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Obliterative Bronchiolitis (obliterative + bronchiolitis)

Distribution by Scientific Domains
Medical Sciences100%

Selected Abstracts

Translational Research: Animal Models of Obliterative Bronchiolitis after Lung Transplantation

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 9 2009
M. Sato
Obliterative bronchiolitis (OB) or chronic graft dysfunction remains the major limitation to long-term success of lung transplantation. Investigation using animal models is a critical component of research to understand the underlying pathological mechanisms and to develop novel preventive and therapeutic strategies for OB. Multiple animal models of OB exist, including orthotopic lung transplantation in rodents and large animals, orthotopic tracheal transplantation and heterotopic transplantation of a trachea in variable sites such as subcutaneous, intraomental and intrapulmonary sites. The most important issue for researchers is not specifically which model is the best but which is the most appropriate model to test their scientific hypothesis. For example, while orthotopic lung transplantation best mimics the overall surgical procedure, a question regarding fibrotic processes of OB may be better answered using heterotopic tracheal transplant models because of their reliable reproducibility of allograft obliterative airway fibrosis. Animal models should be continuously refined, modified and sometimes combined to fit the particular research purpose. We review the available animal models, their modifications and possible applications to assist researchers in choosing the appropriate model for their intended research. [source]

Obliterative bronchiolitis in lung allografts removed at retransplant for intractable airway problems

RESPIROLOGY, Issue 4 2009
Olufemi AKINDIPE
ABSTRACT Background and objective: The role of large airway ischaemia, with resultant airway narrowing, in the development of post-lung transplant bronchiolitis obliterans has not been defined. A determination of clinical bronchiolitis obliterans syndrome (BOS), which is defined as a decline in FEV1 from a stable post-transplant baseline, is difficult in the setting of airway complications. The aim of this study was to assess the evidence for histological bronchiolitis obliterans in lung allografts removed during retransplantation for severe recurrent airway narrowing. Methods: Case records and histological findings in allograft lungs removed at retransplantation were retrospectively reviewed. Results: Five lung transplant recipients, who had undergone retransplantation because of severe recalcitrant airway stenosis, were identified. In each case, explant allograft lung pathology revealed evidence of bronchiolitis obliterans. Conclusions: There is a possible link between airway ischaemia, large airway stenosis and the development of bronchiolitis obliterans, which is the most common cause of death in lung transplant recipients after the first year. These findings may provide an impetus for evaluation of the role of bronchial artery revascularization techniques in the prevention of bronchiolitis obliterans. [source]

CD154 Deficiency Uncouples Allograft CD8+ T-Cell Effector Function from Proliferation and Inhibits Murine Airway Obliteration

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 12 2009
P. D. Shah
Obliterative bronchiolitis (OB) limits the long-term success of lung transplantation, while T-cell effector mechanisms in this process remain incompletely understood. Using the murine heterotopic tracheal transplant model of obliterative airway disease (OAD) to characterize airway allograft rejection, we previously reported an important role for CD8+ T cells in OAD. Herein, we studied the role of CD154/CD40 costimulation in the regulation of allospecific CD8+ T cells, as airway rejection has been reported to be CD154-dependent. Airway allografts from CD154,/, recipients had significantly lower day 28 OAD scores compared to wild-type (WT) recipients, and adoptive transfer of CD8+ T cells from WT recipients, but not CD154,/, recipients, were capable of airway rejection in fresh CD154,/, allograft recipients. Intragraft CD8+ T cells from CD154,/, mice showed similar expression of the surface markers CD69, CD62Llow CD44high and PD-1, but markedly impaired IFN-, and TNF-, secretion and granzyme B expression versus WT controls. Unexpectedly, intragraft and systemic CD8+ T cells from CD154,/, recipients demonstrated robust in vivo expansion similar to WT recipients, consistent with an uncoupling of proliferation from effector function. Together, these data suggest that a lack of CD154/CD40 costimulation results in ineffective allospecific priming of CD8+ T cells required for murine OAD. [source]

Translational Research: Animal Models of Obliterative Bronchiolitis after Lung Transplantation

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 9 2009
M. Sato
Obliterative bronchiolitis (OB) or chronic graft dysfunction remains the major limitation to long-term success of lung transplantation. Investigation using animal models is a critical component of research to understand the underlying pathological mechanisms and to develop novel preventive and therapeutic strategies for OB. Multiple animal models of OB exist, including orthotopic lung transplantation in rodents and large animals, orthotopic tracheal transplantation and heterotopic transplantation of a trachea in variable sites such as subcutaneous, intraomental and intrapulmonary sites. The most important issue for researchers is not specifically which model is the best but which is the most appropriate model to test their scientific hypothesis. For example, while orthotopic lung transplantation best mimics the overall surgical procedure, a question regarding fibrotic processes of OB may be better answered using heterotopic tracheal transplant models because of their reliable reproducibility of allograft obliterative airway fibrosis. Animal models should be continuously refined, modified and sometimes combined to fit the particular research purpose. We review the available animal models, their modifications and possible applications to assist researchers in choosing the appropriate model for their intended research. [source]

Indirect Recognition of MHC Class I Allopeptides Accelerates Lung Allograft Rejection in Miniature Swine

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 7 2005
Tsuyoshi Shoji
The role of indirect allorecognition in graft rejection is examined in two experiments using a swine lung transplantation model. First, two swine received class I mismatched grafts without immunosuppression; another two recipients were treated postoperatively with cyclosporine (CsA). These swine exhibited acute and chronic rejection, respectively. All four recipients developed T-cell reactivity to donor-derived class I major histocompatibility complex (MHC) peptides. Second, six swine were immunized with synthetic donor-derived class I allopeptides prior to transplantation. Control groups consisted of nonimmunized recipients (n = 6) and recipients immunized with an irrelevant peptide (n = 3). These recipients all received a 12-day course of post-operative CsA. Swine immunized with allopeptides exhibited accelerated graft rejection, as compared to both control groups (p < 0.01 and p = 0.03, respectively). Within the experimental group, the dominant histologic finding was acute rejection (AR). Obliterative bronchiolitis (OB) was seen in the graft with the longest survival. Both control groups showed a lesser degree of AR, with four out of six nonimmunized swine ultimately developing OB. These studies suggest that indirect allorecognition is operative during lung allograft rejection, and that pre-transplant sensitization to donor-derived MHC allopeptides can accelerate graft rejection. [source]

The frequency of neuroendocrine cell hyperplasia in patients with pulmonary neuroendocrine tumours and non-neuroendocrine cell carcinomas

HISTOPATHOLOGY, Issue 3 2009
Selim M H Rizvi
Aims:, To evaluate the frequency of neuroendocrine cell hyperplasia (NEH) in resected neuroendocrine tumours and non-neuroendocrine cell carcinomas and to study its relationship to selected clinical parameters. Methods and results:, Random blocks without tumour from resected typical carcinoids (TCs, n = 46), atypical carcinoids (ACs, n = 14), large cell neuroendocrine carcinomas (LCNECs, n = 18), small cell carcinomas (SCLCs, n = 22), adenocarcinomas (ADENOs, n = 26) and squamous cell carcinomas (SCCs, n = 18) were stained for CD56 and evaluated for linear proliferations, cell aggregates (>4 CD56+ cells), and tumourlets (<5 mm with basement membrane invasion). There was a statistically significant difference between the frequency of NEH in all neuroendocrine tumours (TC/AC/LCNEC/SCLC, 35/100, 35%) (P = 0.009) when compared with non-neuroendocrine carcinomas (ADENO/SCC, 6/44, 14%) and in the frequency of NEH in TC (21/46, 46%) versus all other tumours (AC/LCNEC/SCLC/SCC/ADENO, 20/98, 20%) (P = 0.001). There was increased frequency of NEH in peripheral TCs (8/13, 62%) compared with central TCs (14/33, 43%) (P = 0.33). There was no association between smoking history and NEH. Clinical and imaging data showed no evidence of an increased frequency of obliterative bronchiolitis in patients with NEH. Conclusions:, NEH is significantly increased in the background lung of neuroendocrine tumours when compared with non-neuroendocrine carcinomas, supportive data for NEH having neoplastic potential. [source]

Inflammation and Epithelial to Mesenchymal Transition in Lung Transplant Recipients: Role in Dysregulated Epithelial Wound Repair

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 3 2010
L. A. Borthwick
Epithelial to mesenchymal transition (EMT) has been implicated in the pathogenesis of obliterative bronchiolitis (OB) after lung transplant. Although TNF-, accentuates TGF-,1 driven EMT in primary human bronchial epithelial cells (PBECs), we hypothesized that other acute pro-inflammatory cytokines elevated in the airways of patients with OB may also accentuate EMT and contribute to dysregulated epithelial wound repair. PBECs from lung transplant recipients were stimulated with TGF-,1 ± IL-1,, IL-8, TNF-, or activated macrophages in co-culture and EMT assessed. The quality and rate of wound closure in a standardized model of lung epithelial injury was assessed in response to above stimuli. Co-treatment with TGF-,1 + TNF-, or IL-1, significantly accentuates phenotypic and some functional features of EMT compared to TGF-,1 alone. Co-treatment with TGF-,1 + TNF-, or IL-1, accelerates epithelial wound closure however the quality of repair is highly dysregulated. Co-treatment with TGF-,1 + IL-8 has no significant effect on EMT or the speed or quality of wound healing. Activated macrophages dramatically accentuate TGF-,1-driven EMT and cause dysregulated wound repair. Crosstalk between macrophage-derived acute inflammation in the airway and elevated TGF-,1 may favor dysregulated airway epithelial repair and fibrosis in the lung allograft via EMT. [source]

Immunobiology of Chronic Lung Allograft Dysfunction: New Insights from the Bench and Beyond

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 8 2009
R. A. Shilling
The first successful human lung transplants were performed in the 1980s. Since that time lung transplantation has been a therapeutic modality for end-stage pulmonary diseases. However, chronic rejection, known as obliterative bronchiolitis (OB)/bronchiolitis obliterans syndrome (BOS), is the key reason why the 5-year survival is only 50%, which is significantly worse than most other solid organ transplants. Recent studies have provided exciting advances that are beginning to be translated into findings in humans. This review will highlight the current advances in understanding the mechanisms of OB/BOS in lung transplant recipients. [source]

MMP-Dependent Migration of Extrapulmonary Myofibroblast Progenitors Contributing to Posttransplant Airway Fibrosis in the Lung

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 5 2009
M. Sato
Myofibroblasts play a central role in fibroproliferative airway remodeling in obliterative bronchiolitis (OB) after lung transplantation. The purpose of the study is to elucidate the mechanisms whereby matrix metalloproteinases (MMPs) contribute to myofibroblast-mediated allograft airway fibrosis. In an intrapulmonary tracheal transplant model of OB, broad-spectrum MMP inhibitors, SC080 and MMI270 reduced the number of myofibroblasts at day 28 without changing differentiation, proliferation or apoptosis of myofibroblasts or fibroblasts. Next, myofibroblasts in allograft airway fibrosis were demonstrated to be almost exclusively of extrapulmonary origin by analyzing RT1An positive myofibroblasts in an animal model combining orthotopic lung transplantation (from Lewis (RT1Al) to F1 (Brown,Norway (RT1An) × Lewis)) and intrapulmonary tracheal transplantation (from a Wister,Furth rat (RT1Au) into the transplanted Lewis-derived lung). Using peripheral blood mononuclear cells (PBMCs) that can differentiate into ,-SMA positive myofibroblasts in vitro, we demonstrated their contribution to the myofibroblast population of allograft airway fibrosis in vivo using a fluorescence-labeling cell tracking system. Moreover, PBMC-derived fibroblast-like cells expressed high levels of MMP-9 and MMP-12 and their migration was inhibited by MMP inhibitors in a wound healing assay. In conclusion, MMP-dependent migration of PBMC-derived myofibroblast precursors is an important contributing mechanism to the development of allograft airway fibrosis. [source]