Identification, Structure-Activity Relationship, and Biological Characterization of 2,3,4,5-Tetrahydro-1H-pyrido[4,3-b]indoles as a Novel Class of CFTR Potentiators.

J Med Chem. 2020 Sep 18;:

Authors: Brindani N, Gianotti A, Giovani S, Giacomina F, Di Fruscia P, Sorana F, Bertozzi SM, Ottonello G, Goldoni L, Penna I, Russo D, Summa M, Bertorelli R, Ferrera L, Pesce E, Sondo E, Galietta LJV, Bandiera T, Pedemonte N, Bertozzi F

Abstract
Cystic fibrosis (CF) is a life-threatening autosomal recessive disease, caused by mutations in the CF transmembrane conductance regulator (CFTR) chloride channel. CFTR modulators have been reported to address the basic defects associated with CF-causing mutations, partially restoring the CFTR function in terms of protein processing and/or channel gating. Small-molecule compounds, called potentiators, are known to ameliorate the gating defect. In this study, we describe the identification of the 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole core as a novel chemotype of potentiators. In-depth structure-activity relationship studies led to the discovery of enantiomerically pure 39 endowed with a good efficacy in rescuing the gating defect of F508del- and G551D-CFTR and a promising in vitro druglike profile. The in vivo characterization of γ-carboline 39 showed considerable exposure levels and good oral bioavailability, with detectable distribution to the lungs after oral administration to rats. Overall, these findings may represent an encouraging starting point to further expand this chemical class, adding a new chemotype to the existing classes of CFTR potentiators.

PMID: 32946228 [PubMed - as supplied by publisher]

Psychiatric and General Health Effects of COVID-19 Pandemic on Children with Chronic Lung Disease and Parents' Coping Styles.

Pediatr Pulmonol. 2020 Sep 18;:

Authors: Tural DA, Emiralioglu N, Hesapcioglu ST, Karahan S, Ozsezen B, Sunman B, Buyuksahin HN, Yalcin E, Dogru D, Ozcelik U, Kiper N

Abstract
BACKGROUND: We aim to assess the anxiety and depressive symptoms related to COVID-19 pandemic in children with chronic lung disease and their parents and also to evaluate parents' coping strategies.
METHODS: Parents of children aged 4-18 years, with chronic lung disease (study group n:113) and healthy control (n:108) were enrolled in the study. General Health Questionnaire-12, specific COVID-19 related anxiety questions, The Coping Orientation to Problems Experienced inventory, coronavirus-related psychiatric symptom scale in children - parental form were used to analyze the psychiatric effects of COVID-19. Parents were also asked about how online education affected their family life and children. All data were compared between children/parents in the study and control groups. Risk factors related with anxiety scores of children were also analyzed.
RESULTS: Talking about pandemic, concern about coronavirus transmission, taking precaution to prevent coronavirus transmission, making pressure to protect from COVID-19 were significantly higher in parents within the study group (p<0.05). Parents in study group used more problem focused coping than parents in control group (p=0.003). Anxiety symptoms score were higher in children of study group (p=0.007). Parents in study group found online education more useful than parents in control group.
CONCLUSION: Children with chronic lung diseases and their parents have more anxiety due to COVID-19 pandemic and these parents use more mature coping strategies to manage the stress of pandemic. Longitudinal and larger studies should be done in all aspect of online education in children with chronic lung diseases. This article is protected by copyright. All rights reserved.

PMID: 32946202 [PubMed - as supplied by publisher]

Optimization of anti-microbials in the treatment of Cystic Fibrosis Pulmonary Exacerbations:  II. Therapies for Allergic Bronchopulmonary Aspergillosis (ABPA).

Pediatr Pulmonol. 2020 Sep 18;:

Authors: Epps QJ, Epps KL, Zobell JT, Young DC

Abstract
This review is the second article in the State-of-the-Art series and aims to evaluate medications used in the treatment of allergic bronchopulmonary aspergillosis (ABPA) in pediatric and adult patients with cystic fibrosis (CF). ABPA is one of several organisms that are found in the airways of CF patients. This review provides an evidence-based summary of pharmacokinetic/pharmacodynamic (PK/PD), tolerability, and efficacy studies of medications including corticosteroids, amphotericin B, azole anti-fungals (isavuconazole, itraconazole, posaconazole, and voriconazole), and a monoclonal antibody omalizumab in the treatment of ABPA and identifies areas where further study is warranted. This article is protected by copyright. All rights reserved.

PMID: 32946194 [PubMed - as supplied by publisher]

Breathing Easier: Molecular Therapeutics for Cystic Fibrosis.

Hum Gene Ther. 2020 Sep;31(17-18):905-906

Authors: Limberis MP

PMID: 32945723 [PubMed - as supplied by publisher]

Analysis of airway microbiota in adults from a Brazilian cystic fibrosis center.

Braz J Microbiol. 2020 Sep 17;:

Authors: Leite CCF, de Freitas FAD, de Cássia Firmida M, Leão RS, Albano RM, Marques EA

Abstract
The application of next-generation sequencing tools revealed that the cystic fibrosis respiratory tract is a polymicrobial environment. We have characterized the airway bacterial microbiota of five adult patients with cystic fibrosis during a 14-month period by 16S rRNA tag sequencing using the Illumina technology. Microbial diversity, estimated by the Shannon index, varied among patient samples collected throughout the follow-up period. The beta diversity analysis revealed that the composition of the airway microbiota was highly specific for each patient, showing little variation among the samples of each patient analyzed over time. The composition of the bacterial microbiota did not reveal any emerging pathogen predictor of pulmonary disease in cystic fibrosis or of its unfavorable clinical progress, except for unveiling the presence of anaerobic microorganisms, even without any established clinical association. Our results could potentialy help us to translate and develop strategies in response to the pathobiology of this disease, particularly because it represents an innovative approach for CF centers in Brazil.

PMID: 32944872 [PubMed - as supplied by publisher]

Scoring tools to monitor risk of disease progression in patients with cystic fibrosis.

J Thorac Dis. 2020 Aug;12(8):3940-3943

Authors: Donadio MVF, Vendrusculo FM, Pérez-Ruiz M

PMID: 32944304 [PubMed]

Stability of serum precipitins to Aspergillus fumigatus for the diagnosis of allergic bronchopulmonary aspergillosis.

Allergy Asthma Clin Immunol. 2020;16:78

Authors: Lau KSK, Yeung C, Carlsten C

Abstract
Background: Allergic bronchopulmonary aspergillosis (ABPA) reflects hypersensitivity and an exaggerated immune response to Aspergillus fumigatus. ABPA typically occurs in individuals with airway diseases such as asthma or cystic fibrosis and is associated with worse outcomes for individuals with these conditions. Each year, physicians across the province of British Columbia submit over 2600 diagnostic testing requests to a centralized location in Vancouver, requiring specimen collection, storage, and shipment from different clinics across the province. Timely and reliable testing of Aspergillus precipitins is critical to optimizing diagnosis and management of ABPA. At our centre, we analyzed sample stability in varying storage conditions to provide guidance to those using this routine diagnostic test.
Methods: To determine temperature and time stability, 31 serum specimens positive for Aspergillus fumigatus precipitins from routine clinical testing were each aliquoted and incubated at 4 and 37 °C. Samples were repeatedly assayed for precipitins to Aspergillus fumigatus via agarose gel double immunodiffusion (AGID) at 7, 14, and 28 days post-incubation.To determine freeze-thaw stability, 39 serum specimens submitted for routine clinical testing for Aspergillus precipitins were randomly selected. Each specimen was aliquoted and stored at 4 or -20 °C. 4 °C samples were maintained at 4 °C while -20 °C samples were split into three groups corresponding to one, two, or three freeze-thaw cycles. -20 °C samples were thawed at room temperature in the morning and then immediately frozen overnight for up to a total of three freeze-thaw cycles.
Results: Regarding temperature and time stability, median stability time was 47 and 34 days at 4 and 37 °C, respectively. The log-rank model indicates no statistically significant difference between the two temperature storage conditions (p = 0.14) with a hazard ratio of 0.61 (95% CI, 0.31-1.2).In terms of freeze-thaw stability, no indication of serum degradation with regards to Aspergillus fumigatus precipitins was found with repeated freeze-thaw cycles as compared to refrigerated storage.
Conclusions: The stability of serum precipitins to Aspergillus fumigatus was found to be dependent on time, but not temperature and freeze-thaw cycles. Specimens for Aspergillus fumigatus precipitins testing should be shipped at ambient temperature and tested within 2 weeks from collection.

PMID: 32944032 [PubMed]

Treatment strategies for asthma: reshaping the concept of asthma management.

Allergy Asthma Clin Immunol. 2020;16:75

Authors: Papi A, Blasi F, Canonica GW, Morandi L, Richeldi L, Rossi A

Abstract
Asthma is a common chronic disease characterized by episodic or persistent respiratory symptoms and airflow limitation. Asthma treatment is based on a stepwise and control-based approach that involves an iterative cycle of assessment, adjustment of the treatment and review of the response aimed to minimize symptom burden and risk of exacerbations. Anti-inflammatory treatment is the mainstay of asthma management. In this review we will discuss the rationale and barriers to the treatment of asthma that may result in poor outcomes. The benefits of currently available treatments and the possible strategies to overcome the barriers that limit the achievement of asthma control in real-life conditions and how these led to the GINA 2019 guidelines for asthma treatment and prevention will also be discussed.

PMID: 32944030 [PubMed]

Differential response to biologics in a patient with severe asthma and ABPA: a role for dupilumab?

Allergy Asthma Clin Immunol. 2020;16:55

Authors: Mümmler C, Kemmerich B, Behr J, Kneidinger N, Milger K

Abstract
Background: Allergic bronchopulmonary aspergillosis (ABPA) is a severe hypersensitivity reaction to aspergillus species colonizing the airways of patients with asthma or cystic fibrosis. Biologics including anti-IgE and anti-IL5 antibodies have strongly changed the treatment of severe asthmatics and have partly been reported to be effective in the treatment of ABPA. Recently, dupilumab, an anti-IL4-Rα antibody which inhibits signaling by the Th2-cytokines IL4 and IL13, has been approved for the treatment of severe asthma.
Case presentation: Here, we report the case of a 49-year-old woman with severe asthma and ABPA, who was uncontrolled despite maximum inhalative therapy, anti-IL5-Rα antibody and continuous oral steroid therapy. Moreover, trials of itraconazole as well as omalizumab showed insufficient efficacy. Lung function revealed peripheral obstruction. FeNO and IgE were increased, eosinophils were suppressed under treatment while marked increases had been documented previously. Switching to dupilumab led to a complete resolution of pulmonary symptoms, resolution of exacerbations and complete withdrawal of oral steroids. A drastic improvement in lung function was noted, with an increase in FEV1 of almost 1 l. FeNO was normalized and IgE strongly reduced.
Conclusion: Our case highlights that a patient may exhibit differential treatment responses to the currently available asthma biologics and suggests switching treatment if outcome is insufficient. A potential role for dupilumab in the treatment of ABPA warrants future studies.

PMID: 32944023 [PubMed]

Global reprogramming of virulence and antibiotic resistance in Pseudomonas aeruginosa by a single nucleotide polymorphism in elongation factor, fusA1.

J Biol Chem. 2020 Sep 17;:

Authors: Maunders EA, Triniman RC, Western J, Rahman T, Welch M

Abstract
Clinical isolates of the opportunistic pathogen Pseudomonas aeruginosa from patients with cystic fibrosis (CF) frequently contain mutations in the gene encoding an elongation factor, FusA1. Recent work has shown that fusA1 mutants often display elevated aminoglycoside resistance due to increased expression of the efflux pump, MexXY. However, we wondered whether these mutants might also be affected in other virulence-associated phenotypes. Here, we isolated a spontaneous gentamicin-resistant fusA1 mutant (FusA1P443L) in which mexXY expression was increased. Proteomic and transcriptomic analyses revealed that the fusA1 mutant also exhibited discrete changes in the expression of key pathogenicity-associated genes. Most notably, the fusA1 mutant displayed greatly increased expression of the Type III Secretion system (T3SS), widely considered to be the most potent virulence factor in the P. aeruginosa arsenal, and also elevated expression of the Type VI (T6) secretion machinery. This was unexpected because expression of the T3SS is usually reciprocally coordinated with T6 secretion system expression. The fusA1 mutant also displayed elevated exopolysaccharide production, dysregulated siderophore production, elevated ribosome synthesis, and transcriptomic signatures indicative of translational stress. Each of these phenotypes (and almost all of the transcriptomic and proteomic changes associated with the fusA1 mutation) were restored to levels comparable to that in the progenitor strain by expression of the wild-type fusA1 gene in trans, indicating that the mutant gene is recessive. Our data show that in addition to elevating antibiotic resistance through mexXY expression (and also additional contributory resistance mechanisms), mutations in fusA1 can lead to highly-selective dysregulation of virulence gene expression.

PMID: 32943550 [PubMed - as supplied by publisher]

Sputum versus nasopharyngeal samples for the molecular diagnosis of respiratory viral infection in cystic fibrosis: A pilot study.

J Cyst Fibros. 2020 Sep 14;:

Authors: Cardot-Martin E, Guillou-Guillemette HL, Berre RL, Ramel S, Bihan JL, Grenet D, Farfour E, Troussier F, Urban T, Billard L, Pilorgé L, Minoui-Tran A, Payan C, Munck MR, Héry-Arnaud G, Vallet S

Abstract
Viruses are important agents in lung function deterioration in Cystic Fibrosis (CF). To date, no standard operating procedures (SOPs) have been established to determine which sampling method is the most effective for an optimal virological diagnosis of respiratory viral infections in CF. Here we investigated the performances of two sampling sites, sputum samples versus nasopharyngeal (NP) swabs, for thirty participants from three CF centres presenting an acute respiratory infection. Sputum and NP samples were simultaneously collected and multiplex PCR targeting 16 to 18 viruses were performed. Viruses were detected for 18/30 patients (60%). A high concordance between the sputum and NP samples was observed in 25 (83%) paired samples of which 13 tested positive and 12 tested negative. These results highlighted the relevance of sputum sampling for diagnostic of respiratory viruses in CF, which is less invasive and better accepted by CF patients than NP, and allows accurate bacterial detection.

PMID: 32943334 [PubMed - as supplied by publisher]

Correction: Improved residual fat malabsorption and growth in children with cystic fibrosis treated with a novel oral structured lipid supplement: A randomized controlled trial.

PLoS One. 2020;15(9):e0239642

Authors: Stallings VA, Tindall AM, Mascarenhas MR, Maqbool A, Schall JI

Abstract
[This corrects the article DOI: 10.1371/journal.pone.0232685.].

PMID: 32941528 [PubMed - as supplied by publisher]

The changing landscape of cystic fibrosis: new therapies, challenges and a global pandemic.

Curr Opin Pulm Med. 2020 Sep 15;:

Authors: Barry PJ, Plant BJ

PMID: 32941353 [PubMed - as supplied by publisher]

Sexual and reproductive health in cystic fibrosis.

Curr Opin Pulm Med. 2020 Sep 15;:

Authors: Frayman KB, Chin M, Sawyer SM, Bell SC

Abstract
PURPOSE OF REVIEW: With improving life expectancy and quality of life, sexual and reproductive health (SRH) has become an increasingly important aspect of patient-centered cystic fibrosis care. This review aims to describe advances in cystic fibrosis-related SRH and highlight optimal practices.
RECENT FINDINGS: Recent publications suggest that people with cystic fibrosis follow a similar trajectory of sexual development and activity as their noncystic fibrosis peers, although contraception use is lower. Although fertility is reduced in patients with cystic fibrosis, improved survival and assisted reproductive technologies have led to an increasing pursuit and incidence of pregnancy. Cystic fibrosis transmembrane regulator modulators that correct the underlying cystic fibrosis defect might improve fertility and thus far appear safe in pregnancy, though data are limited.Despite medical knowledge of SRH in cystic fibrosis, patients continue to report they lack sufficient education about these aspects of their healthcare, and cystic fibrosis multidisciplinary teams are ill prepared to counsel their patients.
SUMMARY: Understanding of the effects of cystic fibrosis on SRH continues to improve, although many questions remain regarding optimal care from the choice of contraception to the safety of cystic fibrosis-specific medications in pregnancy. Further development of cystic fibrosis-informed interdisciplinary specialist networks and a wider framework of practice would both enhance health outcomes and better support patients.

PMID: 32941352 [PubMed - as supplied by publisher]

Changing landscape: psychological care in the era of cystic fibrosis transmembrane conductance regulator modulators.

Curr Opin Pulm Med. 2020 Sep 15;:

Authors: Havermans T, Duff AJA

Abstract
PURPOSE OF REVIEW: The current review provides an overview of key psychological issues and challenges for the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator era of care. It discusses research from diagnosis and beyond, to patient-team communication with a particular focus on medical trials, adherence and living with CFTR modulators.
RECENT FINDINGS: The impact of the diagnosis on parents is immense and the complexity of treatment now and in the future, are a challenge for both parents and teams. Communicating digitally is starting to become daily practice for many in CF care, with coronavirus disease 2019 accelerating this process. Participating in trials has a psychological impact, but most of all the (delayed) access and timing of accessing CFTR modulators is an important theme. Adherence remains of significance, both to 'old' and 'new' treatments. Living with CF in the era of CFTR modulators is beginning to impact on patients' quality of life, including new possibilities, opportunities and challenges.
SUMMARY: Psychological care needs to engage and keep pace with the rapid medical changes. Some care priorities remain the same, including psychological screening and assessment, as well as psychoeducation, communication training and psychotherapy. The presence of CF psychologist in the CF clinic remains as important as ever.

PMID: 32941351 [PubMed - as supplied by publisher]

Drug Development for Cystic Fibrosis.

Pediatr Pulmonol. 2020 Sep 17;:

Authors: Sanders DB, Chmiel JF

Abstract
The first regulatory approval for a drug developed specifically for cystic fibrosis (CF)occurred in 1993, and since then, several other drugs have been approved. Median predicted survivalin people with CF in the United States has increased from approximately 30 yearsto 44.4 years over thatsame period. Highly-effective modulators of the cystic fibrosis transmembrane conductance regulator became availableto approximately 90% of people with CF ages 12 years and older in the USin 2019 and in Europe in 2020. These transformative therapies will surely reduce morbidity and further extend longevity. The drug development pipeline is filled with therapies that address most aspects of CF disease. As survival and CF therapies advance, and the complexity of CF care increases, the process of drug development has become more sophisticated. In addition, detecting meaningful changes in outcome measures has become more difficult as the health status of people with CF improves. Innovative approaches are required to continue to advance drug developmentin CF. This review provides a general overview of drug development from the preclinical phase through Phase IV. Special considerations with respect to CF are integrated into the discussion of each phase of drug development. As CF care evolves, drug development must continue to evolve as well, until a one-time cure is available to all people with CF. This article is protected by copyright. All rights reserved.

PMID: 32940969 [PubMed - as supplied by publisher]

Promise and Potential Peril with Lumacaftor for the Trafficking Defective Type 2 Long QT Syndrome-Causative Variants, p.G604S, p.N633S, and p.R685P, Using Patient-Specific Re-Engineered Cardiomyocytes.

Circ Genom Precis Med. 2020 Sep 17;:

Authors: O'Hare BJ, Kim CJ, Hamrick SK, Ye D, Tester DJ, Ackerman MJ

Abstract
Background - The KCNH2-encoded Kv11.1 (hERG) potassium channel is a critical regulator of cardiomyocyte (CM) action potential duration (APD). The majority of type 2 long QT syndrome (LQT2) stems from trafficking defective KCNH2 mutations. Recently, FDA-approved cystic fibrosis protein trafficking chaperone, lumacaftor (LUM), has been proposed as novel therapy for LQT2. Here, we test the efficacy of LUM treatment in patient-specific induced pluripotent stem cell-cardiomyocytes (iPSC-CMs) derived from two patients with known LQT2 trafficking defective mutations and a patient with novel KCNH2 variant, p.R685P. Methods - Patient-specific iPSC-CM models of KCNH2-G604S, KCNH2-N633S, and KCNH2-R685P were generated from three unrelated patients diagnosed with severe LQT2 (QTc > 500 ms). LUM efficacy was also tested by ANEPPS, FluoVolt, and ArcLight voltage dye-based APD90 measurements. Results - All three mutations were hERG trafficking defective in iPSC-CMs. While LUM treatment failed to rescue the hERG trafficking defect in TSA201 cells, LUM rescued channel trafficking for all mutations in the iPSC-CM model. All three mutations conferred a prolonged APD90 compared to control. While LUM treatment rescued the phenotype of KCNH2-N633S and KCNH2-R685P, LUM paradoxically prolonged the APD90 in KCNH2-G604S iPSC-CMs. LUM-mediated APD90 rescue were affected by IKr blocker consistent with the increase of IKr by LUM is the underlying mechanism of the LQT2 rescue. Conclusions - While LUM is an effective hERG channel trafficking chaperone and may be therapeutic for LQT2, we urge caution. Without understanding the functionality of the mutant channel to be rescued, LUM therapy could be harmful.

PMID: 32940533 [PubMed - as supplied by publisher]

Antimicrobial susceptibility and phylogenetic relations in a German cohort infected with Mycobacterium abscessus.

J Clin Microbiol. 2020 Sep 16;:

Authors: Wetzstein N, Kohl TA, Schultze TG, Andres S, Bellinghausen C, Hügel C, Kempf VAJ, Lehn A, Hogardt M, Serve H, Vehreschild MJGT, Wolf T, Niemann S, Maurer FP, Wichelhaus TA

Abstract
Background: M. abscessus (Mab) is a highly antibiotic resistant opportunistic pathogen causing clinically challenging infections in patients with preexisting lung diseases or under immunosuppression. Hence, reliable antibiotic susceptibility data is required for effective treatment. Aims of this study were to investigate (i) the congruence of genotypic and phenotypic antimicrobial susceptibility testing, (ii) the relationship between resistance profile and clinical course, as well as (iii) the phylogenetic relations of Mab in a German patient cohort.Materials/methods: A total of 39 isolates from 29 patients infected or colonized with Mab underwent genotypic and phenotypic drug susceptibility testing. Clinical data were correlated to susceptibility data. Phylogenetic analysis was performed by means of whole genome sequencing (WGS) and single nucleotide polymorphism (SNP) analysis.Results: Macrolide resistance was mainly mediated by functional Erm (41) methyltransferases (T28 sequevars) in M. abscessus subsp. abscessus (n=25) and M. abscessus subsp. bolletii (n=2). It was significantly associated with impaired culture conversion (p=0.02). According to the core SNP phylogeny, we identified three clusters of closely related isolates with SNP distances below 25. Representatives of all circulating global clones (Absc. 1, Absc. 2 and Mass. 1) were identified in our cohort. However, we could not determine evidence for in-hospital interhuman transmission from clinical data.Conclusions: In our patient cohort, we identified three Mab clusters with closely related isolates and representatives of the previously described international clusters, but no human-to-human in-hospital transmission. Macrolide and aminoglycoside susceptibility data are critical for therapeutic decision-making in Mab infections.

PMID: 32938741 [PubMed - as supplied by publisher]

Impact of KLF4 on Cell Proliferation and Epithelial Differentiation in the Context of Cystic Fibrosis.

Int J Mol Sci. 2020 Sep 14;21(18):

Authors: Sousa L, Pankonien I, Simões FB, Chanson M, Amaral MD

Abstract
Cystic fibrosis (CF) cells display a more cancer-like phenotype vs. non-CF cells. KLF4 overexpression has been described in CF and this transcriptional factor acts as a negative regulator of wt-CFTR. KLF4 is described as exerting its effects in a cell-context-dependent fashion, but it is generally considered a major regulator of proliferation, differentiation, and wound healing, all the processes that are also altered in CF. Therefore, it is relevant to characterize the differential role of KLF4 in these processes in CF vs. non-CF cells. To this end, we used wt- and F508del-CFTR CFBE cells and their respective KLF4 knockout (KO) counterparts to evaluate processes like cell proliferation, polarization, and wound healing, as well as to compare the expression of several epithelial differentiation markers. Our data indicate no major impact of KLF4 KO in proliferation and a differential impact of KLF4 KO in transepithelial electrical resistance (TEER) acquisition and wound healing in wt- vs. F508del-CFTR cells. In parallel, we also observed a differential impact on the levels of some differentiation markers and epithelial-mesencymal transition (EMT)-associated transcription factors. In conclusion, KLF4 impacts TEER acquisition, wound healing, and the expression of differentiation markers in a way that is partially dependent on the CFTR-status of the cell.

PMID: 32937756 [PubMed - in process]

A B cell-dependent pathway drives chronic lung allograft rejection after ischemia-reperfusion injury in mice.

Am J Transplant. 2019 12;19(12):3377-3389

Authors: Watanabe T, Martinu T, Chruscinski A, Boonstra K, Joe B, Horie M, Guan Z, Bei KF, Hwang DM, Liu M, Keshavjee S, Juvet SC

Abstract
Chronic lung allograft dysfunction (CLAD) limits long-term survival after lung transplant (LT). Ischemia-reperfusion injury (IRI) promotes chronic rejection (CR) and CLAD, but the underlying mechanisms are not well understood. To examine mechanisms linking IRI to CR, a mouse orthotopic LT model using a minor alloantigen strain mismatch (C57BL/10 [B10, H-2b ] → C57BL/6 [B6, H-2b ]) and isograft controls (B6→B6) was used with antecedent minimal or prolonged graft storage. The latter resulted in IRI with subsequent airway and parenchymal fibrosis in prolonged storage allografts but not isografts. This pattern of CR after IRI was associated with the formation of B cell-rich tertiary lymphoid organs within the grafts and circulating autoantibodies. These processes were attenuated by B cell depletion, despite preservation of allograft T cell content. Our observations suggest that IRI may promote B cell recruitment that drives CR after LT. These observations have implications for the mechanisms leading to CLAD after LT.

PMID: 31365766 [PubMed - indexed for MEDLINE]