Ferret Lung Transplant: An Orthotopic Model of Obliterative Bronchiolitis

Sui, Hong-Shu; Olivier, Alicia K.; Klesney-Tait, Julia; Brooks, Leonard; Tyler, Scott R.; Sun, Xingshen; Skopec, A.; Kline, Joel N.; Sánchez, Pablo G.; Meyerholz, David K.; Zavazava, Nicholas; Iannettoni, Mark D.; Engelhardt, John F.; Parekh, Kalpaj R.

doi:10.1111/j.1600-6143.2012.04337.x

Cited by 27 publications

(25 citation statements)

References 30 publications

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“…MHC mismatched orthotopic transplantation models reproduce features of acute rejection, but not necessarily CLAD. (46)(47)(48)(49). Transplantation of B6D2F1/J lungs to DBA recipients has shown promise in development of CLAD-like pathology, but the DBA background may be a limitation because of the paucity of available genetic knockout models.…”

Section: Discussionmentioning

confidence: 99%

Telomere Dysfunction Drives Chronic Lung Allograft Dysfunction Pathology

Naikawadi¹,

Green²,

Jones³

et al. 2019

Preprint

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Rationale:Telomere dysfunction is associated with multiple fibrotic lung processes, including chronic lung allograft dysfunction (CLAD) which is a major limitation to long-term survival following lung transplantation. Although shorter donor telomere lengths are associated with an increased risk of CLAD, it is unknown whether short telomeres are a cause or consequence of CLAD pathology. Objective:Our objective was to test whether telomere dysfunction contributes to pathologic changes seen in CLAD. Methods and Results:Histopathologic and molecular analysis of human CLAD lungs demonstrated shortened telomeres in lung epithelial cells quantified by teloFISH, increased numbers of surfactant protein C immunoreactive type II alveolar epithelial cells (AECs), and increased expression of senescence markers (beta-galactosidase, p16, p53 and p21) in lung epithelial cells. Telomere repeat binding factor 1 flox/flox (TRF1 F/F ) mice were crossed with tamoxifen inducible SCGB1a1-cre mice to generate SCGB1a1-creTRF1 F/F mice. Following 9 months of tamoxifen-induced deletion of TRF1 in club cells, mice developed mixed obstructive and restrictive lung physiology, small airway obliteration on micro-computed tomography, a 4fold decrease in telomere length in airway epithelial cells, collagen deposition around bronchioles and adjacent lung parenchyma, increased type II AEC numbers, expression of senescenceassociated beta-galactosidase in epithelial cells and decreased SCGB1a1 expression in airway epithelial cells. Conclusions:These findings demonstrate that telomere dysfunction isolated to club cells leads to airway-centric lung remodeling and fibrosis similar to that observed in patients with CLAD and suggest that lung epithelial cell telomere dysfunction may be a molecular driver of CLAD.

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Section: Discussionmentioning

confidence: 99%

Telomere Dysfunction Drives Chronic Lung Allograft Dysfunction Pathology

Naikawadi¹,

Green²,

Jones³

et al. 2019

Preprint

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“…CFRD results from the progressive inflammatory destruction of the pancreas [2, 3] and leads to the development of insulin insufficiency with varying levels of insulin resistance during acute illness [4]. The ferret CF model also shows that early inflammation leads to pancreatic cell destruction and replacement with fibrosis [5]. These pathologic changes correspond to significant dysregulation of blood glucose and insulin.…”

Section: Introductionmentioning

confidence: 99%

Glucose >200 mg/dL during Continuous Glucose Monitoring Identifies Adult Patients at Risk for Development of Cystic Fibrosis Related Diabetes

Taylor‐Cousar

Janssen

Wilson

et al. 2016

Journal of Diabetes Research

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Rationale. Cystic fibrosis related diabetes (CFRD) is the most common comorbidity in patients with CF. In spite of increased screening, diagnosis, and treatment of CFRD, the mortality rate in patients with CFRD still far exceeds the mortality rate in those without CFRD. Guidelines suggest that screening for CFRD be performed annually using the 2-hour 75-gram oral glucose tolerance test (OGTT). Adherence to recommended screening has been poor, with only approximately one-quarter of adults with CF undergoing OGTT in 2014. Use of continuous glucose monitoring (CGM) for diagnosis may become an alternative. Objectives. Our objective was to determine whether abnormal CGM predicts subsequent development of CFRD, lung function, and body mass index (BMI) decline and increased rate of CF pulmonary exacerbations in adults with CF. Methods. In a prospective single center pilot trial from September 2009 to September 2010, 21 adult patients due for routine OGTT were recruited to complete simultaneous 3-day CGM and 2-hour 75 gram OGTT. Subsequently, clinical information was reviewed from 2008 to 2015. Conclusions. There was a moderate correlation between interpreted results of 2-hour OGTT and CGM (p = 0.03); CGM indicated a greater level of glucose impairment than OGTT. Glucose >200 mg/dL by CGM predicted development of CFRD (p = 0.0002).

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“…Thus, at present, a consensus on a definitive rat lung transplant model to study OB pathogenesis has not emerged. An intriguing model of lung transplantation in ferrets also develops OB-like lesions (112). Finally, the role of innate immune activation in augmenting OB has also been evaluated using the rat lung transplant model with intratracheal gastric fluid challenge (113).…”

Section: Cladmentioning

confidence: 99%