The Kinetics and Pattern of Tracheal Allograft Re-Epithelialization

Genden, Eric M.; Iskander, Andrew; Bromberg, Jonathan S.; Mayer, Lloyd

doi:10.1165/rcmb.2002-0214oc

Cited by 47 publications

(43 citation statements)

References 24 publications

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“…Conversely, recipient-derived epithelium promotes luminal fibrosis when re-transplanted into syngeneic mice. In contrast to results reported with cyclosporine immunotherapy (18), anti-LFA-1/anti-CD40L immunotherapy resulted in delayed chimerism. Why cyclosporine would promote epithelial chimerism and anti-LFA-1/anti-CD40L would inhibit chimerism is not immediately clear.…”

Section: Discussioncontrasting

confidence: 97%

“…The OTT model is distinguished from HTTs in several ways. Most notably, OTTs do not develop luminal fibrosis, and because they are contiguous with graft recipient airways, are re-epithelialized with recipienttype respiratory epithelium within 4 wk following transplantation (18,19). Additionally, dendritic cell clearance of shed epithelial cell Ags to draining lymph nodes for Ag presentation to T cells is reproduced in its native position in the neck and thorax.…”

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confidence: 99%

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Simultaneous LFA-1 and CD40 Ligand Antagonism Prevents Airway Remodeling in Orthotopic Airway Transplantation: Implications for the Role of Respiratory Epithelium as a Modulator of Fibrosis

Murakawa

Kerklo

Zamora

et al. 2005

The Journal of Immunology

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Airway remodeling is a prominent feature of certain immune-mediated lung diseases such as asthma and chronic lung transplant rejection. Under conditions of airway inflammation, the respiratory epithelium may serve an important role in this remodeling process. Given the proposed role of respiratory epithelium in nonspecific injury models, we investigated the respiratory epithelium in an immune-specific orthotopic airway transplant model. MHC-mismatched tracheal transplants in mice were used to generate alloimmune-mediated airway lesions. Attenuation of this immune injury and alteration of antidonor reactivity were achieved by the administration of combined anti-LFA-1/anti-CD40L mAbs. By contrast, without immunotherapy, transplanted airways remodeled with a flattening of respiratory epithelium and significant subepithelial fibrosis. Unopposed alloimmune injury for 10 days was associated with subsequent epithelial transformation and subepithelial fibrosis that could not be reversed with immunotherapy. The relining of donor airways with recipient-derived epithelium was delayed with immunotherapy resulting in partially chimeric airways by 28 days. Partial epithelial cell chimerism was sufficient to prevent luminal fibrosis. However, epithelial chimerism was also associated with airway remodeling. Therefore, there appears to be an intimate relationship between the morphology and level of chimerism of the respiratory epithelium and the degree of airway remodeling following alloimmune injury.

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Section: Discussioncontrasting

confidence: 97%

mentioning

confidence: 99%

Simultaneous LFA-1 and CD40 Ligand Antagonism Prevents Airway Remodeling in Orthotopic Airway Transplantation: Implications for the Role of Respiratory Epithelium as a Modulator of Fibrosis

Murakawa

Kerklo

Zamora

et al. 2005

The Journal of Immunology

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“…The decrease in luminal obliteration and mononuclear inflammatory cell accumulation and the increase in tracheal re-epithelialization in the absence of allograft or recipient TIMP-1 support the concept that TIMP-1 promotes the development of OAD. Furthermore, the detection of TIMP-1 in the epithelium of isografts at Days 14 and 28 after transplantation coincides with the regeneration of a mature mucociliary epithelium (5,21). The pattern of TIMP-1 expression in the restored isografts was similar to that found in normal tracheas.…”

Section: Discussionsupporting

confidence: 62%

Tissue Inhibitor of Metalloproteinase-1 Deficiency Abrogates Obliterative Airway Disease after Heterotopic Tracheal Transplantation

Chen

Farivar

Mulligan

et al. 2006

Am J Respir Cell Mol Biol

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Obliterative bronchiolitis (OB) is a major cause of allograft dysfunction after lung transplantation and is thought to result from immunologically mediated airway epithelial destruction and luminal fibrosis. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) have been implicated in the regulation of lung inflammation, airway epithelial repair, and extracellular matrix remodeling and therefore may participate in the pathogenesis of OB. The goals of this study were to determine the expression profiles of MMPs and TIMPs and the role of TIMP-1 in the development of airway obliteration using the murine heterotopic tracheal transplant model of OB. We demonstrate the selective induction of MMP-3, MMP-9, MMP-12, and TIMP-1 in a temporally restricted manner in tracheal allografts compared with isografts. In contrast, the expression of MMP-7, TIMP-2, and TIMP-3 was decreased in allografts relative to isografts during the period of graft rejection. TIMP-1 protein localized to epithelial, mesenchymal, and inflammatory cells in the tracheal grafts in a temporally and spatially restricted manner. Using TIMP-1-deficient mice, we demonstrate that the absence of TIMP-1 in the donor trachea or the allograft recipient reduced luminal obliteration and increased re-epithelialization in the allograft compared with wild-type control at 28 d after transplantation. Our findings provide direct evidence that TIMP-1 contributes to the development of airway fibrosis in the heterotopic tracheal transplant model, and suggest a potential role for this proteinase inhibitor in the pathogenesis of OB in patients with lung transplant.Keywords: heterotopic tracheal transplant; matrix metalloproteinase; obliterative bronchiolitis; tissue inhibitor of metalloproteinase Lung transplantation is often the only hope for patients with end-stage lung disease. However, 5-yr survival is only 45%, with the majority of deaths resulting from complications of obliterative bronchiolitis (OB) (1). OB is a histopathologic diagnosis characterized by mature collagen deposition resulting in occlusion of the small airways accompanied by infiltration of inflammatory cells and proliferating fibroblasts (2, 3). Due to the insensitivity of transbronchial biopsies to make a histologic diagnosis of OB in patients with lung transplant, a clinical equivalent, called bronchiolitis obliterans syndrome (BOS), was created and is based on findings from pulmonary function tests that show increased airflow obstruction over baseline (4). Treatment of OB with increased immunosuppression is generally ineffective

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“…The absence of a safe and effective method of monitoring epithelial fate in vivo in humans prohibits observations of the fate of such epithelium. A number of preclinical studies have indicated re‐epithelialization occurs from migration of cells from the wound edge following tracheal transplantation 14, 15, tracheal replacement with aortic grafts 16, 17 or synthetic material 18. While this might question the need for re‐epithelizing grafts prior to transplantation, evidence exists supporting the role of epithelium in reducing postoperative stenosis and it is probable that transplanted epithelia act as a biological dressing as re‐epithelization occurs from the wound edge 19.…”

Section: Discussionmentioning

confidence: 99%

Tissue-Engineered Tracheal Replacement in a Child: A 4-Year Follow-Up Study

Hamilton

Kanani

Roebuck

et al. 2015

American Journal of Transplantation

158

143

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In 2010, a tissue‐engineered trachea was transplanted into a 10‐year‐old child using a decellularized deceased donor trachea repopulated with the recipient's respiratory epithelium and mesenchymal stromal cells. We report the child's clinical progress, tracheal epithelialization and costs over the 4 years. A chronology of events was derived from clinical notes and costs determined using reference costs per procedure. Serial tracheoscopy images, lung function tests and anti‐HLA blood samples were compared. Epithelial morphology and T cell, Ki67 and cleaved caspase 3 activity were examined. Computational fluid dynamic simulations determined flow, velocity and airway pressure drops. After the first year following transplantation, the number of interventions fell and the child is currently clinically well and continues in education. Endoscopy demonstrated a complete mucosal lining at 15 months, despite retention of a stent. Histocytology indicates a differentiated respiratory layer and no abnormal immune activity. Computational fluid dynamic analysis demonstrated increased velocity and pressure drops around a distal tracheal narrowing. Cross‐sectional area analysis showed restriction of growth within an area of in‐stent stenosis. This report demonstrates the long‐term viability of a decellularized tissue‐engineered trachea within a child. Further research is needed to develop bioengineered pediatric tracheal replacements with lower morbidity, better biomechanics and lower costs.

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The Kinetics and Pattern of Tracheal Allograft Re-Epithelialization

Cited by 47 publications

References 24 publications

Simultaneous LFA-1 and CD40 Ligand Antagonism Prevents Airway Remodeling in Orthotopic Airway Transplantation: Implications for the Role of Respiratory Epithelium as a Modulator of Fibrosis

Simultaneous LFA-1 and CD40 Ligand Antagonism Prevents Airway Remodeling in Orthotopic Airway Transplantation: Implications for the Role of Respiratory Epithelium as a Modulator of Fibrosis

Tissue Inhibitor of Metalloproteinase-1 Deficiency Abrogates Obliterative Airway Disease after Heterotopic Tracheal Transplantation

Tissue-Engineered Tracheal Replacement in a Child: A 4-Year Follow-Up Study

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