Pirfenidone Inhibits Obliterative Airway Disease in Mouse Tracheal Allografts

Zhou, Hailan; Latham, Christopher; Zander, Dani S.; Margolin, Solomon B.; Visner, Gary

doi:10.1016/j.healun.2004.11.002

Cited by 34 publications

(32 citation statements)

References 30 publications

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“…ZHOU et al [46] demonstrated a pirfenidone treatment effect in a murine heterotopic tracheal allograft model (table 1). In this model, subcutaneous tracheal transplantation from a BALB/c donor to a C57BL/6 recipient results in rejection of the transplanted tissue with loss of respiratory epithelium, inflammatory cell infiltration, inflammation, intraluminal granulation and fibrosis with eventual occlusion of the airway [46].…”

Section: Transplant-induced Pulmonary Fibrosismentioning

confidence: 99%

“…Chronic lung rejection, which is manifested clinically as obliterative bronchiolitis, is a chronic fibrotic disorder that is a significant cause of death in long-term survivors of lung transplantation. In preclinical lung allograft models, fibrosis develops following injury from rejection and/ or infection, replacing lung parenchyma with fibrotic tissue and resulting in pulmonary dysfunction and airway obstruction [45,46].…”

Section: Transplant-induced Pulmonary Fibrosismentioning

confidence: 99%

“…In this model, subcutaneous tracheal transplantation from a BALB/c donor to a C57BL/6 recipient results in rejection of the transplanted tissue with loss of respiratory epithelium, inflammatory cell infiltration, inflammation, intraluminal granulation and fibrosis with eventual occlusion of the airway [46]. The fibrotic components develop more slowly and were prevalent at day 28.…”

Section: Transplant-induced Pulmonary Fibrosismentioning

confidence: 99%

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Antifibrotic activities of pirfenidone in animal models

Schaefer¹,

Ruhrmund²,

Lin³

et al. 2011

Eur Respir Rev

390

287

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Pirfenidone is an orally active small molecule that has recently been evaluated in large clinical trials for the treatment of idiopathic pulmonary fibrosis, a fatal disease in which the uncontrolled deposition of extracellular matrix leads to progressive loss of lung function. This review describes the activity of pirfenidone in several well-characterised animal models of fibrosis in the lung, liver, heart and kidney. In these studies, treatment-related reductions in fibrosis are associated with modulation of cytokines and growth factors, with the most commonly reported effect being reduction of transforming growth factor-b. The consistent antifibrotic activity of pirfenidone in a broad array of animal models provides a strong preclinical rationale for the clinical characterisation of pirfenidone in pulmonary fibrosis and, potentially, other conditions with a significant fibrotic component. KEYWORDS: Animal model, antifibrotic, fibrosis, idiopathic pulmonary fibrosis, pirfenidone F ibrosis, the dysregulated deposition of extracellular matrix (ECM) with progressive destruction of normal tissue, is a primary or contributing factor in chronic disease states in several organs. Pulmonary fibrosis is associated with numerous diffuse parenchymal lung diseases, of which the most common are idiopathic pulmonary fibrosis (IPF) and sarcoidosis [1]. Cardiac fibrosis is associated with chronic heart failure, atrial fibrillation, and cardiac remodelling following acute myocardial infarction [2,3]. Renal fibrosis is associated with multiple forms of chronic kidney disease and correlates with impairment of kidney function [4,5]. Hepatic fibrosis is associated with chronic hepatitis B and C viral infections and nonalcoholic steatohepatitis [6]. Each of these conditions represents a significant unmet medical need, warranting significant research and clinical study into treatment for fibrotic disease.Pirfenidone (Esbriet1, Pirespa1) is an orally active small molecule comprising a modified phenyl pyridone ( fig. 1). The compound exhibits well documented antifibrotic and anti-inflammatory activities in a variety of animal and cellbased models, although its molecular target has not been elucidated. Pirfenidone was initially identified as having anti-inflammatory activity in animal models and evaluated for use as an antiinflammatory drug [7,8]. However, the unexpected identification of antifibrotic effects in animals treated with pirfenidone redefined the interest in the compound [9]. Subsequently, pirfenidone has been shown to attenuate fibrosis in numerous animal models, including fibrosis of the lung, liver, heart and kidney.The most extensive clinical studies of pirfenidone are for treatment of IPF, a chronic interstitial lung disease characterised by the unregulated deposition of ECM leading to the unremitting destruction of normal lung. Patients diagnosed with IPF typically experience progressive pulmonary insufficiency, and most die of respiratory failure. The estimated median survival upon diagnosis is approximately ...

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Section: Transplant-induced Pulmonary Fibrosismentioning

confidence: 99%

Section: Transplant-induced Pulmonary Fibrosismentioning

confidence: 99%

Section: Transplant-induced Pulmonary Fibrosismentioning

confidence: 99%

See 1 more Smart Citation

Antifibrotic activities of pirfenidone in animal models

Schaefer¹,

Ruhrmund²,

Lin³

et al. 2011

Eur Respir Rev

390

287

View full text Add to dashboard Cite

show abstract

“…Previous studies have demonstrated that OAD pathology in allografts is TGF-b 1 -dependent (16,34,35). To determine if components of the TGF-b 1 fibrogenic pathway are increased in alcohol-mediated exacerbation of OAD, 21-day allografts from control and alcohol-fed SD donors were immunostained for TGF-b 1 .…”

Section: Allografts From Alcohol-fed Donors Display Increased Tgf-b 1mentioning

confidence: 99%

Alcohol Ingestion by Donors Amplifies Experimental Airway Disease after Heterotopic Transplantation

Mitchell¹,

Guidot²

2007

Am J Respir Crit Care Med

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“…11,[35][36][37] Recent work using IL-13-overexpressing mice suggests that IL-13 might exert its profibrotic effects via increasing both the transcription and the activation of TGF-␤1. 38 We studied the level of TGF-␤ expression in the heterotopic tracheal allografts placed into BALB/c (IL-13 ϩ/ϩ ) recipients or IL-13 Ϫ/Ϫ recipients.…”

Section: Effect Of Il-13 In the Production Of Tgf-␤1 In Heterotopic Tmentioning

confidence: 99%

Obligatory Role for Interleukin-13 in Obstructive Lesion Development in Airway Allografts

Lama

Harada

Badri

et al. 2006

The American Journal of Pathology

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The pathogenesis of bronchiolitis obliterans (BO), a common and devastating obliterative disorder of small airways following lung transplantation, remains poorly understood. Lesions are characterized in their early stages by lymphocyte influx that evolves into dense fibrotic infiltrates. Airway specimens taken from patients with histological BO revealed infiltrating myofibroblasts, which strongly expressed the signaling chain of the high affinity interleukin-13 (IL-13) receptor IL-13R␣1. Because IL-13 has proinflammatory and profibrotic actions, a contributory role for IL-13 in BO development was examined using murine models of orthotopic and heterotopic tracheal transplantation. Compared with airway isografts, allografts exhibited a significant increase in relative IL-13 mRNA and protein levels. Allogeneic tracheas transplanted into IL-13-deficient mice were protected from BO in both transplant models. Flow cytometric analysis of orthotopic transplant tissue digests revealed markedly fewer infiltrating mononuclear phagocytes and CD3؉ T lymphocytes in IL-13-deficient recipients. Furthermore, protection from luminal obliteration, collagen deposition, and myofibroblast infiltration was observed in heterotopic airways transplanted into the IL-13 ؊/؊ recipients. Transforming growth factor-␤1 expression was significantly decreased in tracheal allografts into IL-13 ؊/؊ recipients, compared to wild-type counterparts. These human and murine data implicate IL-13 as a critical effector cytokine driving cellular recruitment and subsequent fibrosis in clinical and ex- Bronchiolitis obliterans syndrome (BOS) is the major factor limiting quality of life as well as long-term survival after lung transplantation. BO is a histological diagnosis, characterized by fibrosis and obliteration of the small airways.1 BOS, the clinical correlate of BO, is diagnosed by irreversible deterioration of pulmonary function in the absence of other causes.2 BOS is seen in up to 60% of lung transplant recipients by 5 years after transplantation. There are currently no meaningful therapeutic interventions, providing a compelling rationale to understand fully BOS pathogenesis as this may lead to development of new therapeutic approaches.Data from human as well as animal studies suggest associations between inflammatory cells/mediators and BOS. Lymphocytic bronchitis is considered a risk factor for development of BOS in humans, 3 and lymphocytic infiltration precedes development of luminal obliteration in animal models of tracheal transplantation. 4,5 Similarly, several markers of inflammation (eg, neutrophilia,(6)(7)(8)7 and monocyte chemoattractant protein-1 (MCP-1/ CCL2) 8,9 ) are predictive of development of BO in humans. However, the failure of immunosuppressive therapy and anti-inflammatory agents to demonstrate efficacy in preventing or treating this disease has focused attention on BOS as a fibroproliferative response to airway epithelial injury. Evidence for this is provided by studies suggesting a role for transforming growth factor-␤ (TGF-...

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Pirfenidone Inhibits Obliterative Airway Disease in Mouse Tracheal Allografts

Cited by 34 publications

References 30 publications

Antifibrotic activities of pirfenidone in animal models

Antifibrotic activities of pirfenidone in animal models

Alcohol Ingestion by Donors Amplifies Experimental Airway Disease after Heterotopic Transplantation

Obligatory Role for Interleukin-13 in Obstructive Lesion Development in Airway Allografts

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