Iron metabolism in Pseudomonas aeruginosa biofilm and the involved iron-targeted anti-biofilm strategies.

J Drug Target. 2020 Sep 24;:1-22

Authors: Zhang Y, Pan X, Wang L, Chen L

Abstract
Pseudomonas aeruginosa is a gram-negative bacterium that exists in various ecosystems, causing severe infections in patients with AIDS or cystic fibrosis. P. aeruginosa can form biofilm on a variety of surfaces, whereby the bacteria produce defensive substances and enhance antibiotic-resistance, making themselves more adaptable to hostile environments. P. aeruginosa resistance represents one of the main causes of infection-related morbidity and mortality at a global level. Iron is required for the growth of P. aeruginosa biofilm. This review summarizes how the iron metabolism contributes to develop biofilm, and more importantly, it may provide some references for the clinic to achieve novel anti-biofilm therapeutics by targeting iron activities.

PMID: 32969723 [PubMed - as supplied by publisher]

Safety and Efficacy of Elexacaftor/Tezacaftor/Ivacaftor for ≥24 Weeks in People With CF and ≥1 F508del Allele: Interim Results of an Open-Label Phase Three Clinical Trial.

Am J Respir Crit Care Med. 2020 Sep 24;:

Authors: Griese M, Costa S, Linnemann RW, Mall MA, McKone EF, Polineni D, Quon BS, Ringshausen FC, Taylor-Cousar JL, Withers NJ, Moskowitz SM, Daines CL

PMID: 32969708 [PubMed - as supplied by publisher]

[Lungtransplantation in Sweden - over 1 200 patients transplanted since 1990].

Lakartidningen. 2020 Aug 10;117:

Authors: Riise G, Magnusson J, Larsson H, Hansson L, Ingemansson R, Dellgren G

Abstract
Lung transplantation is an accepted treatment for end stage lung diseases and performed at two national centers in Sweden - Gothenburg and Lund. Since the start in 1990 over 1 200 patients have been transplanted.  The indications are severe progressive lung diseases with short expected survival or severe negative effects on daily life. There are several contraindications among which severe other organ disease, recent malignancy or psychiatric disease are most important.  The most common causes for lung transplantation are chronic obstructive pulmonary disease (COPD), interstitial pulmonary disease, cystic fibrosis and pulmonary hypertension.  Long term survival after 5 years is 63 %, and after 10 years 48 %, which is better than the results reported in the international registry (57 % and 36 % respectively).   Lung transplantation is today a therapy for end stage pulmonary diseases with acceptable survival results. It is likely that the number of patients will increase in the future.

PMID: 32969482 [PubMed - in process]

A phase 3, double-blind, parallel-group study to evaluate the efficacy and safety of tezacaftor in combination with ivacaftor in participants 6 through 11 years of age with cystic fibrosis homozygous for F508del or heterozygous for the F508del-CFTR mutation and a residual function mutation.

J Cyst Fibros. 2020 Sep 17;:

Authors: Davies JC, Sermet-Gaudelus I, Naehrlich L, Harris RS, Campbell D, Ahluwalia N, Short C, Haseltine E, Panorchan P, Saunders C, Owen CA, Wainwright CE, VX16-661-115 Investigator Group

Abstract
BACKGROUND: The CFTR modulator tezacaftor/ivacaftor was efficacious and generally safe and well tolerated in Phase 3 studies in participants ≥12 years of age with cystic fibrosis (CF) homozygous for the F508del-CFTR mutation or heterozygous with a residual function-CFTR mutation (F/F or F/RF respectively). We evaluated tezacaftor/ivacaftor's efficacy and safety over 8 weeks in participants 6 through 11 years of age with these mutations.
METHODS: Participants were randomized 4:1 to tezacaftor/ivacaftor or a blinding group (placebo for F/F, ivacaftor for F/RF). The primary endpoint was within-group change from baseline in the lung clearance index 2·5 (LCI2·5) through Week 8. Secondary endpoints were change from baseline in sweat chloride (SwCl), cystic fibrosis questionnaire-revised (CFQ-R) respiratory domain score, and safety.
RESULTS: Sixty-seven participants received at least one study drug dose. Of those, 54 received tezacaftor/ivacaftor (F/F, 42; F/RF, 12), 10 placebo, and 3 ivacaftor; 66 completed the study. The within-group change in LCI2·5 was significantly reduced (improved) by -0·51 (95% CI: -0·74, -0·29). SwCl concentration decreased (improved) by -12·3 mmol/L and CFQ-R respiratory domain score increased (improved, nonsignificantly) by 2·3 points. There were no serious adverse events (AEs) or AEs leading to tezacaftor/ivacaftor discontinuation or interruption. The most common AEs (≥10%) in participants receiving tezacaftor/ivacaftor were cough, headache, and productive cough.
CONCLUSIONS: Tezacaftor/ivacaftor improved lung function (assessed using LCI) and CFTR function (measured by SwCl concentration) in participants 6 through 11 years of age with F/F or F/RF genotypes. Tezacaftor/ivacaftor was safe and well tolerated; no new safety concerns were identified.

PMID: 32967799 [PubMed - as supplied by publisher]

Choice of Differentiation Media Significantly Impacts Cell Lineage and Response to CFTR Modulators in Fully Differentiated Primary Cultures of Cystic Fibrosis Human Airway Epithelial Cells.

Cells. 2020 Sep 21;9(9):

Authors: Saint-Criq V, Delpiano L, Casement J, Onuora JC, Lin J, Gray MA

Abstract
In vitro cultures of primary human airway epithelial cells (hAECs) grown at air-liquid interface have become a valuable tool to study airway biology under normal and pathologic conditions, and for drug discovery in lung diseases such as cystic fibrosis (CF). An increasing number of different differentiation media, are now available, making comparison of data between studies difficult. Here, we investigated the impact of two common differentiation media on phenotypic, transcriptomic, and physiological features of CF and non-CF epithelia. Cellular architecture and density were strongly impacted by the choice of medium. RNA-sequencing revealed a shift in airway cell lineage; one medium promoting differentiation into club and goblet cells whilst the other enriched the growth of ionocytes and multiciliated cells. Pathway analysis identified differential expression of genes involved in ion and fluid transport. Physiological assays (intracellular/extracellular pH, Ussing chamber) specifically showed that ATP12A and CFTR function were altered, impacting pH and transepithelial ion transport in CF hAECs. Importantly, the two media differentially affected functional responses to CFTR modulators. We argue that the effect of growth conditions should be appropriately determined depending on the scientific question and that our study can act as a guide for choosing the optimal growth medium for specific applications.

PMID: 32967385 [PubMed - in process]

Targeting Aging Pathways in Chronic Obstructive Pulmonary Disease.

Int J Mol Sci. 2020 Sep 21;21(18):

Authors: Easter M, Bollenbecker S, Barnes JW, Krick S

Abstract
Chronic obstructive pulmonary disease (COPD) has become a global epidemic and is the third leading cause of death worldwide. COPD is characterized by chronic airway inflammation, loss of alveolar-capillary units, and progressive decline in lung function. Major risk factors for COPD are cigarette smoking and aging. COPD-associated pathomechanisms include multiple aging pathways such as telomere attrition, epigenetic alterations, altered nutrient sensing, mitochondrial dysfunction, cell senescence, stem cell exhaustion and chronic inflammation. In this review, we will highlight the current literature that focuses on the role of age and aging-associated signaling pathways as well as their impact on current treatment strategies in the pathogenesis of COPD. Furthermore, we will discuss established and experimental COPD treatments including senolytic and anti-aging therapies and their potential use as novel treatment strategies in COPD.

PMID: 32967225 [PubMed - in process]

Pulmonary exacerbations in adults with cystic fibrosis - a grown-up issue in a changing CF landscape.

Chest. 2020 Sep 20;:

Authors: Stanford GE, Dave K, Simmonds NJ

Abstract
Pulmonary exacerbations (PEx) are significant life events in people with cystic fibrosis (CF), associated with declining lung function, reduced quality of life (QoL), hospitalisations and decreased survival. The adult CF population is increasing worldwide, with many patients surviving prolonged periods with severe multi-morbid disease. In many countries the number of adults with CF exceeds the number of children, and PEx are particularly burdensome for adults as they tend to require longer courses and more intravenous treatment than children. The approach to managing PEx is multifactorial and needs to evolve to reflect this changing adult population. In this review, we discuss PEx definitions, precipitants, treatments and the wider implications to healthcare resources. We review current management strategies, their relevance in particular to adults with CF, and highlight some of the gaps in our knowledge. A number of studies are underway to try to answer some of the unmet needs, such as the optimal length of treatment and the use of non-antimicrobial agents alongside antibiotics. We provide an overview of these issues, concluding that with the changing landscape of adult CF care, the definitions and management of PEx may need to evolve to enable continued improvements in outcomes across the age spectrum of CF.

PMID: 32966813 [PubMed - as supplied by publisher]

Airway microbiota is associated with the severity of non-CF bronchiectasis.

Clin Respir J. 2020 Sep 23;:

Authors: Li L, Zhang J, Li Z, Zhang C, Bi J, Zhou J, Song Y, Shao C

Abstract
BACKGROUND: Airway microbiota are associated with several chronic respiratory diseases. However, limited studies examined microbiota in non-cystic fibrosis(non-CF) bronchiectasis, especially its relationship with severity and immunology.
OBJECTIVES: We characterized the microbiota of patients with different severities of bronchiectasis and examined the correlation between microbiota and the immunological indices.
METHODS: The microbiota of 63 sputum samples from 40 patients with bronchiectasis were analyzed by 16S rRNA gene sequencing. Blood tests and related immunological indices were detected.
RESULTS: According to the baseline data of patients with bronchiectasis, we found that more severe bronchiectasis was accompanied by lower prealbumin levels. The 16S rRNA sequencing analyses demonstrated that Pseudomonas-dominated microbiota produced lower levels of interleukin-4 (IL-4) and transforming growth factor-β (TGF-β) compared to other-dominated microbiota. The airway microbiota of patients with mild bronchiectasis clustered apart from those of patients with severe bronchiectasis, which correlated with IL-4 and other clinical indices.
CONCLUSION: There are differences in the airway microbiota between patients with mild and severe bronchiectasis. The airway microbiota was related to some clinical indices that represent effects on the immune system.

PMID: 32966701 [PubMed - as supplied by publisher]

Long-Term Ivacaftor in People Aged 6 Years and Older with Cystic Fibrosis with Ivacaftor-Responsive Mutations.

Pulm Ther. 2020 Sep 23;:

Authors: Pilewski JM, De Boeck K, Nick JA, Tian S, DeSouza C, Higgins M, Moss RB

Abstract
INTRODUCTION: Mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) affect the quantity and/or function of CFTR protein reaching the cell surface. Ivacaftor, a CFTR potentiator that enhances chloride transport, increases the channel-open probability of normal and dysfunctional CFTR. Initially approved for people with CF (pwCF) with G551D-CFTR gating mutations, ivacaftor demonstrated clinical benefit in pwCF with other gating mutations and certain residual function mutations, including R117H-CFTR, in clinical studies. We evaluated the long-term safety and efficacy of ivacaftor in pwCF aged 6 years and older with non-G551D-CFTR ivacaftor-responsive mutations.
METHODS: Efficacy and safety data from a phase 3, multicenter, open-label, extension study for participants from Study 110 (R117H-CFTR mutations), Study 111 (non-G551D-CFTR gating mutations), and Study 113 (n-of-1 pilot study in participants with residual CFTR function) were analyzed. Following washout from the randomized parent study, participants received oral ivacaftor 150 mg once every 12 h for 104 weeks.
RESULTS: Forty-one of 121 participants completed treatment through 104 weeks; 59 participants who did not complete the extension study continued treatment with commercial ivacaftor. The most common adverse events were pulmonary exacerbation (46.3%) and cough (33.9%). Most treatment-emergent adverse events were mild/moderate in severity and consistent with manifestations of CF or the ivacaftor safety profile. Rapid, durable improvement occurred across all efficacy endpoints.
CONCLUSIONS: Ivacaftor was generally safe and well tolerated with no new safety concerns for up to 104 weeks in pwCF with ivacaftor-responsive mutations. The pattern of improvement across efficacy endpoints was durable and generally consistent with parent-study outcomes.
TRIAL REGISTRATION: NCT01707290.

PMID: 32965659 [PubMed - as supplied by publisher]

The Lung Life of a Cystic Fibrosis Patient: A Patient and Physician Perspective.

Pulm Ther. 2020 Sep 23;:

Authors: Balasa G, Chaudary N

Abstract
This article is co-authored by a patient living with cystic fibrosis, and her treating physician. The first section of this commentary article is authored by a patient, who describes their experience of living with cystic fibrosis. The following section is authored by the patient's physician, who discusses the management of cystic fibrosis in the context of the patient's experiences.

PMID: 32965658 [PubMed - as supplied by publisher]

Experiences of family members of children with cystic fibrosis under the light of Callista Roy.

Rev Bras Enferm. 2020;73(suppl 4):e20190662

Authors: Souza TCF, Correa Júnior AJS, Santana ME, Pimentel IMS, Carvalho JN

Abstract
OBJECTIVE: To know the experiences of family members of children with cystic fibrosis under the light of the theory of Callista Roy.
METHOD: Qualitative research that used the adaptation theoretical framework of Callista Roy for inductive content analysis. Fifteen family members, in a university hospital, between 23 and 63 years old, participated in the study, from September to October 2018.
RESULTS: Two categories were elaborated: "Evaluation of stimuli" and "Evaluation of behaviors". The first has three subcategories: "focal", "contextual" and "residual". And the second, four subcategories: "physiological domain", "self-concept", "role function" and "interdependence".
FINAL CONSIDERATIONS: During the evaluation of stimuli, work overload and stress were identified as focal stimuli. Regarding contextual stimuli, it was noticed that the social life of caregivers was prejudiced. As for residual stimuli, the fear of loss is constant, and it appears that the emotional aspect of family members is the most affected comparing with physical exhaustion.

PMID: 32965425 [PubMed - as supplied by publisher]

Predictors of massive haemoptysis after a first episode of mild-to-moderate haemoptysis in patients with cystic fibrosis.

ERJ Open Res. 2020 Jul;6(3):

Authors: Pavaut G, Kyheng M, Le Rouzic O, Perez T, Wallaert B, Prevotat A

Abstract
Mild-to-moderate haemoptysis (m-mH) is common in patients with cystic fibrosis but the risk of subsequent massive haemoptysis (MH) is not known. Allergic bronchopulmonary aspergillosis and diabetes were significant predictors of MH subsequent to m-mH. https://bit.ly/30093Hw.

PMID: 32963988 [PubMed - as supplied by publisher]

Conditional reprogramming: next generation cell culture.

Acta Pharm Sin B. 2020 Aug;10(8):1360-1381

Authors: Wu X, Wang S, Li M, Li J, Shen J, Zhao Y, Pang J, Wen Q, Chen M, Wei B, Kaboli PJ, Du F, Zhao Q, Cho CH, Wang Y, Xiao Z, Wu X

Abstract
Long-term primary culture of mammalian cells has been always difficult due to unavoidable senescence. Conventional methods for generating immortalized cell lines usually require manipulation of genome which leads to change of important biological and genetic characteristics. Recently, conditional reprogramming (CR) emerges as a novel next generation tool for long-term culture of primary epithelium cells derived from almost all origins without alteration of genetic background of primary cells. CR co-cultures primary cells with inactivated mouse 3T3-J2 fibroblasts in the presence of RHO-related protein kinase (ROCK) inhibitor Y-27632, enabling primary cells to acquire stem-like characteristics while retain their ability to fully differentiate. With only a few years' development, CR shows broad prospects in applications in varied areas including disease modeling, regenerative medicine, drug evaluation, drug discovery as well as precision medicine. This review is thus to comprehensively summarize and assess current progress in understanding mechanism of CR and its wide applications, highlighting the value of CR in both basic and translational researches and discussing the challenges faced with CR.

PMID: 32963937 [PubMed - as supplied by publisher]

Aquagenic keratoderma and cystic fibrosis screening.

Med Clin (Barc). 2020 Sep 19;:

Authors: Martín Carmona J, Gómez Moyano E, Gómez Huelgas R, Martínez Pilar L

PMID: 32962850 [PubMed - as supplied by publisher]

Capsaicin-Loaded Chitosan Nanocapsules for wtCFTR-mRNA Delivery to a Cystic Fibrosis Cell Line.

Biomedicines. 2020 Sep 20;8(9):

Authors: Kolonko AK, Efing J, González-Espinosa Y, Bangel-Ruland N, van Driessche W, Goycoolea FM, Weber WM

Abstract
Cystic fibrosis (CF), a lethal hereditary disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene coding for an epithelial chloride channel, is characterized by an imbalanced homeostasis of ion and water transports in secretory epithelia. As the disease is single-gene based, transcript therapy using therapeutic mRNA is a promising concept of treatment in order to correct many aspects of the fatal pathology on a cellular level. Hence, we developed chitosan nanocapsules surface-loaded with wtCFTR-mRNA to restore CFTR function. Furthermore, we loaded the nanocapsules with capsaicin, aiming to enhance the overall efficiency of transcript therapy by reducing sodium hyperabsorption by the epithelial sodium channel (ENaC). Dynamic light scattering with non-invasive back scattering (DLS-NIBS) revealed nanocapsules with an average hydrodynamic diameter of ~200 nm and a Zeta potential of ~+60 mV. The results of DLS-NIBS measurements were confirmed by asymmetric flow field-flow fractionation (AF4) with multidetection, while transmission electron microscopy (TEM) images confirmed the spherical morphology and size range. After stability measurements showed that the nanocapsules were highly stable in cell culture transfection medium, and cytotoxicity was ruled out, transfection experiments were performed with the CF cell line CFBE41o-. Finally, transepithelial measurements with a new state-of-the-art Ussing chamber confirmed successfully restored CFTR function in transfected cells. This study demonstrates that CS nanocapsules as a natural and non-toxic delivery system for mRNA to target cells could effectively replace risky vectors for gene delivery. The nanocapsules are not only suitable as a transcript therapy for treatment of CF, but open aspiring possibilities for safe gene delivery in general.

PMID: 32962254 [PubMed - as supplied by publisher]

Rates of depression and anxiety in Italian patients with cystic fibrosis and parent caregivers: Implementation of the Mental Health Guidelines.

Respir Med. 2020 Sep 10;172:106147

Authors: Graziano S, Spanò B, Majo F, Righelli D, Vincenzina L, Quittner A, Tabarini P

Abstract
BACKGROUND: Individuals with chronic respiratory conditions are at-risk for depression and anxiety. In the largest mental health screening study of over 6000 people with cystic fibrosis (CF) and 4000 parent caregivers (TIDES, 2014), rates of symptomatology were two to three times higher than in the general population. International guidelines recommend annual screening of mental health. This is the first study to implement these guidelines in one of the largest CF Centers in Italy.
METHODS: All individuals with CF, 12 and older (n = 167) and caregivers of children with CF (n = 186), birth to 18, were screened. Health outcome data were also collected (i.e FEV1, BMI, pulmonary exacerbations, CF-related diabetes). Prevalence data and associations between psychological symptoms and health outcomes were examined.
RESULTS: A high percentage of patients and parent caregivers reported scored above the clinical cut-off for depression and anxiety (37%-48% of adolescents, 45%-46% of adults, 49%-66% of mothers and fathers). Most scores fell in the mild range, however, over 30% were in the moderate to severe range. Elevations in depression and anxiety were correlated. Adolescents who had more pulmonary exacerbations reported higher anxiety. Adults with recent events of hemoptysis reported higher symptoms of depression.
CONCLUSIONS: Symptoms of depression and anxiety were elevated in both individuals with CF and parents. Implementation of mental health screening was critical for identifying those in need of psychological interventions. These results strongly suggest that mental health should be integrated into physical health care for those with complex, chronic respiratory conditions, including COPD, PCD.

PMID: 32961510 [PubMed - as supplied by publisher]

Oral Glutathione and Growth in Cystic Fibrosis: A Multi-Center, Randomized, Placebo-Controlled, Double-Blind Trial.

J Pediatr Gastroenterol Nutr. 2020 Sep 21;:

Authors: Bozic M, Goss CH, Tirouvanziam RM, Baines A, Kloster M, Antoine L, Borowitz D, Schwarzenberg SJ, GROW study group

Abstract
OBJECTIVES: The nutritional status of children with cystic fibrosis (CF) is associated with mortality and morbidity. Intestinal inflammation may contribute to impaired digestion, absorption and nutrient utilization in patients with CF and oral glutathione may reduce inflammation, promoting improved nutritional status in patients with CF.
METHODS: The GROW study was a prospective, multi-center, randomized, placebo-controlled, double-blind, Phase II clinical trial in pancreatic insufficient patients with CF between the ages of 2-10 years. Patients received reduced glutathione or placebo orally daily for 24 weeks. The primary endpoint was the difference in change in weight-for-age z-scores from baseline through week 24 between treatment groups. Secondary endpoints included other anthropometrics, serum and fecal inflammatory markers in addition to other clinical outcomes.
RESULTS: 58 participants completed the study. No significant differences were seen between glutathione (n = 30) and placebo (n = 28) groups in the 6 month change in weight-for-age z-score (-0.08; 95% CI: -0.22, 0.06; p = 0.25); absolute change in weight (kg) (-0.18; 95% CI: -0.55, 0.20; p = 0.35); or absolute change in BMI kg/m (-0.06; 95% CI: -0.37, 0.25; p = 0.69). There were no significant differences in other secondary endpoints. Overall, glutathione was safe and well tolerated.
CONCLUSIONS: Oral glutathione supplementation did not impact growth or change serum or fecal inflammatory markers in pancreatic insufficient children with CF when compared to placebo.

PMID: 32960827 [PubMed - as supplied by publisher]

Of onions and men: Report of cavitary community acquired pneumonia due to <em>Burkholderia cepacia</em> complex in an immunocompetent patient and review of the literature.

Monaldi Arch Chest Dis. 2020 Sep 22;90(4):

Authors: Manglani R, Sherman E, Shengelia A, Epelbaum O

Abstract
Burkholderia cepacia complex consists of highly antibiotic resistant gram negative bacilli that are plant symbionts and also potential agents of human infection.  This bacterial family's claim to fame in clinical medicine is as the scourge of cystic fibrosis patients, in whom it is a notorious respiratory pathogen.  Outside of cystic fibrosis, it rarely comes to mind as an etiology of community acquired pneumonia with or without lung cavitation in immunocompetent hosts.  We describe a case of an otherwise healthy, community-dwelling man who presented with subacute cavitary lung disease, the causative organism of which turned out to be Burkholderia cepacia complex.  Our report is accompanied by a review of the literature, which identified an additional eleven cases in the same category.  We analyze all of the available cases for the emergence of any identifiable patterns or peculiarities.

PMID: 32959626 [PubMed - in process]

Characterization of the genomically encoded fosfomycin resistance enzyme from Mycobacterium abscessus.

Medchemcomm. 2019 Nov 01;10(11):1948-1957

Authors: Travis S, Shay MR, Manabe S, Gilbert NC, Frantom PA, Thompson MK

Abstract
Mycobacterium abscessus belongs to a group of rapidly growing mycobacteria (RGM) and accounts for approximately 65-80% of lung disease caused by RGM. It is highly pathogenic and is considered the prominent Mycobacterium involved in pulmonary infection in patients with cystic fibrosis and chronic pulmonary disease (CPD). FosM is a putative 134 amino acid fosfomycin resistance enzyme from M. abscessus subsp. bolletii that shares approximately 30-55% sequence identity with other vicinal oxygen chelate (VOC) fosfomycin resistance enzymes and represents the first of its type found in any Mycobacterium species. Genes encoding VOC fosfomycin resistance enzymes have been found in both Gram-positive and Gram-negative pathogens. Given that FosA enzymes from Gram-negative bacteria have evolved optimum activity towards glutathione (GSH) and FosB enzymes from Gram-positive bacteria have evolved optimum activity towards bacillithiol (BSH), it was originally suggested that FosM might represent a fourth class of enzyme that has evolved to utilize mycothiol (MSH). However, a sequence similarity network (SSN) analysis identifies FosM as a member of the FosX subfamily, indicating that it may utilize water as a substrate. Here we have synthesized MSH and characterized FosM with respect to divalent metal ion activation and nucleophile selectivity. Our results indicate that FosM is a Mn2+-dependent FosX-type hydrase with no selectivity toward MSH or other thiols as analyzed by NMR and mass spectroscopy.

PMID: 32952996 [PubMed]

Review: Pathogenesis of cholestatic liver diseases.

World J Hepatol. 2020 Aug 27;12(8):423-435

Authors: Yokoda RT, Rodriguez EA

Abstract
Cholestatic liver diseases (CLD) begin to develop after an impairment of bile flow start to affect the biliary tree. Cholangiocytes actively participate in the liver response to injury and repair and the intensity of this reaction is a determinant factor for the development of CLD. Progressive cholangiopathies may ultimately lead to end-stage liver disease requiring at the end orthotopic liver transplantation. This narrative review will discuss cholangiocyte biology and pathogenesis mechanisms involved in four intrahepatic CLD: Primary biliary cholangitis, primary sclerosing cholangitis, cystic fibrosis involving the liver, and polycystic liver disease.

PMID: 32952871 [PubMed]