A Novel Model for Post-Transplant Obliterative Airway Disease Reveals Angiogenesis from the Pulmonary Circulation

Dutly, André; Andrade, Cristiano Feijó; Verkaik, Ryan; Kugathasan, Lakshmi; Trogadis, Judy; Liu, Mingyao; Waddell, Thomas K.; Stewart, Duncan J.; Keshavjee, Shaf

doi:10.1111/j.1600-6143.2004.00680.x

Cited by 37 publications

(28 citation statements)

References 19 publications

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“…F 1 rats were bred from male BN and female Lewis rats at the Toronto General Research Institute (Toronto, Canada). Intrapulmonary tracheal transplantation was conducted as previously described (20). Animals were sacrificed at postoperative days 7, 28, 60, and 120 for the following analyses (n ϭ 5 for each time point and group).…”

Section: Animal Modelsmentioning

confidence: 99%

“…A rat intrapulmonary tracheal transplant model of OB is an animal model of OB that reflects the influences of the pulmonary milieu (20,22). This model enables examination of the pulmonary immune system's reaction to allogenic stimuli.…”

Section: Alloantigen-dependent Elt Formation After Rat Intrapulmonarymentioning

confidence: 99%

“…To address the hypothesis, we conducted careful histological and immunohistochemical analyses of the lungs that were explanted at the time of retransplantation due to OB/BOS after the initial lung transplantation. Furthermore, we have devised an animal model that combines a rat intrapulmonary tracheal transplant model of OB (20) and orthotopic lung transplantation to examine the effector function of intrapulmonary de novo lymphoid tissue after transplantation.…”

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confidence: 99%

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The Role of Intrapulmonary De Novo Lymphoid Tissue in Obliterative Bronchiolitis after Lung Transplantation

Sato

Hirayama

Hwang

et al. 2009

The Journal of Immunology

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Chronic rejection after lung transplantation is manifested as obliterative bronchiolitis (OB). The development of de novo lymphoid tissue (lymphoid neogenesis) may contribute to local immune responses in small airways. Compared with normal lungs, the lung tissue of 13 lung transplant recipients who developed OB demonstrated a significantly larger number of small, airway-associated, peripheral node addressin-positive (PNAd+) high endothelial venules (HEVs) unique to lymphoid tissue (p < 0.001). HEVs were most abundant in lesions of lymphocytic bronchiolitis and “active” OB infiltrated by lymphocytes compared with those of “inactive” OB. T cells in lymphocytic bronchiolitis and active OB were predominantly of the CD45RO+CCR7− effector memory phenotype. Similar lymphoid tissue was also observed in the rat lung after intrapulmonary transplantation of allograft trachea (Brown Norway (BN) to Lewis), but not after isograft transplantation. Subsequent orthotopic transplantation of the recipient Lewis lung containing a BN trachea into an F1 (Lewis × BN) rat demonstrated stable homing of Lewis-derived T cells in the lung and their Ag-specific effector function against the secondary intrapulmonary BN trachea. In conclusion, we found de novo lymphoid tissue in the lung composed of effector memory T cells and HEVs but lacking delineated T cell and B cell zones. This de novo lymphoid tissue may play a critical role in chronic local immune responses after lung transplantation.

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Section: Animal Modelsmentioning

confidence: 99%

Section: Alloantigen-dependent Elt Formation After Rat Intrapulmonarymentioning

confidence: 99%

mentioning

confidence: 99%

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The Role of Intrapulmonary De Novo Lymphoid Tissue in Obliterative Bronchiolitis after Lung Transplantation

Sato

Hirayama

Hwang

et al. 2009

The Journal of Immunology

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“…Heterotopic transplantation of the grafts has been employed in most reported studies. We previously described a novel intrapulmonary tracheal transplantation model of OB in rats, and demonstrated the connection of the grafts with the pulmonary circulation (10). Although obliterative fibrosis develops with similar kinetics to previously reported tracheal subcutaneous transplant models, the advantage of this model is that the graft is in the pulmonary milieu, which may have a significant relevance to the accommodation of implanted lung tissue (11).…”

Section: Introductionmentioning

confidence: 99%

Allograft Airway Fibrosis in the Pulmonary Milieu: A Disorder of Tissue Remodeling

Sato

Liu

Anraku

et al. 2008

American Journal of Transplantation

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Obliterative bronchiolitis (OB) is thought to be a form of chronic allograft rejection. However, immunosuppressive therapy is not effective once fibrosis has developed. We hypothesize that disordered tissue remodeling is a mechanism for the pathogenesis of OB. We examined allograft airway fibrosis in an intrapulmonary tracheal transplant model of OB. Allograft airways were completely obliterated at day 21 by fibrotic tissue; however, tissue remodeling continued thereafter, as demonstrated by the change of collagen deposition density, shift from type I to type III collagen, shift from fibroblasts to myofibroblasts and shift of expression profiles and activities of matrix metalloproteinases (MMPs). We then used a broad-spectrum MMP inhibitor, SC080, to attempt to manipulate tissue remodeling. Administration of the MMP inhibitor from day 0 to day 28 reduced airway obliteration, without inhibiting T-cell activation. MMP inhibition from day 14 to day 28 showed similar effects on airway obliteration. MMP inhibition from day 21 to day 35 did not reverse the airway obliteration, but significantly reduced the collagen deposition, type III collagen and myofibroblasts in the lumen. We conclude that tissue remodeling plays a critical role in the development and maintenance of fibrosis after transplantation.

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“…In order to investigate the angiogenic capacity of the pulmonary circulation, a model of fibrous airway obliteration (BO), 7 in which a trachea was implanted into the lung parenchyma, was utilized. Yellow-green microspheres were injected either into the pulmonary artery or aortic root.…”

Section: Fluorescent Microangiographymentioning

confidence: 99%

Fluorescent microangiography (FMA): an improved tool to visualize the pulmonary microvasculature

Dutly

Kugathasan

Trogadis

et al. 2006

Laboratory Investigation

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Visualization of the complex lung microvasculature and resolution of its three-dimensional architecture remains a difficult experimental challenge. We present a novel fluorescent microscopy technique to visualize both the normal and diseased pulmonary microvasculature. Physiologically relevant pulmonary perfusion conditions were applied using a low-viscosity perfusate infused under continuous airway ventilation. Intensely fluorescent polystyrene microspheres, confined to the vascular space, were imaged through confocal optical sectioning of 200 lm-thick lung sections. We applied this technique to rat lungs and the markedly enhanced depth of field in projected images allowed us to follow vascular branching patterns in both normal lungs and lungs from animals with experimentally induced pulmonary arterial hypertension. In addition, this method allowed complementary immunostaining and identification of cellular components surrounding the blood vessels. Fluorescent microangiography is a widely applicable and quantitative tool for the study of vascular changes in animal models of pulmonary disease. Keywords: confocal microscopy; microvasculature; pulmonary hypertensionThe circulatory bed of the lung is uniquely designed to accommodate the entire cardiac output and thus, remodeling of the microvasculature can play a dominant role in the progression of many pulmonary pathologies. For example, pulmonary hypertension (PH) is characterized by a marked increase in vascular resistance, likely resulting from a loss of pulmonary microvessels and/or from excessive smooth muscle hyperplasia in arterioles that normally display only incomplete muscularization. 1 Therefore, obtaining accurate three-dimensional (3D) morphological information on arteriolar and capillary structure along with spatial colocalization of biological mediators will provide fundamental mechanistic insights into the pathogenesis of many pulmonary diseases. 2 Animal models have been instrumental in the study of pulmonary diseases and numerous rodent models have been established. First generation models have involved toxin-induced pulmonary injuries, 3,4 whereas second and third generation models have been developed with transgenic techniques in combination with environmental or other biological stimuli. 5,6 Such models are powerful tools, yet require specialized techniques in order to efficiently characterize the temporal and spatial patterns of pulmonary pathogenesis. Owing to the technical complexity of current techniques, indepth characterization of pulmonary microvasculature remodeling has not been performed in these rodent models. Consequently, in order for these models to reach their full potential, newer, readily available techniques need to be developed.In this study, we present a novel and reproducible method to evaluate the morphometry of the pulmonary circulation and colocalize relevant pathological changes in the surrounding tissue, on a microscopic

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A Novel Model for Post-Transplant Obliterative Airway Disease Reveals Angiogenesis from the Pulmonary Circulation

Cited by 37 publications

References 19 publications

The Role of Intrapulmonary De Novo Lymphoid Tissue in Obliterative Bronchiolitis after Lung Transplantation

The Role of Intrapulmonary De Novo Lymphoid Tissue in Obliterative Bronchiolitis after Lung Transplantation

Allograft Airway Fibrosis in the Pulmonary Milieu: A Disorder of Tissue Remodeling

Fluorescent microangiography (FMA): an improved tool to visualize the pulmonary microvasculature

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