, the de-epithelialized trachea supported on the bioreactor allowed attachment and growth of exogenous cells seeded topically on its denuded tissue surface. Collectively, the results suggest that our imaging-enabled rat trachea bioreactor and localized cell replacement method can facilitate creation of bioengineered in vitro airway tissue that can be used in different biomedical applications.
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Affiliation(s)
- Mohammad Mir
- Department of Biomedical Engineering, Stevens Institute of Technology, Hoboken, NJ, USA.
| | - Jiawen Chen
- Department of Biomedical Engineering, Stevens Institute of Technology, Hoboken, NJ, USA.
| | - Meghan R Pinezich
- Department of Biomedical Engineering, Columbia University, New York, NY, USA
| | - John D O'Neill
- Department of Cell Biology, State University of New York Downstate Medical Center, Brooklyn, NY, USA
| | - Sarah X L Huang
- Center for Stem Cell and Regenerative Medicine, University of Texas Health Science Center, Houston, TX, USA
| | | | - Jinho Kim
- Department of Biomedical Engineering, Stevens Institute of Technology, Hoboken, NJ, USA.
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36
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Poerio N, Riva C, Olimpieri T, Rossi M, Lorè NI, De Santis F, Henrici De Angelis L, Ciciriello F, D’Andrea MM, Lucidi V, Cirillo DM, Fraziano M. Combined Host- and Pathogen-Directed Therapy for the Control of Mycobacterium abscessus Infection. Microbiol Spectr 2022; 10:e0254621. [PMID: 35080463 PMCID: PMC8791191 DOI: 10.1128/spectrum.02546-21] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 01/07/2022] [Indexed: 12/14/2022] Open
Abstract
Mycobacterium abscessus is the etiological agent of severe pulmonary infections in vulnerable patients, such as those with cystic fibrosis (CF), where it represents a relevant cause of morbidity and mortality. Treatment of pulmonary infections caused by M. abscessus remains extremely difficult, as this species is resistant to most classes of antibiotics, including macrolides, aminoglycosides, rifamycins, tetracyclines, and β-lactams. Here, we show that apoptotic body like liposomes loaded with phosphatidylinositol 5-phosphate (ABL/PI5P) enhance the antimycobacterial response, both in macrophages from healthy donors exposed to pharmacological inhibition of cystic fibrosis transmembrane conductance regulator (CFTR) and in macrophages from CF patients, by enhancing phagosome acidification and reactive oxygen species (ROS) production. The treatment with liposomes of wild-type as well as CF mice, intratracheally infected with M. abscessus, resulted in about a 2-log reduction of pulmonary mycobacterial burden and a significant reduction of macrophages and neutrophils in bronchoalveolar lavage fluid (BALF). Finally, the combination treatment with ABL/PI5P and amikacin, to specifically target intracellular and extracellular bacilli, resulted in a further significant reduction of both pulmonary mycobacterial burden and inflammatory response in comparison with the single treatments. These results offer the conceptual basis for a novel therapeutic regimen based on antibiotic and bioactive liposomes, used as a combined host- and pathogen-directed therapeutic strategy, aimed at the control of M. abscessus infection, and of related immunopathogenic responses, for which therapeutic options are still limited. IMPORTANCE Mycobacterium abscessus is an opportunistic pathogen intrinsically resistant to many antibiotics, frequently linked to chronic pulmonary infections, and representing a relevant cause of morbidity and mortality, especially in immunocompromised patients, such as those affected by cystic fibrosis. M. abscessus-caused pulmonary infection treatment is extremely difficult due to its high toxicity and long-lasting regimen with life-impairing side effects and the scarce availability of new antibiotics approved for human use. In this context, there is an urgent need for the development of an alternative therapeutic strategy that aims at improving the current management of patients affected by chronic M. abscessus infections. Our data support the therapeutic value of a combined host- and pathogen-directed therapy as a promising approach, as an alternative to single treatments, to simultaneously target intracellular and extracellular pathogens and improve the clinical management of patients infected with multidrug-resistant pathogens such as M. abscessus.
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Affiliation(s)
- Noemi Poerio
- Department of Biology, University of Rome “Tor Vergata”, Rome, Italy
| | - Camilla Riva
- Emerging Bacteria Pathogens Unit, San Raffaele Scientific Institute, Milan, Italy
| | - Tommaso Olimpieri
- Department of Biology, University of Rome “Tor Vergata”, Rome, Italy
| | - Marco Rossi
- Emerging Bacteria Pathogens Unit, San Raffaele Scientific Institute, Milan, Italy
| | - Nicola I. Lorè
- Emerging Bacteria Pathogens Unit, San Raffaele Scientific Institute, Milan, Italy
| | | | | | - Fabiana Ciciriello
- Department of Pediatric Medicine, Cystic Fibrosis Complex Operating Unit, Bambino Gesù Pediatric Hospital, Rome, Italy
| | - Marco M. D’Andrea
- Department of Biology, University of Rome “Tor Vergata”, Rome, Italy
| | - Vincenzina Lucidi
- Department of Pediatric Medicine, Cystic Fibrosis Complex Operating Unit, Bambino Gesù Pediatric Hospital, Rome, Italy
| | - Daniela M. Cirillo
- Emerging Bacteria Pathogens Unit, San Raffaele Scientific Institute, Milan, Italy
| | - Maurizio Fraziano
- Department of Biology, University of Rome “Tor Vergata”, Rome, Italy
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37
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Azimi S, Lewin GR, Whiteley M. The biogeography of infection revisited. Nat Rev Microbiol 2022; 20:579-592. [PMID: 35136217 PMCID: PMC9357866 DOI: 10.1038/s41579-022-00683-3] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/04/2022] [Indexed: 01/01/2023]
Abstract
Many microbial communities, including those involved in chronic human infections, are patterned at the micron scale. In this Review, we summarize recent work that has defined the spatial arrangement of microorganisms in infection and begun to demonstrate how changes in spatial patterning correlate with disease. Advances in microscopy have refined our understanding of microbial micron-scale biogeography in samples from humans. These findings then serve as a benchmark for studying the role of spatial patterning in preclinical models, which provide experimental versatility to investigate the interplay between biogeography and pathogenesis. Experimentation using preclinical models has begun to show how spatial patterning influences the interactions between cells, their ability to coexist, their virulence and their recalcitrance to treatment. Future work to study the role of biogeography in infection and the functional biogeography of microorganisms will further refine our understanding of the interplay of spatial patterning, pathogen virulence and disease outcomes.
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Affiliation(s)
- Sheyda Azimi
- School of Biological Sciences and Center for Microbial Dynamics and Infection, Georgia Institute of Technology, Atlanta, GA, USA
| | - Gina R Lewin
- Emory-Children's Cystic Fibrosis Center, Atlanta, GA, USA
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38
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Tony-Odigie A, Wilke L, Boutin S, Dalpke AH, Yi B. Commensal Bacteria in the Cystic Fibrosis Airway Microbiome Reduce P. aeruginosa Induced Inflammation. Front Cell Infect Microbiol 2022; 12:824101. [PMID: 35174108 PMCID: PMC8842722 DOI: 10.3389/fcimb.2022.824101] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Accepted: 01/12/2022] [Indexed: 12/13/2022] Open
Abstract
Chronic Pseudomonas aeruginosa infections play an important role in the progress of lung disease in patients suffering from cystic fibrosis (CF). Recent studies indicate that polymicrobial microbiome profiles in the airway are associated with less inflammation. Thus, the hypothesis was raised that certain commensal bacteria might protect the host from inflammation. We therefore performed a screening study with commensals isolated from CF airway microbiome samples to identify potential beneficial commensals. We isolated more than 80 aerobic or facultative anaerobic commensal strains, including strains from genera Streptococcus, Neisseria, Actinomyces, Corynebacterium, Dermabacter, Micrococcus and Rothia. Through a screening experiment of co-infection in human epithelial cell lines, we identified multiple commensal strains, especially strains belonging to Streptococcus mitis, that reduced P. aeruginosa triggered inflammatory responses. The results were confirmed by co-infection experiments in ex-vivo precision cut lung slices (PCLS) from mice. The underlying mechanisms of the complex host-pathogen-commensal crosstalk were investigated from both the host and the bacterial sides with a focus on S. mitis. Transcriptome changes in the host in response to co-infection and mono-infection were evaluated, and the results indicated that several signalling pathways mediating inflammatory responses were downregulated by co-infection with S. mitis and P. aeruginosa compared to P. aeruginosa mono-infection, such as neutrophil extracellular trap formation. The genomic differences among S. mitis strains with and without protective effects were investigated by whole genome sequencing, revealing genes only present in the S. mitis strains showing protective effects. In summary, through both in vitro and ex vivo studies, we could identify a variety of commensal strains that may reduce host inflammatory responses induced by P. aeruginosa infection. These findings support the hypothesis that CF airway commensals may protect the host from inflammation.
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Affiliation(s)
- Andrew Tony-Odigie
- Institute of Medical Microbiology and Virology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Leonie Wilke
- Institute of Medical Microbiology and Virology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Sébastien Boutin
- Translational Lung Research Center (TLRC), Member of the German Center for Lung Research (DZL), Heidelberg, Germany
- Department of Infectious Diseases, Medical Microbiology and Hygiene, University of Heidelberg, Heidelberg, Germany
| | - Alexander H. Dalpke
- Institute of Medical Microbiology and Virology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Buqing Yi
- Institute of Medical Microbiology and Virology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- *Correspondence: Buqing Yi,
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39
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Lee AJ, Huffmyer JL, Thiele EL, Zeitlin PL, Chatterjee D. The Changing Face of Cystic Fibrosis: An Update for Anesthesiologists. Anesth Analg 2022; 134:1245-1259. [PMID: 35020677 DOI: 10.1213/ane.0000000000005856] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Cystic fibrosis (CF) is the most common fatal genetic disease in North America. While CF is more common among Whites, it is increasingly being recognized in other races and ethnicities. Although there is no cure, life expectancy has steadily improved, with the median survival exceeding 46 years in the United States. There are now more adults than children with CF in the United States. CF is caused by mutations in a gene that encodes the cystic fibrosis transmembrane conductance regulator (CFTR) protein, expressed in many epithelial cells. More than 2100 CFTR mutations have been linked to CF, and newer CFTR modulator drugs are being used to improve the production, intracellular processing, and function of the defective CFTR protein. CF is a multisystem disease that affects primarily the lungs, pancreas, hepatobiliary system, and reproductive organs. Anesthesiologists routinely encounter CF patients for various surgical and medical procedures, depending on the age group. This review article focuses on the changing epidemiology of CF, advances in the classification of CFTR mutations, the latest innovations in CFTR modulator therapies, the impact of the coronavirus disease pandemic, and perioperative considerations that anesthesiologists must know while caring for patients with CF.
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Affiliation(s)
- Amy J Lee
- From the Department of Anesthesiology, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, Colorado
| | - Julie L Huffmyer
- Department of Anesthesiology, University of Virginia Health, Charlottesville, Virginia
| | - Eryn L Thiele
- Department of Anesthesiology, University of Virginia Health, Charlottesville, Virginia
| | - Pamela L Zeitlin
- Department of Pediatrics, National Jewish Health, Denver, Colorado
| | - Debnath Chatterjee
- From the Department of Anesthesiology, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, Colorado
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40
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Chen J, Mir SM, Pinezich MR, O'Neill JD, Guenthart BA, Bacchetta M, Vunjak-Novakovic G, Huang SXL, Kim J. Homogeneous Distribution of Exogenous Cells onto De-epithelialized Rat Trachea via Instillation of Cell-Loaded Hydrogel. ACS Biomater Sci Eng 2022; 8:82-88. [PMID: 34874712 PMCID: PMC9195637 DOI: 10.1021/acsbiomaterials.1c01031] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Injured or diseased airway epithelium due to repeated environmental insults or genetic mutations can lead to a functional decline of the lung and incurable lung diseases. Bioengineered airway tissue constructs can facilitate in vitro investigation of human lung diseases and accelerate the development of effective therapeutics. Here, we report robust tissue manipulation modalities that allow: (i) selective removal of the endogenous epithelium of in vitro cultured airway tissues and (ii) spatially uniform distribution and prolonged cultivation of exogenous cells that are implanted topically onto the denuded airway lumen. Results obtained highlight that our approach to airway tissue manipulation can facilitate controlled removal of the airway epithelium and subsequent homogeneous distribution of newly implanted cells. This study can contribute to the creation of innovative tissue engineering methodologies that can facilitate the treatment of lung diseases, such as cystic fibrosis, primary ciliary dyskinesia, and chronic obstructive pulmonary disease.
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Affiliation(s)
- Jiawen Chen
- Department of Biomedical Engineering, Stevens Institute of Technology, Hoboken, New Jersey 07302, United States
| | - Seyed Mohammad Mir
- Department of Biomedical Engineering, Stevens Institute of Technology, Hoboken, New Jersey 07302, United States
| | - Meghan R Pinezich
- Department of Biomedical Engineering, Columbia University, New York, New York 10032, United States
| | - John D O'Neill
- Department of Cell Biology, State University of New York Downstate Medical Center, Brooklyn, New York 11203, United States
| | - Brandon A Guenthart
- Department of Cardiothoracic Surgery, Stanford University, Stanford, California 94305, United States
| | - Matthew Bacchetta
- Department of Thoracic Surgery, Vanderbilt University, Nashville, Tennessee 37232, United States
| | - Gordana Vunjak-Novakovic
- Department of Biomedical Engineering, Columbia University, New York, New York 10032, United States
| | - Sarah X L Huang
- Center for Stem Cell and Regenerative Medicine, University of Texas Health Science Center, Houston, Texas 77030, United States
| | - Jinho Kim
- Department of Biomedical Engineering, Stevens Institute of Technology, Hoboken, New Jersey 07302, United States
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41
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Novel Immunomodulatory Therapies for Respiratory Pathologies. COMPREHENSIVE PHARMACOLOGY 2022. [PMCID: PMC8238403 DOI: 10.1016/b978-0-12-820472-6.00073-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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Bojanowski CM, Lu S, Kolls JK. Mucosal Immunity in Cystic Fibrosis. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2021; 207:2901-2912. [PMID: 35802761 PMCID: PMC9270582 DOI: 10.4049/jimmunol.2100424] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 10/21/2021] [Indexed: 05/27/2023]
Abstract
The highly complex and variable genotype-phenotype relationships observed in cystic fibrosis (CF) have been an area of growing interest since the discovery of the CF transmembrane conductance regulator (CFTR) gene >30 y ago. The consistently observed excessive, yet ineffective, activation of both the innate and adaptive host immune systems and the establishment of chronic infections within the lung, leading to destruction and functional decline, remain the primary causes of morbidity and mortality in CF. The fact that both inflammation and pathogenic bacteria persist despite the introduction of modulator therapies targeting the defective protein, CFTR, highlights that we still have much to discover regarding mucosal immunity determinants in CF. Gene modifier studies have overwhelmingly implicated immune genes in the pulmonary phenotype of the disease. In this context, we aim to review recent advances in our understanding of the innate and adaptive immune systems in CF lung disease.
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Affiliation(s)
- Christine M Bojanowski
- Section of Pulmonary Diseases, Critical Care, and Environmental Medicine, Department of Medicine, Tulane University School of Medicine, New Orleans, LA;
| | - Shiping Lu
- Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA; and
| | - Jay K Kolls
- Center for Translational Research in Infection and Inflammation, Department of Medicine, Tulane University School of Medicine, New Orleans, LA
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Maniam P, Essilfie AT, Kalimutho M, Ling D, Frazer DM, Phipps S, Anderson GJ, Reid DW. Increased susceptibility of cystic fibrosis airway epithelial cells to ferroptosis. Biol Res 2021; 54:38. [PMID: 34903297 PMCID: PMC8670191 DOI: 10.1186/s40659-021-00361-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 11/28/2021] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Defective chloride transport in airway epithelial cells (AECs) and the associated lung disease are the main causes of morbidity and early mortality in cystic fibrosis (CF). Abnormal airway iron homeostasis and the presence of lipid peroxidation products, indicative of oxidative stress, are features of CF lung disease. RESULTS Here, we report that CF AECs (IB3-1) are susceptible to ferroptosis, a type of cell death associated with iron accumulation and lipid peroxidation. Compared to isogenic CFTR corrected cells (C38), the IB3-1 cells showed increased susceptibility to cell death upon exposure to iron in the form of ferric ammonium citrate (FAC) and the ferroptosis inducer, erastin. This phenotype was accompanied by accumulation of intracellular ferrous iron and lipid peroxides and the extracellular release of malondialdehyde, all indicative of redox stress, and increased levels of lactate dehydrogenase in the culture supernatant, indicating enhanced cell injury. The ferric iron chelator deferoxamine (DFO) and the lipophilic antioxidant ferrostatin-1 inhibited FAC and erastin induced ferroptosis in IB3-1 cells. Glutathione peroxidase 4 (GPX4) expression was decreased in IB3-1 cells treated with FAC and erastin, but was unchanged in C38 AECs. Necroptosis appeared to be involved in the enhanced susceptibility of IB3-1 AECs to ferroptosis, as evidenced by partial cell death rescue with necroptosis inhibitors and enhanced mixed lineage kinase domain-like (MLKL) localisation to the plasma membrane. CONCLUSION These studies suggest that the increased susceptibility of CF AECs to ferroptosis is linked to abnormal intracellular ferrous iron accumulation and reduced antioxidant defences. In addition, the process of ferroptotic cell death in CF AECs does not appear to be a single entity and for the first time we describe necroptosis as a potential contributory factor. Iron chelation and antioxidant treatments may be promising therapeutic interventions in cystic fibrosis.
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Affiliation(s)
- Pramila Maniam
- Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Ama-Tawiah Essilfie
- Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Murugan Kalimutho
- Cell and Molecular Biology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Dora Ling
- Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - David M Frazer
- Cell and Molecular Biology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Simon Phipps
- Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Gregory J Anderson
- Cell and Molecular Biology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia
- School of Chemistry and Molecular Bioscience, University of Queensland, St Lucia, Australia
| | - David W Reid
- Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
- Adult Cystic Fibrosis Centre, The Prince Charles Hospital, Chermside, Australia.
- Lung Inflammation and Infection Laboratory, Immunology Department, QIMR Berghofer Medical Research Institute, Herston, QLD, 4003, Australia.
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Chadwick HK, Abbott J, Hurley MA, Dye L, Lawton CL, Mansfield MW, Peckham D. Cystic fibrosis-related diabetes (CFRD) and cognitive function in adults with cystic fibrosis. J Cyst Fibros 2021; 21:519-528. [PMID: 34134937 DOI: 10.1016/j.jcf.2021.04.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 03/15/2021] [Accepted: 04/26/2021] [Indexed: 01/03/2023]
Abstract
BACKGROUND Being able to function cognitively is imperative for successful achievement in school, working life, and disease self-management. Diabetes is known to cause changes in brain structure and long-term cognitive dysfunction. This work investigated cystic fibrosis-related diabetes (CFRD) as a mechanism for cognitive impairment in people with CF. It was hypothesised that cognition would be poorer in adults with CFRD than in those with CF without diabetes (CFND) or in healthy controls. METHODS Cognitive performance was assessed using the Cambridge Neuropsychological Test Automated Battery which provides a comprehensive cognitive assessment with tests mapping onto specific brain regions. Demographic, clinical and self-reported health data were documented for all participants. CF specific clinical variables were recorded for the two CF groups. RESULTS Ninety-eight people with CF (49CFRD,49CFND) and 49 healthy controls were recruited. People with CF demonstrated deficits in aspects of verbal and spatial memory, processing speed and cognitive flexibility compared with healthy controls, with all areas of the brain implicated. Those with CFRD had additional difficulties with higher-level processes known collectively as 'executive function', which demand greater cognitive load and recruit the prefrontal cortex. Compared with healthy controls, those with CFND and CFRD had an estimated 20% and up to 40% reduction in processing speed respectively. CONCLUSION Managing CF requires higher order executive function. Impairments may be sufficient to interfere with self-care and the ability to perform everyday tasks efficiently. At which point in the CF disease trajectory these difficulties begin, and what may attenuate them, has yet to be determined.
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Affiliation(s)
- Helen K Chadwick
- School of Psychology, University of Leeds, Leeds LS2 9JT, UK; Leeds Institute of Medical Research at St James's, University of Leeds, Leeds LS2 9JT, UK; Adult Cystic Fibrosis Unit, St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Leeds LS9 7TF, UK.
| | - Janice Abbott
- School of Psychology, University of Central Lancashire, Preston PR1 2HE, UK
| | - Margaret Anne Hurley
- Faculty of Health and Wellbeing, University of Central Lancashire, Preston PR1 2HE, UK
| | - Louise Dye
- School of Psychology, University of Leeds, Leeds LS2 9JT, UK
| | - Clare L Lawton
- School of Psychology, University of Leeds, Leeds LS2 9JT, UK
| | - Michael W Mansfield
- Leeds Centre for Diabetes and Endocrinology, St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Leeds LS9 7TF, UK
| | - Daniel Peckham
- Leeds Institute of Medical Research at St James's, University of Leeds, Leeds LS2 9JT, UK; Adult Cystic Fibrosis Unit, St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Leeds LS9 7TF, UK
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45
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Nigro E, Polito R, Elce A, Signoriello G, Iacotucci P, Carnovale V, Gelzo M, Zarrilli F, Castaldo G, Daniele A. Physical Activity Regulates TNFα and IL-6 Expression to Counteract Inflammation in Cystic Fibrosis Patients. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:4691. [PMID: 33924887 PMCID: PMC8125516 DOI: 10.3390/ijerph18094691] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 04/22/2021] [Accepted: 04/26/2021] [Indexed: 12/21/2022]
Abstract
BACKGROUND Cystic fibrosis (CF) is one of the most common inherited diseases. It is characterised by a severe decline in pulmonary function associated with metabolic perturbations and an increased production of inflammatory cytokines. The key role of physical activity (PA) in improving the health status of CF patients and reducing lung function decline has recently been demonstrated. This study evaluated interleukin-6 (IL-6) and tumour necrosis factor α (TNFα) expression in two subgroups of CF patients classified based on PA. METHODS We selected 85 CF patients; half of them regularly undertook supervised PA in the three years leading up to the study and half of them were not physically active. Patients were analysed for serum IL-6 and TNFα levels using enzyme-linked immunosorbent assays. RESULTS We found that the expression levels of IL-6 and TNFα differed in terms of their regulation by PA. In particular, TNFα levels negatively correlated with FEV1% decrease/year and FEV1% decrease (p = 0.023 and p = 0.02, respectively), and positively correlated with serum fasting glucose (p = 0.019) in PA CF patients. In contrast, in the NPA subgroup, TNFα levels were positively correlated with IL-6 (p = 0.001) and negatively correlated with adiponectin (p = 0.000). In addition, multiple logistic regression analysis confirmed that PA is an independent modulator of the inflammatory state. CONCLUSIONS PA modulates inflammatory processes in CF patients by regulating the secretion of pro-inflammatory cytokines and thus ameliorating lung function. Our data show that PA is a useful complementary strategy in the management of CF and that TNFα may be a marker of these effects of PA.
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Affiliation(s)
- Ersilia Nigro
- Dipartimento di Scienze e Tecnologie Ambientali, Biologiche, Farmaceutiche, Università della Campania “Luigi Vanvitelli”, 81100 Caserta, Italy; (E.N.); (R.P.)
- CEINGE-Biotecnologie Avanzate Scarl, Via G. Salvatore 486, 80145 Napoli, Italy; (A.E.); (M.G.); (F.Z.); (G.C.)
| | - Rita Polito
- Dipartimento di Scienze e Tecnologie Ambientali, Biologiche, Farmaceutiche, Università della Campania “Luigi Vanvitelli”, 81100 Caserta, Italy; (E.N.); (R.P.)
- Dipartimento di Sanità Pubblica, Università degli Studi di Napoli “Federico II”, 80131 Napoli, Italy
| | - Ausilia Elce
- CEINGE-Biotecnologie Avanzate Scarl, Via G. Salvatore 486, 80145 Napoli, Italy; (A.E.); (M.G.); (F.Z.); (G.C.)
- Dipartimento di Scienze Umanistiche, Università Telematica Pegaso, 80132 Napoli, Italy
| | - Giuseppe Signoriello
- Dipartimento di Salute Mentale e Fisica e Medicina Preventiva dell’Università degli Studi della Campania “Luigi Vanvitelli”, 80138 Naples, Italy;
| | - Paola Iacotucci
- Centro Regionale Fibrosi Cistica Adulti, Dipartimento di Scienze Mediche Traslazionali, Università degli Studi di Napoli Federico II, 80131 Napoli, Italy; (P.I.); (V.C.)
| | - Vincenzo Carnovale
- Centro Regionale Fibrosi Cistica Adulti, Dipartimento di Scienze Mediche Traslazionali, Università degli Studi di Napoli Federico II, 80131 Napoli, Italy; (P.I.); (V.C.)
| | - Monica Gelzo
- CEINGE-Biotecnologie Avanzate Scarl, Via G. Salvatore 486, 80145 Napoli, Italy; (A.E.); (M.G.); (F.Z.); (G.C.)
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, 80131 Napoli, Italy
| | - Federica Zarrilli
- CEINGE-Biotecnologie Avanzate Scarl, Via G. Salvatore 486, 80145 Napoli, Italy; (A.E.); (M.G.); (F.Z.); (G.C.)
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, 80131 Napoli, Italy
| | - Giuseppe Castaldo
- CEINGE-Biotecnologie Avanzate Scarl, Via G. Salvatore 486, 80145 Napoli, Italy; (A.E.); (M.G.); (F.Z.); (G.C.)
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, 80131 Napoli, Italy
| | - Aurora Daniele
- Dipartimento di Scienze e Tecnologie Ambientali, Biologiche, Farmaceutiche, Università della Campania “Luigi Vanvitelli”, 81100 Caserta, Italy; (E.N.); (R.P.)
- CEINGE-Biotecnologie Avanzate Scarl, Via G. Salvatore 486, 80145 Napoli, Italy; (A.E.); (M.G.); (F.Z.); (G.C.)
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Girón Moreno RM, García-Clemente M, Diab-Cáceres L, Martínez-Vergara A, Martínez-García MÁ, Gómez-Punter RM. Treatment of Pulmonary Disease of Cystic Fibrosis: A Comprehensive Review. Antibiotics (Basel) 2021; 10:486. [PMID: 33922413 PMCID: PMC8144952 DOI: 10.3390/antibiotics10050486] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 04/13/2021] [Accepted: 04/17/2021] [Indexed: 01/08/2023] Open
Abstract
Cystic fibrosis (CF) is a genetic disease that causes absence or dysfunction of a protein named transmembrane conductance regulatory protein (CFTR) that works as an anion channel. As a result, the secretions of the organs where CFTR is expressed are very viscous, so their functionality is altered. The main cause of morbidity is due to the involvement of the respiratory system as a result of recurrent respiratory infections by different pathogens. In recent decades, survival has been increasing, rising by around age 50. This is due to the monitoring of patients in multidisciplinary units, early diagnosis with neonatal screening, and advances in treatments. In this chapter, we will approach the different therapies used in CF for the treatment of symptoms, obstruction, inflammation, and infection. Moreover, we will discuss specific and personalized treatments to correct the defective gene and repair the altered protein CFTR. The obstacle for personalized CF treatment is to predict the drug response of patients due to genetic complexity and heterogeneity of uncommon mutations.
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Affiliation(s)
- Rosa María Girón Moreno
- Servicio de Neumología, Instituto de Investigación Sanitaria La Princesa, 28006 Madrid, Spain; (R.M.G.M.); (R.M.G.-P.)
| | - Marta García-Clemente
- Servicio de Neumología, Hospital Universitario Central de Asturias, C/Avenida de Roma S/n, 33011 Oviedo, Spain
| | - Layla Diab-Cáceres
- Servicio de Neumología, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain;
| | | | | | - Rosa Mar Gómez-Punter
- Servicio de Neumología, Instituto de Investigación Sanitaria La Princesa, 28006 Madrid, Spain; (R.M.G.M.); (R.M.G.-P.)
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Gentzsch M, Cholon DM, Quinney NL, Martino MEB, Minges JT, Boyles SE, Guhr Lee TN, Esther CR, Ribeiro CMP. Airway Epithelial Inflammation In Vitro Augments the Rescue of Mutant CFTR by Current CFTR Modulator Therapies. Front Pharmacol 2021; 12:628722. [PMID: 33859562 PMCID: PMC8042279 DOI: 10.3389/fphar.2021.628722] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 02/01/2021] [Indexed: 12/28/2022] Open
Abstract
In cystic fibrosis (CF), defective biogenesis and activity of the cystic fibrosis transmembrane conductance regulator (CFTR) leads to airway dehydration and impaired mucociliary clearance, resulting in chronic airway infection and inflammation. The most common CFTR mutation, F508del, results in a processing defect in which the protein is retained in the endoplasmic reticulum and does not reach the apical surface. CFTR corrector compounds address this processing defect to promote mutant CFTR transfer to the apical membrane. When coupled with potentiators to increase CFTR channel activity, these drugs yield significant clinical benefits in CF patients carrying the F508del mutation. However, processing of CFTR and other proteins can be influenced by environmental factors such as inflammation, and the impact of airway inflammation on pharmacological activity of CFTR correctors is not established. The present study evaluated CFTR-rescuing therapies in inflamed CF airway epithelial cultures, utilizing models that mimic the inflammatory environment of CF airways. Primary bronchial epithelial cultures from F508del/F508del CF patients were inflamed by mucosal exposure to one of two inflammatory stimuli: 1) supernatant from mucopurulent material from CF airways with advanced lung disease, or 2) bronchoalveolar lavage fluid from pediatric CF patients. Cultures inflamed with either stimulus exhibited augmented F508del responses following therapy with correctors VX-809 or VX-661, and overcame the detrimental effects of chronic exposure to the CFTR potentiator VX-770. Remarkably, even the improved CFTR rescue responses resulting from a clinically effective triple therapy (VX-659/VX-661/VX-770) were enhanced by epithelial inflammation. Thus, the airway inflammatory milieu from late- and early-stage CF lung disease improves the efficacy of CFTR modulators, regardless of the combination therapy used. Our findings suggest that pre-clinical evaluation of CFTR corrector therapies should be performed under conditions mimicking the native inflammatory status of CF airways, and altering the inflammatory status of CF airways may change the efficacy of CFTR modulator therapies.
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Affiliation(s)
- Martina Gentzsch
- Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, University of North Carolina, Chapel Hill, NC, United States.,Department of Pediatrics, Division of Pediatric Pulmonology, School of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, United States.,Department of Cell Biology and Physiology, School of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, United States
| | - Deborah M Cholon
- Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, University of North Carolina, Chapel Hill, NC, United States
| | - Nancy L Quinney
- Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, University of North Carolina, Chapel Hill, NC, United States
| | - Mary E B Martino
- Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, University of North Carolina, Chapel Hill, NC, United States
| | - John T Minges
- Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, University of North Carolina, Chapel Hill, NC, United States
| | - Susan E Boyles
- Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, University of North Carolina, Chapel Hill, NC, United States
| | - Tara N Guhr Lee
- Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, University of North Carolina, Chapel Hill, NC, United States
| | - Charles R Esther
- Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, University of North Carolina, Chapel Hill, NC, United States.,Department of Pediatrics, Division of Pediatric Pulmonology, School of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, United States
| | - Carla M P Ribeiro
- Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, University of North Carolina, Chapel Hill, NC, United States.,Department of Cell Biology and Physiology, School of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, United States.,Department of Medicine, Division of Pulmonary Diseases, School of Medicine, University of North Carolina, Chapel Hill, NC, United States
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Ghaffaripour H, Mirkarimi M, Hassanzad M, Boloursaz M, Mohammadi S. Evaluation of Inflammatory Biomarkers in Iranian Patients with Cystic Fibrosis. CURRENT RESPIRATORY MEDICINE REVIEWS 2021. [DOI: 10.2174/1573398x16999201026223411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Background::
Cystic fibrosis (CF) is an autosomal recessive disease characterized by a
progressive and recurrent lung infection.
Objective::
This study aimed to evaluate the levels of pro-inflammatory cytokines and their correlations
with lung function in CF patients.
Methods::
A matched case-control study was conducted among 18 CF (children and adults) and 18
control patients (age and gender-matched) who were admitted to Masih Daneshvari Hospital
(Tehran, Iran). The controls had no obvious inflammatory lung disease. The samples of bronchoalveolar
lavage (BAL) fluid, serum, and sputum of participants were collected to determine concentrations
of inflammatory cytokines such as interleukins (IL-8, IL-1β) and tumour necrosis factor-
alpha (TNF-α) using enzyme-linked immunosorbent assay (ELISA). Spirometry was applied
and functional pulmonary indices [forced vital capacity (FVC) and forced expiratory volume in 1
second (FEV1)] were assessed.
Results::
The mean age of CF patients was 15.43 ± 5.970 years (range 4-24). The FVC in a majority
of the CF patients (66.7%) was below 60% and only 33.3% of the patients exhibited normal or
mild respiratory dysfunction. There were significant differences between FVC and FEV1 measurements
before and after bronchoscopy. In addition, IL-8 levels in all three samples (serum, sputum,
and BAL) of CF patients and levels of IL-1β and TNF-α in BAL and sputum samples of CF patients
were significantly higher than the control group (p<0.001). However, increased cytokine levels
were not associated with lung function.
Conclusion::
Increased IL-8 and TNF-α levels seemed to be associated with signs of clinical deterioration
and might be useful as diagnostic markers.
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Affiliation(s)
- Hosseinali Ghaffaripour
- Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammadreza Mirkarimi
- Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Hassanzad
- Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammadreza Boloursaz
- Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shooka Mohammadi
- Department of Pediatrics, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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Maule G, Ensinck M, Bulcaen M, Carlon MS. Rewriting CFTR to cure cystic fibrosis. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2021; 182:185-224. [PMID: 34175042 DOI: 10.1016/bs.pmbts.2020.12.018] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Cystic fibrosis (CF) is an autosomal recessive monogenic disease caused by mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. Although F508del is the most frequent mutation, there are in total 360 confirmed disease-causing CFTR mutations, impairing CFTR production, function and stability. Currently, the only causal treatments available are CFTR correctors and potentiators that directly target the mutant protein. While these pharmacological advances and better symptomatic care have improved life expectancy of people with CF, none of these treatments provides a cure. The discovery and development of programmable nucleases, in particular CRISPR nucleases and derived systems, rekindled the field of CF gene therapy, offering the possibility of a permanent correction of the CFTR gene. In this review we will discuss different strategies to restore CFTR function via gene editing correction of CFTR mutations or enhanced CFTR expression, and address how best to deliver these treatments to target cells.
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Affiliation(s)
- Giulia Maule
- Department CIBIO, University of Trento, Trento, Italy; Institute of Biophysics, National Research Council, Trento, Italy
| | - Marjolein Ensinck
- Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Flanders, Belgium
| | - Mattijs Bulcaen
- Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Flanders, Belgium
| | - Marianne S Carlon
- Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Flanders, Belgium.
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Microstructured Lipid Carriers (MLC) Based on N-Acetylcysteine and Chitosan Preventing Pseudomonas aeruginosa Biofilm. Int J Mol Sci 2021; 22:ijms22020891. [PMID: 33477393 PMCID: PMC7830306 DOI: 10.3390/ijms22020891] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Revised: 01/09/2021] [Accepted: 01/11/2021] [Indexed: 12/31/2022] Open
Abstract
The aim of this work was the development of microstructured lipid carriers (MLC) based on chitosan (CH) and containing N-acetylcysteine (NAC), a mucolytic and antioxidant agent, to inhibit the formation of Pseudomonas aeruginosa biofilm. MLC were prepared using the high shear homogenization technique. The MLC were characterized for morphology, particle size, Z potential, encapsulation efficiency and drug release. The antioxidant properties of NAC-loaded microstructured carriers were evaluated through an in vitro spectrophotometer assay. Finally, the activity of NAC-CH-MLC on biofilm production by Pseudomonas aeruginosa was also evaluated. Results obtained from this study highlighted that the use of chitosan into the inner aqueous phase permitted to obtain microstructured particles with a narrow size range and with good encapsulation efficiency. NAC-loaded MLC showed higher antioxidant activity than the free molecule, demonstrating how encapsulation increases the antioxidant effect of the molecule. Furthermore, the reduction of biofilm growth resulted extremely high with MLC being 64.74% ± 6.2% and 83.74% ± 9.95%, respectively, at 0.5 mg/mL and 2 mg/mL. In conclusion, this work represents a favorable technological strategy against diseases in which bacterial biofilm is relevant, such as cystic fibrosis.
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