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Torous VF, Basler D, McEnery C, Astor T, Ly A. Utilization of Oil Red O staining for assessing aspiration risk in lung transplant patients: A multidisciplinary prospective study with clinical practice insights. Cancer Cytopathol 2023; 131:30-36. [PMID: 35946954 DOI: 10.1002/cncy.22636] [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: 05/10/2022] [Revised: 06/18/2022] [Accepted: 06/28/2022] [Indexed: 01/04/2023]
Abstract
BACKGROUND Gastroesophageal reflux disease with microaspiration has been associated with graft dysfunction in lung transplant patients. Identifying patients with aspiration is clinically important because it enables implementation of appropriate interventions like antireflux therapy. Oil Red O (ORO) staining with determination of the lipid-laden macrophage index (LLMI) has been proposed as a noninvasive surrogate marker in the detection of aspiration. The aim of this study was to prospectively evaluate clinical utilization of ORO staining in the assessment of aspiration risk. METHODS All transbronchial surgical pathology biopsies obtained in lung transplant patients undergoing routine surveillance from August 2020 through November 2021 were included in this study. Clinical team members prospectively ascertained the aspiration risk category (ARC) of each patient both before and after biopsy findings and recorded reasons for change in ARC. RESULTS A total of 132 transbronchial biopsies with concurrent LLMI were included in the study. LLMI was low in 51 cases (38.6%), including 21 of the 54 cases (38.9%) where aspiration was suggested based on the transbronchial biopsy findings. In total, 19 cases (14.4%) underwent a change in ARC post-biopsy including 10 that were upgraded and nine cases that were downgraded. Transbronchial biopsy findings were noted as the reason for change in ARC in the majority (15/19; 79%) of cases; only a minority (2/19; 10.5%) were due to the LLMI. Notably, 16 cases (12.1%) had a low LLMI with high-risk post-biopsy ARC and nine cases (6.8%) had a high LLMI with low-risk post-biopsy ARC. CONCLUSIONS This study observed that clinical evaluation for aspiration relied more heavily on transbronchial biopsy findings. Although LLMI may retain clinical utility in some scenarios, reevaluation of the clinical value of ORO testing would be prudent.
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Affiliation(s)
- Vanda F Torous
- Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Debra Basler
- Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Caroline McEnery
- Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Todd Astor
- Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Amy Ly
- Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA
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Torous VF, Ly A. Correlation between cytology Oil Red O staining and lung biopsy specimens: utility of the lipid-laden macrophage index. J Am Soc Cytopathol 2022; 11:226-233. [PMID: 35597768 DOI: 10.1016/j.jasc.2022.04.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 04/07/2022] [Accepted: 04/14/2022] [Indexed: 06/15/2023]
Abstract
INTRODUCTION Oil Red O staining is used for enumeration of the lipid-laden macrophage index (LLMI) as a surrogate for aspiration. As part of quality improvement efforts aimed at optimizing resource utilization, the utility of this stain in current cytopathology practice was re-evaluated. The objective of this study was to explore the clinical utility of Oil Red O staining in bronchoalveolar lavage (BAL) samples by correlating the LLMI with findings in concurrent histologic tissue samples. MATERIALS AND METHODS Lung transbronchial biopsy specimens that suggested aspiration that were submitted with concurrent BAL cytology samples were retrieved. Lung tissue biopsies were reviewed for the presence of foamy alveolar macrophages (graded as 0, 1+, and 2+), foreign material, and giant cells. The concurrent BAL was reviewed with consensus determination of the LLMI. RESULTS A total of 53 cases were identified. On histology, 13 cases (24.5%) were found to have no foamy alveolar macrophages, 23 cases (43.4%) were found to have 1+ foamy alveolar macrophages, and 17 cases (32.1%) were found to have 2+ foamy alveolar macrophages. Six cases (11.3%) were found to have foreign material, and 10 cases (18.9%) were found to have multinucleated giant cells. The average LLMI score was 16, with 44 (83.0%) in the low range (LLMI <40) and 9 (17.0%) in the intermediate range (LLMI of 40-90). CONCLUSIONS None of the cases in our study had an LLMI that exceeded the cutoff value for which aspiration would be suspected. We found no correlation of the LLMI with lung biopsies that suggested aspiration.
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Affiliation(s)
- Vanda F Torous
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
| | - Amy Ly
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
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Williams KM, Pavletic SZ, Lee SJ, Martin PJ, Farthing DE, Hakim FT, Rose J, Manning-Geist BL, Gea-Banacloche JC, Comis LE, Cowen EW, Justus DG, Baird K, Cheng GS, Avila D, Steinberg SM, Mitchell SA, Gress RE. Prospective phase II trial of montelukast to treat bronchiolitis obliterans syndrome after hematopoietic cell transplant and investigation into BOS pathogenesis. Transplant Cell Ther 2022; 28:264.e1-264.e9. [PMID: 35114411 PMCID: PMC9081205 DOI: 10.1016/j.jtct.2022.01.021] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/16/2022] [Accepted: 01/24/2022] [Indexed: 11/30/2022]
Abstract
BACKGROUND Bronchiolitis obliterans syndrome (BOS) is a severe manifestation of chronic graft-versus-host disease (cGVHD) following hematopoietic cell transplantation (HCT). Montelukast interrupts cysteinyl leukotriene activity and may diminish the activation and homing of cells to bronchioles and subsequent fibrosis. OBJECTIVE We performed a prospective phase II trial to test whether montelukast altered lung decline for patients with BOS after HCT. STUDY DESIGN We performed a single arm, open-label, multi-institutional study with primary endpoints of: i) FEV1 stability or improvement (<15% decline) and ii) slope of FEV1<1 point decline after six months treatment. Secondary endpoints included symptom and functional response, and immune correlates investigating the role of leukotrienes in BOS progression. RESULTS 25 patients enrolled with moderate to severe lung disease after three months of stable cGVHD therapy. Montelukast was well-tolerated and no patient required escalation of BOS-directed therapy. At the primary endpoint, all evaluable patients (n=23) met criteria for treatment success using FEV1% predicted, and all but one had stable or improved FEV1 slope. In those with >5% FEV1 improvement, clinically meaningful improvements were seen in the Lee scores of breathing, energy, and mood. Improvements in the Human Activity Profile and 6-minute-walk test were observed in those with <5% FEV1 decline. Overall survival was 87% at two-years. Immune correlates showed elevated leukotriene receptor levels on blood eosinophils and monocytes vs. healthy controls, elevated urine leukotrienes in 45% of cohort, and cysteinyl leukotriene receptors on bronchoalveolar lavage subsets and a predominance of Th2 T cells, all pre-treatment. CONCLUSIONS These data suggest that montelukast may safely halt progression of BOS after HCT and that leukotrienes may play a role in the biology of BOS.
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Affiliation(s)
- Kirsten M Williams
- Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, 1760 Haygood Drive, 3rd floor W362, Atlanta GA, US, 30322.
| | - Steven Z Pavletic
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Bethesda MD, US, 20892
| | - Stephanie J Lee
- Fred Hutchinson Cancer Research Center, 1100 Fairview Ave, Seattle, WA, US 98109
| | - Paul J Martin
- Fred Hutchinson Cancer Research Center, 1100 Fairview Ave, Seattle, WA, US 98109
| | - Don E Farthing
- Experimental Transplantation and Immunotherapy Branch, National Cancer Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD, US, 20892
| | - Frances T Hakim
- Experimental Transplantation and Immunotherapy Branch, National Cancer Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD, US, 20892
| | - Jeremy Rose
- Experimental Transplantation and Immunotherapy Branch, National Cancer Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD, US, 20892
| | - Beryl L Manning-Geist
- Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY, US, 10065
| | - Juan C Gea-Banacloche
- Division of Clinical Research, National Institute of Allergy and Immunology, National Institutes of Health, 10 Center Drive, Bethesda, MD, US, 20892
| | - Leora E Comis
- Rehabilitation Medicine Department, Clinical Center, NIH, Bethesda, MD
| | - Edward W Cowen
- Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, 10 Center Dr, Room 12N240A, Bethesda, MD, US, 20892
| | - David G Justus
- Department of Laboratory Medicine, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, US
| | - Kristin Baird
- Pediatric Oncology Branch, National Cancer Institute, NIH, Bethesda, MD
| | - Guang-Shing Cheng
- Department of Medicine, University of Washington, Seattle, WA, US, 98109; Fred Hutchinson Cancer Research Center, 1100 Fairview Ave, Seattle, WA, US 98109
| | - Daniele Avila
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Bethesda MD, US, 20892
| | - Seth M Steinberg
- Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, US, 20892
| | - Sandra A Mitchell
- Outcomes Research Branch, Division of Cancer Control and Population Sciences, National Cancer Institute, NIH, 9609 Medical Center Drive, Bethesda MD, US, 20892
| | - Ronald E Gress
- Experimental Transplantation and Immunotherapy Branch, National Cancer Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD, US, 20892
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Kazmi S, Khan MA, Shamma T, Altuhami A, Ahmed HA, Mohammed Assiri A, Broering DC. Targeting Interleukin-10 Restores Graft Microvascular Supply and Airway Epithelium in Rejecting Allografts. Int J Mol Sci 2022; 23:1269. [PMID: 35163192 PMCID: PMC8836023 DOI: 10.3390/ijms23031269] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/09/2022] [Accepted: 01/12/2022] [Indexed: 12/12/2022] Open
Abstract
Interleukin-10 (IL-10) is a vital regulatory cytokine, which plays a constructive role in maintaining immune tolerance during an alloimmune inflammation. Our previous study highlighted that IL-10 mediated immunosuppression established the immune tolerance phase and thereby modulated both microvascular and epithelial integrity, which affected inflammation-associated graft malfunctioning and sub-epithelial fibrosis in rejecting allografts. Here, we further investigated the reparative effects of IL-10 on microvasculature and epithelium in a mouse model of airway transplantation. To investigate the IL-10 mediated microvascular and epithelial repair, we depleted and reconstituted IL-10, and monitored graft microvasculature, airway epithelium, and associated repair proteins. Our data demonstrated that both untreated control allografts and IL-10 (-) allografts showed a significant early (d6) increase in microvascular leakiness, drop-in tissue oxygenation, blood perfusion, and denuded airway epithelium, which is associated with loss of adhesion protein Fascin-1 and β-catenin on vascular endothelial cells at d10 post-transplantation. However, IL-10 (+) promotes early microvascular and airway epithelial repair, and a proportional increase in endothelial Fascin-1, and β-catenin at d10 post-transplantation. Moreover, airway epithelial cells also express a significantly higher expression of FOXJ1 and β-catenin in syngrafts and IL-10 (+) allografts as compared to IL-10 (-) and untreated controls at d10 post-transplantation. Collectively, these findings demonstrated that IL-10 mediated microvascular and epithelial changes are associated with the expression of FOXJ1, β-catenin, and Fascin-1 proteins on the airway epithelial and vascular endothelial cells, respectively. These findings establish a potential reparative modulation of IL-10 associated microvascular and epithelial repair, which could provide a vital therapeutic strategy to facilitate graft repair in clinical settings.
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Affiliation(s)
- Shadab Kazmi
- Transplantation Research and Innovation Department, Organ Transplant Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh 12713, Saudi Arabia; (S.K.); (T.S.); (A.A.); (D.C.B.)
| | - Mohammad Afzal Khan
- Transplantation Research and Innovation Department, Organ Transplant Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh 12713, Saudi Arabia; (S.K.); (T.S.); (A.A.); (D.C.B.)
| | - Talal Shamma
- Transplantation Research and Innovation Department, Organ Transplant Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh 12713, Saudi Arabia; (S.K.); (T.S.); (A.A.); (D.C.B.)
| | - Abdullah Altuhami
- Transplantation Research and Innovation Department, Organ Transplant Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh 12713, Saudi Arabia; (S.K.); (T.S.); (A.A.); (D.C.B.)
| | - Hala Abdalrahman Ahmed
- Comparative Medicine Department, King Faisal Specialist Hospital and Research Centre, Riyadh 12713, Saudi Arabia; (H.A.A.); (A.M.A.)
| | - Abdullah Mohammed Assiri
- Comparative Medicine Department, King Faisal Specialist Hospital and Research Centre, Riyadh 12713, Saudi Arabia; (H.A.A.); (A.M.A.)
- College of Medicine, Alfaisal University, Riyadh 12713, Saudi Arabia
| | - Dieter Clemens Broering
- Transplantation Research and Innovation Department, Organ Transplant Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh 12713, Saudi Arabia; (S.K.); (T.S.); (A.A.); (D.C.B.)
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Fujita Y, Miyamoto K, Imataka G, Yoshihara S. Postinfectious Bronchiolitis Obliterans Misdiagnosed as Bronchial Asthma in a Pediatric Patient. TOHOKU J EXP MED 2021; 254:257-260. [PMID: 34408104 DOI: 10.1620/tjem.254.257] [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: 11/18/2022]
Abstract
Bronchiolitis obliterans is a chronic obstructive respiratory disease involving stenosis or occlusion of the bronchioles and smaller airways. The prognosis of bronchiolitis obliterans is poor, and the patient might require home oxygen therapy and/or lung transplantation. Bronchiolitis obliterans has various etiologies; in children, the most common causes are infections by respiratory pathogens like adenoviruses. In such cases, the condition is termed as postinfectious bronchiolitis obliterans. A 7-year-old girl was diagnosed with bronchial asthma at the age of 1 year and was on a regimen of a leukotriene receptor antagonist and an inhaled corticosteroid. At 1 year of age, she was admitted to our hospital with a respiratory syncytial virus infection, and despite continued treatment with the above drugs, she required frequent readmissions. At the age of 7 years, she was diagnosed with postinfectious bronchiolitis obliterans based on the following findings: mosaic perfusion on high-resolution chest computed tomography and ventilation-perfusion mismatch on ventilation-perfusion scintigraphy. A lung biopsy was not performed due to its invasiveness. It has been suggested that appropriate treatment during the early stage improves the prognosis of bronchiolitis obliterans. This disease might be misdiagnosed as bronchial asthma because of the clinical similarities. In patients who do not respond to the treatment for bronchial asthma, pediatricians should consider other diseases with similar signs and symptoms, such as bronchiolitis obliterans, in the differential diagnosis.
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Affiliation(s)
- Yuji Fujita
- Department of Pediatrics, Dokkyo Medical University
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Khan MA, Ashoor GA, Shamma T, Alanazi F, Altuhami A, Kazmi S, Ahmed HA, Mohammed Assiri A, Clemens Broering D. IL-10 Mediated Immunomodulation Limits Subepithelial Fibrosis and Repairs Airway Epithelium in Rejecting Airway Allografts. Cells 2021; 10:1248. [PMID: 34069395 PMCID: PMC8158696 DOI: 10.3390/cells10051248] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 04/01/2021] [Accepted: 04/20/2021] [Indexed: 12/11/2022] Open
Abstract
Interleukin-10 plays a vital role in maintaining peripheral immunotolerance and favors a regulatory immune milieu through the suppression of T effector cells. Inflammation-induced microvascular loss has been associated with airway epithelial injury, which is a key pathological source of graft malfunctioning and subepithelial fibrosis in rejecting allografts. The regulatory immune phase maneuvers alloimmune inflammation through various regulatory modulators, and thereby promotes graft microvascular repair and suppresses the progression of fibrosis after transplantation. The present study was designed to investigate the therapeutic impact of IL-10 on immunotolerance, in particular, the reparative microenvironment, which negates airway epithelial injury, and fibrosis in a mouse model of airway graft rejection. Here, we depleted and reconstituted IL-10, and serially monitored the phase of immunotolerance, graft microvasculature, inflammatory cytokines, airway epithelium, and subepithelial collagen in rejecting airway transplants. We demonstrated that the IL-10 depletion suppresses FOXP3+ Tregs, tumor necrosis factor-inducible gene 6 protein (TSG-6), graft microvasculature, and establishes a pro-inflammatory phase, which augments airway epithelial injury and subepithelial collagen deposition while the IL-10 reconstitution facilitates FOXP3+ Tregs, TSG-6 deposition, graft microvasculature, and thereby favors airway epithelial repair and subepithelial collagen suppression. These findings establish a potential reparative modulation of IL-10-associated immunotolerance on microvascular, epithelial, and fibrotic remodeling, which could provide a vital therapeutic option to rescue rejecting transplants in clinical settings.
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Affiliation(s)
- Mohammad Afzal Khan
- Organ Transplant Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh 12713, Saudi Arabia; (T.S.); (F.A.); (A.A.); (S.K.); (D.C.B.)
| | | | - Talal Shamma
- Organ Transplant Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh 12713, Saudi Arabia; (T.S.); (F.A.); (A.A.); (S.K.); (D.C.B.)
| | - Fatimah Alanazi
- Organ Transplant Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh 12713, Saudi Arabia; (T.S.); (F.A.); (A.A.); (S.K.); (D.C.B.)
| | - Abdullah Altuhami
- Organ Transplant Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh 12713, Saudi Arabia; (T.S.); (F.A.); (A.A.); (S.K.); (D.C.B.)
| | - Shadab Kazmi
- Organ Transplant Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh 12713, Saudi Arabia; (T.S.); (F.A.); (A.A.); (S.K.); (D.C.B.)
| | - Hala Abdalrahman Ahmed
- Comparative Medicine Department, King Faisal Specialist Hospital and Research Centre, Riyadh 12713, Saudi Arabia; (H.A.A.); (A.M.A.)
| | - Abdullah Mohammed Assiri
- Comparative Medicine Department, King Faisal Specialist Hospital and Research Centre, Riyadh 12713, Saudi Arabia; (H.A.A.); (A.M.A.)
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Dieter Clemens Broering
- Organ Transplant Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh 12713, Saudi Arabia; (T.S.); (F.A.); (A.A.); (S.K.); (D.C.B.)
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Werlein C, Ackermann M, Hoffmann TL, Laenger F, Jonigk D. [Fibrotic remodeling of the lung following lung and stem-cell transplantation]. DER PATHOLOGE 2021; 42:17-24. [PMID: 33416936 DOI: 10.1007/s00292-020-00898-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 12/16/2020] [Indexed: 10/22/2022]
Abstract
Transplantation of solid organs and hematopoietic stem cells represents an important therapeutic option for a variety of end-stage pulmonary diseases, aggressive hematopoietic neoplasms, or severe immunodeficiencies. Although the overall survival following transplantation has generally improved over recent decades, long-time survival of lung and stem-cell transplant recipients is still alarmingly low with an average 5‑year survival rate of only 50-60%. Chronic allo-immunoreactions in general and pulmonary allo-immunoreactions with subsequent fibrosis in particular are major reasons for this poor outcome. Comparable patterns of fibrotic lung remodeling are observed following both lung and hematopoietic stem-cell transplantation. Besides the meanwhile well-established obliterative and functionally obstructive remodeling of the small airways - obliterative bronchiolitis - a specific restrictive subform of fibrosis, namely alveolar fibroelastosis, has been identified. Despite their crucial impact on patient outcome, both entities can be very challenging to detect by conventional histopathological analysis. Their underlying mechanisms are considered overreaching aberrant repair attempts to acute lung injuries with overactivation of (myo-) fibroblasts and excessive and irreversible deposition of extracellular matrix. Of note, the underlying molecular mechanisms are widely divergent between these two morphological entities and are independent of the underlying clinical setting.Further comprehensive investigations of these fibrotic alterations are key to the development of much-needed predictive diagnostics and curative concepts, considering the high mortality of pulmonary fibrosis following transplantation.
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Affiliation(s)
- Christopher Werlein
- Institut für Pathologie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, OE 5110, 30625, Hannover, Deutschland
| | - Max Ackermann
- Institut für Pathologie und Molekularpathologie, Helios Universitätsklinikum Wuppertal, Universität Witten-Herdecke, Wuppertal, Deutschland.,Institut für Funktionelle und Klinische Anatomie, Universitätsmedizin, Johannes Gutenberg-Universität Mainz, Mainz, Deutschland
| | - Thia Leandra Hoffmann
- Institut für Pathologie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, OE 5110, 30625, Hannover, Deutschland
| | - Florian Laenger
- Institut für Pathologie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, OE 5110, 30625, Hannover, Deutschland.,Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Standort Hannover, Deutsches Zentrum für Lungenforschung (DZL), Hannover, Deutschland
| | - Danny Jonigk
- Institut für Pathologie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, OE 5110, 30625, Hannover, Deutschland. .,Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Standort Hannover, Deutsches Zentrum für Lungenforschung (DZL), Hannover, Deutschland.
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Effect of Smoking on Outcomes of Allogeneic Transplantation: A Single-Center Analysis. Biol Blood Marrow Transplant 2020; 26:1131-1136. [PMID: 32200122 DOI: 10.1016/j.bbmt.2020.03.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 01/25/2020] [Accepted: 03/12/2020] [Indexed: 12/18/2022]
Abstract
Pulmonary complications are fatal adverse events after allogeneic hematopoietic cell transplantation (allo-HCT). On the other hand, smoking is a well-known risk factor for various pulmonary diseases and also increases the incidence of pulmonary complications and overall mortality in allo-HCT recipients. In this study, we retrospectively assessed the impact of smoking intensity on survival outcomes. This study included consecutive allo-HCT recipients at our center between June 2007 and May 2019 whose smoking profiles were available (n = 408); they were divided into high (pack-years >10, n = 171) and low (pack-years ≤10, n = 231) pack-years groups. In univariate analyses, nonrelapse mortality (NRM) and overall survival (OS) were significantly inferior in the high pack-years group (1-year NRM 26.6% versus 13.9%, P < .001; 1-year OS 58.4% versus 70.1%, P = .0067). However, this association was not observed in multivariate analyses. In subgroup analyses according to sex, the survival outcomes in the high pack-years group were significantly inferior in males (NRM hazard ratio [HR], 2.24 [95% confidence interval (CI), 1.23 to 4.07], P = .0082; OS HR, 1.54 [95% CI, 1.04 to 2.28], P = .031), but not in females (NRM HR, 0.587 [95% CI, 0.241 to 1.43], P = .24; OS HR, 0.689 [95% CI, 0.400 to 1.19], P = .18). In summary, high pack-years were associated with inferior survival of allo-HCT recipients, especially in males.
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Yang M, Chen G, Zhang X, Ding Z, Miao Y, Yang Y, Chen ZK, Jiang F, Chang S, Zhou P. A novel MyD88 inhibitor attenuates allograft rejection after heterotopic tracheal transplantation in mice. Transpl Immunol 2018; 53:1-6. [PMID: 30472390 DOI: 10.1016/j.trim.2018.11.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2018] [Accepted: 11/21/2018] [Indexed: 01/14/2023]
Abstract
BACKGROUND After lung transplantation, the major complication limiting the long-term survival of allografts is obliterative bronchiolitis (OB), characterized by chronic rejection. Innate immune responses contribute to the development of OB. In this study, we used a murine heterotopic tracheal transplantation mouse model to examine the effects of a newtype of innate immune inhibitor, TJ-M2010-5. METHODS Syngeneic tracheal grafts were transplanted heterotopically from C57BL/6 mice to C57BL/6 mice. Allografts from BALB/c mice were transplanted to C57BL/6 mice. The allograft recipients were treated with TJ-M2010-5, and anti-mouse CD154 (MR-1). The grafts were harvested at 7, 14, and 28 days and evaluated by histological and real-time RT-PCR analyses. RESULTS In untreated allografts, almost all epithelial cells fell off at 7 days and tracheal occlusion reached a peak at 28 days. However, the loss of the epithelium and airway obstruction were significantly improved in mice treated with TJ-M2010-5 combined with MR-1. The relative mRNA expression levels of pro-inflammatory cytokines were upregulated in allogeneic tracheal grafts, and treatment with the two drugs reduced the production of pro-inflammatory cytokines and infiltration of inflammatory cells. CONCLUSIONS In heterotopic tracheal transplantation models, TJ-M2010-5 combined with MR-1 could ameliorate the development of OB.
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Affiliation(s)
- Min Yang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 43003, China
| | - Gen Chen
- Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xue Zhang
- Department of Breast Surgery, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Zuochuan Ding
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 43003, China
| | - Yan Miao
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 43003, China
| | - Yang Yang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 43003, China
| | - Zhonghua Klaus Chen
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 43003, China
| | - Fengchao Jiang
- Academy of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Sheng Chang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 43003, China.
| | - Ping Zhou
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 43003, China.
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Hathorn KE, Chan WW, Lo WK. Role of gastroesophageal reflux disease in lung transplantation. World J Transplant 2017; 7:103-116. [PMID: 28507913 PMCID: PMC5409910 DOI: 10.5500/wjt.v7.i2.103] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Revised: 11/16/2016] [Accepted: 02/13/2017] [Indexed: 02/05/2023] Open
Abstract
Lung transplantation is one of the highest risk solid organ transplant modalities. Recent studies have demonstrated a relationship between gastroesophageal reflux disease (GERD) and lung transplant outcomes, including acute and chronic rejection. The aim of this review is to discuss the pathophysiology, evaluation, and management of GERD in lung transplantation, as informed by the most recent publications in the field. The pathophysiology of reflux-induced lung injury includes the effects of aspiration and local immunomodulation in the development of pulmonary decline and histologic rejection, as reflective of allograft injury. Modalities of reflux and esophageal assessment, including ambulatory pH testing, impedance, and esophageal manometry, are discussed, as well as timing of these evaluations relative to transplantation. Finally, antireflux treatments are reviewed, including medical acid suppression and surgical fundoplication, as well as the safety, efficacy, and timing of such treatments relative to transplantation. Our review of the data supports an association between GERD and allograft injury, encouraging a strategy of early diagnosis and aggressive reflux management in lung transplant recipients to improve transplant outcomes. Further studies are needed to explore additional objective measures of reflux and aspiration, better compare medical and surgical antireflux treatment options, extend follow-up times to capture longer-term clinical outcomes, and investigate newer interventions including minimally invasive surgery and advanced endoscopic techniques.
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11
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How I treat bronchiolitis obliterans syndrome after hematopoietic stem cell transplantation. Blood 2016; 129:448-455. [PMID: 27856461 DOI: 10.1182/blood-2016-08-693507] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Accepted: 11/05/2016] [Indexed: 12/30/2022] Open
Abstract
In past years, a diagnosis of bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic cell transplant (HCT) conferred nearly universal mortality secondary to lack of consensus for diagnostic criteria, poorly understood disease pathogenesis, and very few studies of therapeutic or supportive care interventions. Recently, however, progress has been made in these areas: revised consensus diagnostic guidelines are now available, supportive care has improved, there is greater understanding of potential mechanisms of disease, and prospective trials are being conducted. This article describes these advances and provides suggestions to optimize therapy for patients with BOS after HCT.
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Liu X, Yue Z, Yu J, Daguindau E, Kushekhar K, Zhang Q, Ogata Y, Gafken PR, Inamoto Y, Gracon A, Wilkes DS, Hansen JA, Lee SJ, Chen JY, Paczesny S. Proteomic Characterization Reveals That MMP-3 Correlates With Bronchiolitis Obliterans Syndrome Following Allogeneic Hematopoietic Cell and Lung Transplantation. Am J Transplant 2016; 16:2342-51. [PMID: 26887344 PMCID: PMC4956556 DOI: 10.1111/ajt.13750] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Revised: 02/03/2016] [Accepted: 02/05/2016] [Indexed: 01/25/2023]
Abstract
Improved diagnostic methods are needed for bronchiolitis obliterans syndrome (BOS), a serious complication after allogeneic hematopoietic cell transplantation (HCT) and lung transplantation. For protein candidate discovery, we compared plasma pools from HCT transplantation recipients with BOS at onset (n = 12), pulmonary infection (n = 16), chronic graft-versus-host disease without pulmonary involvement (n = 15) and no chronic complications after HCT (n = 15). Pools were labeled with different tags (isobaric tags for relative and absolute quantification), and two software tools identified differentially expressed proteins (≥1.5-fold change). Candidate proteins were further selected using a six-step computational biology approach. The diagnostic value of the lead candidate, matrix metalloproteinase 3 (MMP3), was evaluated by enzyme-linked immunosorbent assay in plasma of a verification cohort (n = 112) with and without BOS following HCT (n = 76) or lung transplantation (n = 36). MMP3 plasma concentrations differed significantly between patients with and without BOS (area under the receiver operating characteristic curve 0.77). Consequently, MMP3 represents a potential noninvasive blood test for diagnosis of BOS.
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Affiliation(s)
- Xiaowen Liu
- Departement of BioHealth Informatics, Indiana University
School of Informatics and Computing, Indianapolis, IN
| | - Zongliang Yue
- Departement of BioHealth Informatics, Indiana University
School of Informatics and Computing, Indianapolis, IN
| | - Jeffrey Yu
- Department of Pediatrics, Indiana University School of
Medicine, Indianapolis, IN, USA
- Herman B Wells Center for Pediatric Research, Indiana
University School of Medicine, Indianapolis, IN, USA
- Department of Microbiology & Immunology, Indiana
University School of Medicine, Indianapolis, IN, USA
- Indiana University Simon Cancer Center, Indiana University
School of Medicine, Indianapolis, IN, USA
| | - Etienne Daguindau
- Department of Pediatrics, Indiana University School of
Medicine, Indianapolis, IN, USA
- Herman B Wells Center for Pediatric Research, Indiana
University School of Medicine, Indianapolis, IN, USA
- Department of Microbiology & Immunology, Indiana
University School of Medicine, Indianapolis, IN, USA
- Indiana University Simon Cancer Center, Indiana University
School of Medicine, Indianapolis, IN, USA
| | - Kushi Kushekhar
- Department of Pediatrics, Indiana University School of
Medicine, Indianapolis, IN, USA
- Herman B Wells Center for Pediatric Research, Indiana
University School of Medicine, Indianapolis, IN, USA
- Department of Microbiology & Immunology, Indiana
University School of Medicine, Indianapolis, IN, USA
- Indiana University Simon Cancer Center, Indiana University
School of Medicine, Indianapolis, IN, USA
| | - Qing Zhang
- Proteomics Shared Resource, Fred Hutchinson Cancer Research
Center, Seattle, WA, USA
| | - Yuko Ogata
- Proteomics Shared Resource, Fred Hutchinson Cancer Research
Center, Seattle, WA, USA
| | - Philip R. Gafken
- Proteomics Shared Resource, Fred Hutchinson Cancer Research
Center, Seattle, WA, USA
| | - Yoshihiro Inamoto
- Clinical Research Division, Fred Hutchinson Cancer Research
Center, Seattle, WA, USA
- Division of Hematopoietic Stem Cell Transplantation,
National Cancer Center Hospital, Tokyo, Japan
| | - Adam Gracon
- Pulmonary Division, Indiana University School of Medicine,
Indianapolis, IN, USA
| | - David S. Wilkes
- Pulmonary Division, Indiana University School of Medicine,
Indianapolis, IN, USA
| | - John A. Hansen
- Clinical Research Division, Fred Hutchinson Cancer Research
Center, Seattle, WA, USA
- University of Washington School of Medicine, Seattle, WA,
USA
| | - Stephanie J. Lee
- Clinical Research Division, Fred Hutchinson Cancer Research
Center, Seattle, WA, USA
- University of Washington School of Medicine, Seattle, WA,
USA
| | - Jake Y. Chen
- Departement of BioHealth Informatics, Indiana University
School of Informatics and Computing, Indianapolis, IN
| | - Sophie Paczesny
- Department of Pediatrics, Indiana University School of
Medicine, Indianapolis, IN, USA
- Herman B Wells Center for Pediatric Research, Indiana
University School of Medicine, Indianapolis, IN, USA
- Department of Microbiology & Immunology, Indiana
University School of Medicine, Indianapolis, IN, USA
- Indiana University Simon Cancer Center, Indiana University
School of Medicine, Indianapolis, IN, USA
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13
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Tejwani V, Panchabhai TS, Kotloff RM, Mehta AC. Complications of Lung Transplantation. Chest 2016; 149:1535-1545. [DOI: 10.1016/j.chest.2015.12.019] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2015] [Revised: 11/16/2015] [Accepted: 12/11/2015] [Indexed: 01/30/2023] Open
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Ladak SS, Ward C, Ali S. The potential role of microRNAs in lung allograft rejection. J Heart Lung Transplant 2016; 35:550-9. [DOI: 10.1016/j.healun.2016.03.018] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Revised: 02/18/2016] [Accepted: 03/21/2016] [Indexed: 01/13/2023] Open
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15
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Williams KM, Cheng GS, Pusic I, Jagasia M, Burns L, Ho VT, Pidala J, Palmer J, Johnston L, Mayer S, Chien JW, Jacobsohn DA, Pavletic SZ, Martin PJ, Storer BE, Inamoto Y, Chai X, Flowers MED, Lee SJ. Fluticasone, Azithromycin, and Montelukast Treatment for New-Onset Bronchiolitis Obliterans Syndrome after Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant 2016; 22:710-716. [PMID: 26475726 PMCID: PMC4801753 DOI: 10.1016/j.bbmt.2015.10.009] [Citation(s) in RCA: 143] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2015] [Accepted: 10/07/2015] [Indexed: 12/13/2022]
Abstract
Bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic cell transplantation (HCT) is associated with high mortality. We hypothesized that inhaled fluticasone, azithromycin, and montelukast (FAM) with a brief steroid pulse could avert progression of new-onset BOS. We tested this in a phase II, single-arm, open-label, multicenter study (NCT01307462). Thirty-six patients were enrolled within 6 months of BOS diagnosis. The primary endpoint was treatment failure, defined as 10% or greater forced expiratory volume in 1 second decline at 3 months. At 3 months, 6% (2 of 36, 95% confidence interval, 1% to 19%) had treatment failure (versus 40% in historical controls, P < .001). FAM was well tolerated. Steroid dose was reduced by 50% or more at 3 months in 48% of patients who could be evaluated (n = 27). Patient-reported outcomes at 3 months were statistically significantly improved for Short-Form 36 social functioning score and mental component score, Functional Assessment of Cancer Therapies emotional well-being, and Lee symptom scores in lung, skin, mouth, and the overall summary score compared to enrollment (n = 24). At 6 months, 36% had treatment failure (95% confidence interval, 21% to 54%, n = 13 of 36, with 6 documented failures, 7 missing pulmonary function tests). Overall survival was 97% (95% confidence interval, 84% to 100%) at 6 months. These data suggest that FAM was well tolerated and that treatment with FAM and steroid pulse may halt pulmonary decline in new-onset BOS in the majority of patients and permit reductions in systemic steroid exposure, which collectively may improve quality of life. However, additional treatments are needed for progressive BOS despite FAM.
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Affiliation(s)
- Kirsten M Williams
- Division of Blood and Marrow Transplantation, Children's Research Institute, Children's National Health System, Washington, DC; Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
| | - Guang-Shing Cheng
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Iskra Pusic
- Division of Medicine and Oncology, Washington University, Saint Louis, Missouri
| | - Madan Jagasia
- Division of Hematology/Oncology, Vandebilt University, Nashville, Tennessee
| | - Linda Burns
- Division of Hematology/Oncology and Transplantation, University of Minnesota, Minneapolis, Minnesota
| | - Vincent T Ho
- Division of Hematological Malignancies, Dana Farber Cancer Institute, Boston, Massachusetts
| | - Joseph Pidala
- Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center, Tampa, Florida
| | - Jeanne Palmer
- Division of Hematology/Oncology, Mayo Clinic- Scottsdale, Scottsdale, Arizona
| | - Laura Johnston
- Division of Blood and Marrow Transplantation, Stanford University, Stanford, California
| | - Sebastian Mayer
- Department of Medicine, Weill Cornell Medical College, New York, New York
| | | | - David A Jacobsohn
- Division of Blood and Marrow Transplantation, Children's Research Institute, Children's National Health System, Washington, DC
| | - Steven Z Pavletic
- Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Paul J Martin
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Barry E Storer
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Yoshihiro Inamoto
- Division of Hematopoietic stem cell transplantation, National Cancer Center Hospital, Tokyo, Japan
| | - Xiaoyu Chai
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Mary E D Flowers
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Stephanie J Lee
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
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16
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17
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Li Y, Cheng H, Wang H, Wang Y, Liu L. Composite factors, including mycoplasmal pneumonia, hypersensitivity syndrome, and medicine, leading to bronchiolitis obliterans in a school-age child. Clin Pediatr (Phila) 2014; 53:1409-12. [PMID: 25022946 DOI: 10.1177/0009922814541808] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Affiliation(s)
- Yanchun Li
- First Hospital of Jilin University, Changchun, China
| | - Huanji Cheng
- First Hospital of Jilin University, Changchun, China
| | - Hongbo Wang
- First Hospital of Jilin University, Changchun, China
| | | | - Li Liu
- First Hospital of Jilin University, Changchun, China
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18
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Budding K, van de Graaf E, Otten H. Humoral immunity and complement effector mechanisms after lung transplantation. Transpl Immunol 2014; 31:260-5. [DOI: 10.1016/j.trim.2014.08.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2014] [Revised: 08/29/2014] [Accepted: 08/29/2014] [Indexed: 11/28/2022]
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Kobayashi K, Ohshima N, Shimada M, Kawashima M, Matsui H, Hebisawa A. An autopsy case of unicentric Castleman's disease associated with bronchiolitis obliterans. Respirol Case Rep 2014; 2:105-7. [PMID: 25473583 PMCID: PMC4184740 DOI: 10.1002/rcr2.60] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2014] [Revised: 04/20/2014] [Accepted: 05/01/2014] [Indexed: 12/04/2022] Open
Abstract
A 34-year-old woman visited the hospital suffering from enanthema of the tongue, hair loss, and nonproductive cough. Corticosteroid administration slightly resolved the enanthema and hair loss, but not the nonproductive cough. She was transferred to another hospital for the resection of a retroperitoneal mass, which was histopathologically diagnosed as unicentric, hyaline vascular type Castleman’s disease. She was then referred to our hospital due to progressive dyspnea and was diagnosed as having bronchiolitis obliterans based on computed tomography scan findings and a lung function test, while paraneoplastic pemphigus was clinically considered for her enanthema. After her death from respiratory failure in spite of corticosteroid administration, autopsy confirmed constrictive bronchiolitis in the lung. Mucocutaneous lesions, clinically considered as paraneoplastic pemphigus, were histologically different from pemphigus. The constrictive bronchiolitis and other pathological findings, including nonviral chronic hepatitis and interstitial nephritis, confirmed the diagnosis of paraneoplastic autoimmune multiorgan syndrome associated with the Castleman’s disease.
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Affiliation(s)
- Koichi Kobayashi
- Center for Pulmonary Diseases, National Hospital Organization Tokyo National Hospital Tokyo, Japan
| | - Nobuharu Ohshima
- Asthma and Allergy Center, National Hospital Organization Tokyo National Hospital Tokyo, Japan
| | - Masahiro Shimada
- Department of Clinical Research, National Hospital Organization Tokyo National Hospital Tokyo, Japan
| | - Masahiro Kawashima
- Center for Pulmonary Diseases, National Hospital Organization Tokyo National Hospital Tokyo, Japan
| | - Hirotoshi Matsui
- Center for Pulmonary Diseases, National Hospital Organization Tokyo National Hospital Tokyo, Japan
| | - Akira Hebisawa
- Department of Clinical Research, National Hospital Organization Tokyo National Hospital Tokyo, Japan
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20
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Suwara MI, Vanaudenaerde BM, Verleden SE, Vos R, Green NJ, Ward C, Borthwick LA, Vandermeulen E, Lordan J, Van Raemdonck DE, Corris PA, Verleden GM, Fisher AJ. Mechanistic differences between phenotypes of chronic lung allograft dysfunction after lung transplantation. Transpl Int 2014; 27:857-67. [PMID: 24750386 PMCID: PMC4282071 DOI: 10.1111/tri.12341] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2013] [Revised: 01/14/2014] [Accepted: 04/14/2014] [Indexed: 12/12/2022]
Abstract
Distinct phenotypes of chronic lung allograft dysfunction (CLAD) after lung transplantation are emerging with lymphocytic bronchiolitis (LB)/azithromycin reversible allograft dysfunction (ARAD), classical or fibrotic bronchiolitis obliterans syndrome (BOS), and restrictive allograft syndrome (RAS) proposed as separate entities. We have additionally identified lung transplant recipients with prior LB, demonstrating persistent airway neutrophilia (PAN) despite azithromycin treatment. The aim of this study was to evaluate differences in the airway microenvironment in different phenotypes of CLAD. Bronchoalveolar lavage (BAL) from recipients identified as stable (control), LB/ARAD, PAN, BOS, and RAS were evaluated for differential cell counts and concentrations of IL-1α, IL-1β, IL-6, IL-8, and TNF-α. Primary human bronchial epithelial cells were exposed to BAL supernatants from different phenotypes and their viability measured. BOS and RAS showed increased BAL neutrophilia but no change in cytokine concentrations compared with prediagnosis. In both LB/ARAD and PAN, significant increases in IL-1α, IL-1β, and IL-8 were present. BAL IL-6 and TNF-α concentrations were increased in PAN and only this phenotype demonstrated decreased epithelial cell viability after exposure to BAL fluid. This study demonstrates clear differences in the airway microenvironment between different CLAD phenotypes. Systematic phenotyping of CLAD may help the development of more personalized approaches to treatment.
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Affiliation(s)
- Monika I Suwara
- Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
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21
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Epler GR. Constrictive bronchiolitis obliterans: the fibrotic airway disorder. Expert Rev Respir Med 2014; 1:139-47. [DOI: 10.1586/17476348.1.1.139] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Sugino K, Hebisawa A, Uekusa T, Hatanaka K, Abe H, Homma S. Bronchiolitis obliterans associated with Stevens-Johnson Syndrome: histopathological bronchial reconstruction of the whole lung and immunohistochemical study. Diagn Pathol 2013; 8:134. [PMID: 23919759 PMCID: PMC3751748 DOI: 10.1186/1746-1596-8-134] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2013] [Accepted: 07/30/2013] [Indexed: 11/16/2022] Open
Abstract
This study presents an extremely rare case of constrictive bronchiolitis obliterans (BO) associated with Stevens-Johnson Syndrome (SJS) provides the morphological and immunohistochemical features using histopathological bronchial reconstruction technique. A 27-year-old female developed progressive dyspnea after SJS induced by taking amoxicillin at the age of 10. Finally, she died of exacerbation of type II respiratory failure after 17 years from clinically diagnosed as having BO. Macroscopic bronchial reconstruction of the whole lungs at autopsy showed the beginning of bronchial obliterations was in the 4th to 5th branches, numbering from each segmental bronchus. Once they were obliterated, the distal and proximal bronchi were dilated. Microscopic bronchial reconstruction demonstrated the localization of obliteration was mainly from small bronchi to membranous bronchioli with intermittent airway luminal narrowing or obliteration. Moreover, CD3-, CD20-, and CD68-positive cells were found in the BO lesions. CD34- and D2-40-positive cells were mainly distributed in the peribronchiolar lesions and bronchiolar lumens, respectively. SMA- and TGF-β-positive cells were seen in the fibrous tissue of BO lesions.
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Affiliation(s)
- Keishi Sugino
- Department of Respiratory Medicine, Toho University Omori Medical Center, Omorinishi 6-11-1, Ota-ku, Tokyo 143-8541, Japan.
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Guo Z, Zhou X, Li J, Meng Q, Cao H, Kang L, Ni Y, Fan H, Liu Z. Mesenchymal stem cells reprogram host macrophages to attenuate obliterative bronchiolitis in murine orthotopic tracheal transplantation. Int Immunopharmacol 2013; 15:726-34. [DOI: 10.1016/j.intimp.2013.03.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2012] [Revised: 02/04/2013] [Accepted: 03/01/2013] [Indexed: 02/06/2023]
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Emtiazjoo AM, Wilkes DS. Humoral immunity and the development of obliterative bronchiolitis after lung transplantation: is there a link? Am J Respir Cell Mol Biol 2012; 48:145-9. [PMID: 23087052 DOI: 10.1165/rcmb.2012-0349rt] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Lung transplantation is considered the definitive treatment for many end-stage lung diseases. However, the lung is rejected more commonly than other solid organ allografts. Obliterative bronchiolitis (OB) is the leading cause of chronic allograft dysfunction, and the key reason why the 5-year survival of lung transplant recipients is only 50%. The pathophysiology of OB is incompletely understood. Although a clear role for the immune response to donor antigens has been observed (also known as anti-human leukocyte antigens), evidence is emerging about the role of autoimmunity to self-antigens. This review highlights the current understanding of humoral immunity in the development of OB after lung transplantation.
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Affiliation(s)
- Amir M Emtiazjoo
- Division of Pulmonary and Critical Care, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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25
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Sarma NJ, Tiriveedhi V, Angaswamy N, Mohanakumar T. Role of antibodies to self-antigens in chronic allograft rejection: potential mechanism and therapeutic implications. Hum Immunol 2012; 73:1275-81. [PMID: 22789626 DOI: 10.1016/j.humimm.2012.06.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2012] [Revised: 03/21/2012] [Accepted: 06/29/2012] [Indexed: 02/07/2023]
Abstract
Significant progress has been made in preventing acute allograft rejection following solid organ transplantation resulting in improved allograft survival. However, long term function still remains disappointing primarily due to chronic allograft rejection. Alloimmune responses primarily defined by the development of antibodies (Abs) to donor mismatched major histocompatibility antigens during the post-transplantation period have been strongly correlated to the development of chronic rejection. In addition, recent studies have demonstrated an important role for autoimmunity including the development of Abs to organ specific self-antigens in the pathogenesis of chronic allograft rejection. Based on this, a new paradigm has evolved indicating a possible cross-talk between the alloimmune responses and autoimmunity leading to chronic rejection. In this review, we will discuss the emerging concept for the role of cellular and humoral immune responses to self-antigens in the immunopathogenesis of chronic allograft rejection which has the potential to develop new strategies for the prevention and/or treatment of chronic rejection.
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Affiliation(s)
- Nayan J Sarma
- Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, United States
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26
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Roman A, Ussetti P, Zurbano F, Borro JM, Solé A, Carreño MC, Santos F. A retrospective 12-month study of conversion to everolimus in lung transplant recipients. Transplant Proc 2012; 43:2693-8. [PMID: 21911148 DOI: 10.1016/j.transproceed.2011.06.028] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2011] [Revised: 05/16/2011] [Accepted: 06/06/2011] [Indexed: 12/22/2022]
Abstract
BACKGROUND Everolimus has potent antifibrotic effects that may potentially affect the clinical course of bronchiolitis obliterans syndrome (BOS) or provide nephroprotective immunosuppressive regimens for lung transplantation. METHODS We retrospectively assessed the 12-month outcomes of the conversion to everolimus among lung recipients in six Spanish centers. RESULTS From March 2005 to December 2007, 65 lung recipients who were at a mean posttransplantation time of 10.2 ± 7.9 months were converted to everolimus, mainly because of BOS (64.6%) or renal insufficiency (RI; 12.3%). The initial dose of everolimus was 1.9 ± 0.6 mg/d and the mean blood trough levels were stable over time (6.4 ± 2.8 ng/mL at 12 months). Conversion to everolimus allowed us to eliminate the calcineurin inhibitor (CNI) in 21% of patients. Among the overall population, the forced expiratory volume at 1 second (FEV(1)) and renal function remained stable. Mean FEV(1) did not change among the 35 (81%) patients surviving BOS at 12 months: preconversion FEV(1): 1.449.5 ± 641.9 mL vs 12-month FEV(1): 1420.0 ± 734.6 mL (P = .866). There was a significant improvement in renal function among the RI patients with mean glomerular filtration rates of 42.2 ± 15.2 mL/min/1.73 m(2) (P = .043) at 6 and 44.4 ± 18.8 mL/min/1.73 m(2) at 12 months, (P = .063) and a decrease in the use of CNIs from 1% of RI patients preconversion to 57% at 6 and 75% at 12 months. With a mean of 8.1- months follow-up (range: 1-31.3) overall survival was 84.6% at 1 year and 50% at 22.3 months. Progressive BOS was the main cause of death. Reasons for everolimus discontinuation were patient death (n = 10), lack of efficacy (n = 4), gastrointestinal adverse events (n = 2), and edema (n = 2). CONCLUSIONS BOS and RI were the main indications for conversion to everolimus among lung recipients. Conversion to everolimus improved renal function among patients converted because of RI. The present results were inconclusive regarding effects of everolimus on BOS.
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Affiliation(s)
- A Roman
- Department of Pulmonology, University Hospital Vall d'Hebron, Barcelona, Spain.
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27
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Feltracco P, Falasco G, Barbieri S, Milevoj M, Serra E, Ori C. Anesthetic considerations for nontransplant procedures in lung transplant patients. J Clin Anesth 2012; 23:508-16. [PMID: 21911200 DOI: 10.1016/j.jclinane.2011.05.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2010] [Revised: 05/03/2011] [Accepted: 05/08/2011] [Indexed: 12/26/2022]
Abstract
Lung transplantation has become an accepted option for many patients with end-stage pulmonary diseases. Anesthesia and surgery following lung transplantation may be required for various diseases that may affect both systemic organs and the transplanted graft. When a patient with a lung transplant undergoes surgery, there is the potential for interference with lung function, depending on the type of intervention and its anatomical site. Accurate preoperative evaluation, an understanding of the physiology of the transplanted lung, proper airway instrumentation, individualized management of intraoperative ventilation, and fluid balance are essential for a positive perioperative outcome.
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Affiliation(s)
- Paolo Feltracco
- Department of Pharmacology and Anesthesiology, University Hospital of Padova, 2-35121 Padua, Italy.
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Regression of allograft airway fibrosis: the role of MMP-dependent tissue remodeling in obliterative bronchiolitis after lung transplantation. THE AMERICAN JOURNAL OF PATHOLOGY 2011; 179:1287-300. [PMID: 21763265 DOI: 10.1016/j.ajpath.2011.05.032] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/22/2010] [Revised: 04/21/2011] [Accepted: 05/09/2011] [Indexed: 01/06/2023]
Abstract
Obliterative bronchiolitis after lung transplantation is a chronic inflammatory and fibrotic condition of small airways. The fibrosis associated with obliterative bronchiolitis might be reversible. Matrix metalloproteinases (MMPs) participate in inflammation and tissue remodeling. MMP-2 localized to myofibroblasts in post-transplant human obliterative bronchiolitis lesions and to allograft fibrosis in a rat intrapulmonary tracheal transplant model. Small numbers of infiltrating T cells were also observed within the fibrosis. To modulate inflammation and tissue remodeling, the broad-spectrum MMP inhibitor SC080 was administered after the allograft was obliterated, starting at post-transplant day 21. The allograft lumen remained obliterated after treatment. Only low-dose (2.5 mg/kg per day) SC080 significantly reduced collagen deposition, reduced the number of myofibroblasts and the infiltration of T cells in association with increased collagenolytic activity, increased MMP-2 gene expression, and decreased MMP-8, MMP-9, and MMP-13 gene expression. In in vitro experiments using cultured myofibroblasts, a relatively low concentration of SC080 increased MMP-2 activity and degradation of type I collagen. Moreover, coculture with T cells facilitated persistence of myofibroblasts, suggesting a role for T-cell infiltration in myofibroblast persistence in fibrosis. By combining low-dose SC080 with cyclosporine in vivo at post-transplant day 28, partial reversal of obliterative fibrosis was observed at day 42. Thus, modulating MMP activity might reverse established allograft airway fibrosis by regulating inflammation and tissue remodeling.
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Andersson-Sjöland A, Nihlberg K, Eriksson L, Bjermer L, Westergren-Thorsson G. Fibrocytes and the tissue niche in lung repair. Respir Res 2011; 12:76. [PMID: 21658209 PMCID: PMC3138446 DOI: 10.1186/1465-9921-12-76] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2011] [Accepted: 06/09/2011] [Indexed: 12/13/2022] Open
Abstract
Human fibrocytes are bone marrow-derived mesenchymal progenitor cells that express a variety of markers related to leukocytes, hematopoietic stem cells and a diverse set of fibroblast phenotypes. Fibrocytes can be recruited from the circulation to the tissue where they further can differentiate and proliferate into various mesenchymal cell types depending on the tissue niche. This local tissue niche is important because it modulates the fibrocytes and coordinates their role in tissue behaviour and repair. However, plasticity of a niche may be co-opted in chronic airway diseases such as asthma, idiopathic pulmonary fibrosis and obliterative bronchiolitis. This review will therefore focus on a possible role of fibrocytes in pathological tissue repair processes in those diseases.
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Raviv Y, D’Ovidio F, Pierre A, Chaparro C, Freeman M, Keshavjee S, Singer LG. Prevalence of gastroparesis before and after lung transplantation and its association with lung allograft outcomes. Clin Transplant 2011; 26:133-42. [DOI: 10.1111/j.1399-0012.2011.01434.x] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Federica M, Nadia S, Monica M, Alessandro C, Tiberio O, Francesco B, Mario V, Maria FA. Clinical and immunological evaluation of 12-month azithromycin therapy in chronic lung allograft rejection. Clin Transplant 2011; 25:E381-9. [DOI: 10.1111/j.1399-0012.2011.01435.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Ropponen JO, Syrjälä SO, Krebs R, Nykänen A, Tikkanen JM, Lemström KB. Innate and adaptive immune responses in obliterative airway disease in rat tracheal allografts. J Heart Lung Transplant 2011; 30:707-16. [PMID: 21411341 DOI: 10.1016/j.healun.2010.12.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2010] [Revised: 12/08/2010] [Accepted: 12/29/2010] [Indexed: 10/18/2022] Open
Abstract
BACKGROUND We assessed cellular innate and adaptive immune responses in a rat heterotopic tracheal allograft model during the development of obliterative airway disease. METHODS Syngeneic tracheal grafts were transplanted heterotopically from DA to DA rats and fully MHC-mismatched allografts from DA to WF rats. The recipients received either no immunosuppression or two different doses of cyclosporine and were euthanized at 3, 10 and 30 days. Non-transplanted DA tracheas served as controls. Histologic, immunohistochemical and real-time RT-PCR analyses were performed. RESULTS The syngrafts had normal epithelium at 10 days and no tracheal occlusion was seen at 30 days. In non-immunosuppressed allografts, almost total loss of epithelium was observed at 10 days, culminating in tracheal occlusion at 30 days. The activation of innate immune response was observed during the ischemic period at 3 days in both groups. Influx of the infiltrating inflammatory cells was more prominent in the allografts. In syngrafts, mRNA expression of pro-inflammatory, but also tolerogenic, cytokines was significantly upregulated, whereas Th1 and Th17 priming factors were significantly downregulated. In allografts, prominent mRNA expression of pro-inflammatory cytokines was seen and adaptive Th1 and Th17 alloresponses were increased. Cyclosporine treatment reduced tracheal occlusion and inhibited both tolerogenic and pro-inflammatory T-cell responses in allografts. CONCLUSIONS Ischemia induced a self-limiting, alloantigen-independent innate immune response in syngrafts. In allografts, the predominant pro-inflammatory milieu and alloantigen-dependent Th1 and Th17 responses were linked to the development of obliterative airway disease and were inhibited by cyclosporine treatment.
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Affiliation(s)
- Jussi O Ropponen
- Cardiopulmonary Research Group, Transplantation Laboratory, Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
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Sugino K, Hebisawa A, Uekusa T, Hatanaka K, Abe H, Homma S. Histopathological bronchial reconstruction of human bronchiolitis obliterans. Pathol Int 2011; 61:192-201. [DOI: 10.1111/j.1440-1827.2010.02637.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Grove DA, Xu J, Joodi R, Torres-Gonzales E, Neujahr D, Mora AL, Rojas M. Attenuation of early airway obstruction by mesenchymal stem cells in a murine model of heterotopic tracheal transplantation. J Heart Lung Transplant 2010; 30:341-50. [PMID: 21093298 DOI: 10.1016/j.healun.2010.09.012] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2010] [Revised: 08/24/2010] [Accepted: 09/21/2010] [Indexed: 10/18/2022] Open
Abstract
BACKGROUND Long-term success in lung transplantation is limited by obliterative bronchiolitis (OB). Presently, complete understanding of the mechanisms of OB has been elusive. Bone marrow-derived mesenchymal stem cells (MSC) have been shown to modulate repair of the injured lung in multiple disease models. We hypothesized that the injection of MSC would prevent development of early airway obstruction (AO) in the heterotopic tracheal transplant model. METHODS Forty-four tracheas from BALB/c and C57BL/6 donors were transplanted into 22 C57BL/6 recipients. At the time of transplant, 13 of the allogeneic recipient mice were injected with 5 × 10(5) MSC from various murine sources. To confirm the role of the immune response in the generation of AO we used a permeable inhibitor of nuclear factor-kappaB (NF-κB) in 11 recipients after transplantation with 22 BALB/c tracheas. RESULTS After transplantation, administration of MSC inhibited intraluminal obstruction by collagen in 98% of the mice and transforming factor-beta (TGF-β) expression decreased to levels similar to those observed in isograft controls. These effects were associated with a significant (p < 0.05) increase in expression of the anti-inflammatory cytokine interleukin-10 (IL-10). NF-κB inhibitor showed decreased expression of transforming growth factor-beta (TGF-β) in the Day 7 and Day 14 groups, resulting in a 60% reduction of luminal obstruction as well as a decrease in inflammatory cells to the airway. CONCLUSION Our observations suggest that administration of MSC prevents development of airway occlusion in a mouse model, probably through the modulated immune response altering TGF-β expression.
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Affiliation(s)
- Daniel A Grove
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
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Kastelijn EA, Rijkers GT, Van Moorsel CH, Zanen P, Kwakkel-van Erp JM, Van De Graaf EA, Van Kessel DA, Grutters JC, Van Den Bosch JM. Systemic and exhaled cytokine and chemokine profiles are associated with the development of bronchiolitis obliterans syndrome. J Heart Lung Transplant 2010; 29:997-1008. [DOI: 10.1016/j.healun.2010.04.013] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2009] [Revised: 04/13/2010] [Accepted: 04/28/2010] [Indexed: 12/13/2022] Open
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Davis CS, Jellish WS, Fisichella PM. Laparoscopic fundoplication with or without pyloroplasty in patients with gastroesophageal reflux disease after lung transplantation: how I do it. J Gastrointest Surg 2010; 14:1434-41. [PMID: 20499201 PMCID: PMC3066265 DOI: 10.1007/s11605-010-1233-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2010] [Accepted: 05/11/2010] [Indexed: 01/31/2023]
Abstract
INTRODUCTION Several studies have confirmed that gastroesophageal reflux disease (GERD) in lung transplant patients is a risk factor for the development and progression of bronchiolitis obliterans syndrome (BOS), a form of rejection after lung transplantation. Moreover, numerous reports indicate that surgical correction of GERD may control the decline in lung function characteristic of BOS. Although laparoscopic fundoplication is an accepted treatment option for these patients with GERD, the surgical technique, which often includes a laparoscopic pyloroplasty, has not been standardized. METHODS The purpose of this article is to describe a step-by-step approach to the laparoscopic treatment of GERD in lung transplant patients. We also address specific technical concerns encountered in the surgical management of this high-risk patient population; we provide data on the safety of this operation; and we illustrate the evidence-based rationale for each technical step of the procedure.
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Affiliation(s)
- Christopher S. Davis
- Departments of Surgery and Anesthesia, Loyola University Medical Center, Maywood, IL, USA
| | - W. Scott Jellish
- Departments of Surgery and Anesthesia, Loyola University Medical Center, Maywood, IL, USA
| | - P. Marco Fisichella
- Departments of Surgery and Anesthesia, Loyola University Medical Center, Maywood, IL, USA, Swallowing Center, Department of Surgery, Stritch School of Medicine, Loyola University Medical Center, 2160 South First Avenue—Room 3226, Maywood, IL 60153, USA
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Oil red O stain of alveolar macrophages is an effective screening test for gastroesophageal reflux disease in lung transplant recipients. J Heart Lung Transplant 2010; 29:859-64. [DOI: 10.1016/j.healun.2010.03.015] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2009] [Revised: 03/08/2010] [Accepted: 03/18/2010] [Indexed: 11/21/2022] Open
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Abstract
PURPOSE OF REVIEW Recent studies demonstrate an increasing role for alloimmune responses in the disruption of self-tolerance leading to immune responses to self-antigens that play a role in the immunopathogenesis of chronic rejection following solid organ transplantation. This review summarizes recent studies and implications for the alloimmune-response-induced de-novo development of autoimmune responses following solid organ transplantations. RECENT FINDINGS Immediately following organ transplantation, several factors lead to enduring an inflammatory milieu. Studies from our laboratory and others have demonstrated that development of antihuman leukocyte antigen antibodies precedes the development of chronic rejection. Using an in-vivo murine model, we have demonstrated that administration of anti-major histocompatibility complex (MHC) class I directly into the native lungs leads to chronic rejection pathology. Further, the in-vitro ligation of epithelial cell surface MHC class I molecules by specific anti-MHC can lead to cell activation and production of fibrinogenic growth factors. SUMMARY On the basis of these findings, we hypothesized that alloimmune responses can lead to autoimmunity, thus playing an important role in chronic rejection. Characterization of both the temporal occurrence and functional significance of antibodies to self-antigens may provide insight into the pathogenesis of chronic rejection and these antibodies can serve as clinically useful biomarkers.
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Affiliation(s)
- Anil Seetharam
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri, USA
| | | | - T. Mohanakumar
- Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA
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Wood KL, Nunley DR, Moffatt-Bruce S, Pope-Harman A, Huang Q, Shamo EN, Phillips GS, Baran C, Batra S, Marsh CB, Doseff AI. The role of heat shock protein 27 in bronchiolitis obliterans syndrome after lung transplantation. J Heart Lung Transplant 2010; 29:786-91. [PMID: 20456980 PMCID: PMC2902709 DOI: 10.1016/j.healun.2010.03.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2009] [Revised: 01/25/2010] [Accepted: 03/02/2010] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Heat shock proteins (Hsps) are a family of evolutionary conserved proteins classified according to their size as small and large Hsps. They have a cytoprotective role and have been shown to be immunogenic molecules. In addition, self-reactivity to Hsps has been implicated in various autoimmune diseases and in the development of alloimmunity. This study examined the relationship of large and small Hsps and anti-Hsp antibodies in lung transplant (LTx) recipients who have bronchiolitis obliterans syndrome (BOS). METHODS Anti-Hsp27 and Hsp70 antibodies, and Hsp27, Hsp60, and Hsp70 protein expression levels were evaluated in serum and bronchoalveolar lavage samples collected from 8 LTx recipients with established BOS and 8 recipients without BOS (controls). Serum from 8 healthy individuals was examined for Hsp levels as a comparison. RESULTS Elevated serum Hsp27 levels were observed in recipients with BOS compared with controls or healthy individuals, whereas Hsp70 and Hsp60 expression showed no difference. Anti-Hsp27 antibody levels were significantly higher in the BAL of recipients with BOS than in those without BOS. In contrast, anti-Hsp70 antibodies levels in serum or BAL showed no difference between groups. CONCLUSIONS These results support the novel concept that Hsp27, but not the classic Hsp60 and Hsp70, may be associated with the development BOS. The expression of anti-Hsp27 antibodies found only in the BAL fluid suggests a local response occurring at the level of the alveoli and terminal airways.
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Affiliation(s)
- Karen L Wood
- The Ohio State University College of Medicine, Columbus, OH, USA.
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Woodrow JP, Shlobin OA, Barnett SD, Burton N, Nathan SD. Comparison of bronchiolitis obliterans syndrome to other forms of chronic lung allograft dysfunction after lung transplantation. J Heart Lung Transplant 2010; 29:1159-64. [PMID: 20580267 DOI: 10.1016/j.healun.2010.05.012] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2009] [Revised: 04/05/2010] [Accepted: 05/06/2010] [Indexed: 10/19/2022] Open
Abstract
BACKGROUND The radiographic presence of allograft infiltrates is atypical of bronchiolitis obliterans (BO) and inconsistent with the definition of bronchiolitis obliterans requires that restrictive processes are ruled out. The natural history of these other forms of chronic allograft dysfunction has not been well characterized. We examined the prognostic significance of radiographic and spirometric restrictive processes in comparison to BOS among lung transplant recipients. METHODS We performed a retrospective review of lung transplant recipients with chronic lung allograft dysfunction (CLAD) as defined by spirometry. Subgroups based on the presence or absence of persistent radiographic abnormalities were labeled as non-specific (CLAD-NS) and CLAD due to BOS (CLAD-BOS), respectively. The CLAD-BOS group was further divided into obstructive (OBOS) and restrictive (RBOS) phenotypes based on spirometry. Groups were compared with respect to survival and decline in forced expiratory volume in 1 second (FEV(1)). RESULTS Among 241 lung transplant recipients, 96 (40%) were identified as having CLAD, of whom 62 (65%) had CLAD-BOS and 34 (35%) CLAD-NS. No difference between groups was identified with respect to post-CLAD survival or decline in FEV(1). CLAD-BOS subgroups included 35 (56%) patients with OBOS and 27 (44%) with RBOS. There was no difference in these subgroups with respect to survival or subsequent FEV(1) decline. CONCLUSIONS Patients with CLAD and persistent radiographic infiltrates have a similar prognosis to BOS patients but may still represent a clinically distinct phenotype. BOS patients frequently exhibited a restrictive pattern on spirometry, which also did not offer further prognostic information, but could still represent a unique disease phenotype.
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Affiliation(s)
- James P Woodrow
- Department of Internal Medicine, Walter Reed Army Medical Center, Washington, DC 20307, USA.
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Davis CS, Gagermeier J, Dilling D, Alex C, Lowery E, Kovacs EJ, Love RB, Fisichella PM. A review of the potential applications and controversies of non-invasive testing for biomarkers of aspiration in the lung transplant population. Clin Transplant 2010; 24:E54-61. [PMID: 20331688 PMCID: PMC3066066 DOI: 10.1111/j.1399-0012.2010.01243.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Despite improvements in one-yr survival following lung transplantation, five-yr survival lags significantly behind the transplantation of other solid organs. The contrast in survival persists despite advancements in anti-rejection regimens, suggesting a non-alloimmune mechanism to chronic lung transplant failure. Notably, markers of aspiration have been demonstrated in bronchoalveolar lavage (BAL) fluid concurrent with bronchiolitis obliterans syndrome (BOS). This recent evidence has underscored gastroesophageal reflux (GER) and its associated aspiration risk as a non-alloimmune mechanism of chronic lung transplant failure. Given the suggested safety and efficacy of laparoscopic anti-reflux procedures in the lung transplant population, identifying those at risk for aspiration is of prime importance, especially concerning the potential for long-term improvements in morbidity and mortality. Conventional diagnostic methods for GER and aspiration, such as pH monitoring and detecting pepsin and bile salts in BAL fluid, have gaps in their effectiveness. Therefore, we review the applications and controversies of a non-invasive method of defining reflux injury in the lung transplant population: the detection of biomarkers of aspiration in the exhaled breath condensate. Only by means of assay standardization and directed collaboration may such a non-invasive method be a realization in lung transplantation.
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Affiliation(s)
- C S Davis
- Department of Surgery, Loyola University Medical Center, Maywood, IL 60153, USA
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Bobadilla JL, Jankowska-Gan E, Xu Q, Haynes LD, Munoz del Rio A, Meyer K, Greenspan DS, De Oliveira N, Burlingham WJ, Maloney JD. Reflux-induced collagen type v sensitization: potential mediator of bronchiolitis obliterans syndrome. Chest 2010; 138:363-70. [PMID: 20418369 DOI: 10.1378/chest.09-2610] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022] Open
Abstract
BACKGROUND Lung transplantation continues to have poor long-term survival partly because of the high incidence of bronchiolitis obliterans syndrome (BOS). Gastroesophageal reflux disease (GERD) has been implicated in BOS pathogenesis. We investigated the role of collagen type V [col(V)] sensitization in this process. METHODS Only primary lung transplant recipients were included. Reflux status was assessed with pH monitoring, impedance plethysmography, and esophagogastroduodenoscopy. Sensitivity to col(V) was determined with trans vivo delayed-type hypersensitivity reaction (DTH). Kaplan-Meier analyses were performed. RESULTS Of the 54 recipients, 26 had proven GERD. There were no significant between-group differences in diagnosis; donor and recipient age; sex; ischemic time; single vs bilateral; human leukocyte antigen A, B, and DR matching cytomegalovirus status; acute rejections; or mean follow-up period. The mean DTH response in the GERD group was 25.7 x 10(-4) inches vs 18.3 x 10(-4) inches in the non-GERD group (P = .023). There was a significant reduction in BOS-free survival in the GERD group for both BOS-I (GERD+, 28.3%; GERD-, 86.6%; P = .0001) and BOS-II/III (GERD+, 66.2%; GERD-, 91.7%; P = .0374). A second cohort of 53 patients awaiting lung transplantation also was assayed. The mean DTH response in the GERD group was 24.0 x 10(-4) inches vs 13.1 x 10(-4) inches in the non-GERD group (P = .003). There were no differences in age or sex. CONCLUSIONS GERD is strongly associated with the development of BOS after primary lung transplantation. Col(V) sensitization is associated with reflux and BOS and may play an intermediary role in the pathogenesis of BOS. Trials using col(V) reactivity to assess the impact of antireflux procedures in patients with lung transplantation and idiopathic pulmonary fibrosis are warranted.
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Affiliation(s)
- Joseph L Bobadilla
- Department of Surgery, Division of Cardiothoracic Surgery, University of Wisconsin-Madison, Madison, WI 53792, USA.
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Kastelijn EA, van Moorsel CHM, Rijkers GT, Ruven HJT, Karthaus V, Kwakkel-van Erp JM, van de Graaf EA, Zanen P, van Kessel DA, Grutters JC, van den Bosch JMM. Polymorphisms in innate immunity genes associated with development of bronchiolitis obliterans after lung transplantation. J Heart Lung Transplant 2010; 29:665-71. [PMID: 20227302 DOI: 10.1016/j.healun.2009.12.013] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2009] [Revised: 12/12/2009] [Accepted: 12/15/2009] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Activation of the immune system is suggested to prevent transplant tolerance and to promote the development of bronchiolitis obliterans syndrome (BOS). The innate immune system is activated by the interaction of pathogen-associated molecular patterns of microorganisms with Toll-like receptors (TLRs). Activation of innate immunity via TLRs was shown to be a barrier to the induction of transplantation tolerance after lung transplantation. We hypothesized that polymorphisms in 10 genes coding for TLR1 to TLR10 might contribute to an altered immune response and the subsequent development of BOS. METHODS DNA was collected from 110 lung transplant recipients. Twenty patients developed BOS. The control group comprised 422 individuals. Sixty-four single-nucleotide polymorphisms (SNPs) in 10 genes coding for TLR1 to TLR10 were genotyped. RESULTS The genotype distribution of TLR2 (rs1898830 and rs7656411), TLR4 (rs1927911) and TLR9 (rs352162 and rs187084) was significantly different between BOS(pos) patients and BOS(neg) patients and controls. The BOS(pos) group had significantly more patients with 3 or 4 of these risk alleles compared with the BOS(neg) and control groups. CONCLUSIONS Polymorphisms in TLR2, TLR4 and TLR9 that recognize bacterial and viral pathogens are associated with BOS after lung transplantation.
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Affiliation(s)
- Elisabeth A Kastelijn
- Centre of Interstitial Lung Diseases, Department of Pulmonology, St Antonius Hospital, Nieuwegein, The Netherlands
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Molina EJ, Short S, Monteiro G, Gaughan JP, Macha M. Symptomatic gastroesophageal reflux disease after lung transplantation. Gen Thorac Cardiovasc Surg 2009; 57:647-53. [DOI: 10.1007/s11748-009-0486-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2009] [Accepted: 05/21/2009] [Indexed: 01/04/2023]
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Bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation-an increasingly recognized manifestation of chronic graft-versus-host disease. Biol Blood Marrow Transplant 2009; 16:S106-14. [PMID: 19896545 DOI: 10.1016/j.bbmt.2009.11.002] [Citation(s) in RCA: 139] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Bronchiolitis obliterans syndrome (BOS) is a progressive, insidious, and often fatal lung alloreaction that can occur following allogeneic hematopoietic stem cell transplantation (HSCT) or allogeneic lung transplantation. Current estimates in the literature suggest that approximately 2% to 3% of all allogeneic HSCT recipients and 6% of patients who develop chronic graft-versus-host disease (cGVHD) will develop this syndrome. However, based on newer data it is likely that the true incidence of BOS is higher. Unfortunately, the survival and treatment of patients with BOS after HSCT has not improved over the last 20 years. Attempts at clinical trials have been hindered by the lack of uniform diagnostic criteria and inability to detect the syndrome at a reversible stage in its natural history. Recently, the National Institutes of Health (NIH) consensus project for criteria in cGVHD has made recommendations regarding the diagnosis of BOS and monitoring of lung disease among long-term survivors. Although a rare and poorly understood manifestation of cGVHD, BOS occurs commonly after lung transplantation and is similar in pathology, clinical presentation, radiographic presentation, and presumed immunologic pathogenesis. This review describes the current understanding of the epidemiology and pathogenesis of BOS and presents information on evaluations and therapies for patients with BOS after HSCT.
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Madill J, Aghdassi E, Arendt B, Gutierrez C, Singer L, Chow CW, Keshavjee S, Allard J. Oxidative Stress and Nutritional Intakes in Lung Patients With Bronchiolitis Obliterans Syndrome. Transplant Proc 2009; 41:3838-44. [DOI: 10.1016/j.transproceed.2009.04.012] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2008] [Accepted: 04/13/2009] [Indexed: 01/31/2023]
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Vandemheen KL, O'Connor A, Bell SC, Freitag A, Bye P, Jeanneret A, Berthiaume Y, Brown N, Wilcox P, Ryan G, Brager N, Rabin H, Morrison N, Gibson P, Jackson M, Paterson N, Middleton P, Aaron SD. Randomized Trial of a Decision Aid for Patients with Cystic Fibrosis Considering Lung Transplantation. Am J Respir Crit Care Med 2009; 180:761-8. [DOI: 10.1164/rccm.200903-0421oc] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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Abstract
With improvements in supportive care, both long-term survival following allogeneic hematopoietic stem cell transplantations (HSCTs) and the indications for this procedure have increased. As a result, the number of patients living with long-term toxic effects due to HSCT has increased. A once rare condition of the donor immune cells attacking healthy host tissues, termed chronic graft-vs-host disease, has become a more common phenomenon. When chronic graft-vs-host disease affects the lung tissue, bronchiolitis obliterans syndrome ensues. Recent data suggest that bronchiolitis obliterans syndrome may affect up to 6% of HSCT recipients and dramatically alters survival, with overall survival of only 13% at 5 years. These statistics have not improved since the first presentation of this disease over 20 years ago. Challenges to the progress of medical management of bronchiolitis obliterans syndrome include difficulties and delays in diagnosis and a paucity of data on pathogenesis to direct new therapies. This article critically evaluates the current diagnostic criteria for bronchiolitis obliterans syndrome and reviews the epidemiology, pathogenesis, and available treatments. Improvements in survival will likely require early disease recognition, allowing for therapeutic modulation of disease prior to the development of irreversible airway obliteration.
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Affiliation(s)
- Kirsten M Williams
- Experimental Transplantation and Immunology Branch, National Cancer Institute, Bldg 10 CRC, Room 3-3288, 10 Center Dr, Bethesda, MD 20892, USA.
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Local C-reactive protein expression in obliterative lesions and the bronchial wall in posttransplant obliterative bronchiolitis. Mediators Inflamm 2009; 2009:510254. [PMID: 19503785 PMCID: PMC2686807 DOI: 10.1155/2009/510254] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2009] [Accepted: 03/26/2009] [Indexed: 01/21/2023] Open
Abstract
The local immunoreactivity of C-reactive protein (CRP) was studied in a heterotopic porcine model of posttranplant obliterative bronchiolitis (OB). Bronchial allografts and control autografts were examined serially 2–28 days after subcutaneous transplantation. The autografts stayed patent. In the allografts, proliferation of inflammatory cells (P < .0001) and fibroblasts (P = .02) resulted in occlusion of the bronchial lumens (P < .01). Influx of CD4+ (P < .001) and CD8+ (P < .0001) cells demonstrated allograft immune response. CRP positivity simultaneously increased in the bronchial walls (P < .01), in macrophages, myofibroblasts, and endothelial cells. Local CRP was predictive of features characteristic of OB (R = 0.456–0.879, P < .05−P < .0001). Early obliterative lesions also showed CRP positivity, but not mature, collagen-rich obliterative plugs (P < .05). During OB development, CRP is localized in inflammatory cells, myofibroblasts and endothelial cells probably as a part of the local inflammatory response.
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50
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Ward C, Eger K, Diboll J, Jones D, Haniffa MA, Brodlie M, Fisher A, Lordan JL, Corris PA, Hilkens CMU. Bronchial epithelial cells cultured from clinically stable lung allograft patients promote the development of macrophages from monocytes rather than dendritic cells. Thorax 2009; 64:430-5. [PMID: 19158119 PMCID: PMC2669498 DOI: 10.1136/thx.2008.104067] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2008] [Accepted: 12/31/2008] [Indexed: 02/01/2023]
Abstract
BACKGROUND It is understood that chronic allograft failure occurs as a result of alloimmune and non-alloimmune injury. Dendritic cells (DC) are thought to be crucial in regulating (allo)immune airway damage and interactions with epithelial cells are likely. Studies in human lung transplantation are limited, however, and the available literature on DC is inconsistent. This study focused on the ex vivo influence of primary bronchial epithelial cells derived from lung allografts on DC differentiation. METHODS Epithelial cell conditioned media (ECCM) were added to monocytes differentiating into DC under the influence of interleukin-4 and granulocyte macrophage-colony stimulating factor. The resultant cells were compared with DC cultured without ECCM and with monocyte-derived macrophages. Expression of typical DC (eg, CD1a) and macrophage (eg, CD14) markers was assessed by flow cytometry. Phenotypical assessments were complemented by functional studies of mannose receptor-mediated phagocytosis (FITC-dextran uptake) and antigen-presenting capability (mixed lymphocyte reactions). RESULTS Cells exposed to ECCM expressed significantly lower levels of CD1a than unexposed DC. CD14 expression and phagocytic function were increased. ECCM cultured cells also expressed lower levels of T cell co-stimulatory molecules, secreted an anti-inflammatory cytokine profile and had significantly reduced antigen-presenting capability. CONCLUSION Using phenotypic and functional approaches, this study has shown that ECCM from lung allografts drives the production of macrophage-like cells from monocytes rather than DC. The data suggest that epithelial cells may restrain airway DC and potential alloimmunity. It is unclear whether the observed effect is specifically seen in lung transplant recipients or is a general property of bronchial epithelial cells. This may reflect a homeostatic inter-relationship between airway epithelial and DC populations relevant both to lung allografts and the lung more generally.
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Affiliation(s)
- C Ward
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
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