Lung rejection
Pirfenidone Inhibits Obliterative Airway Disease in Mouse Tracheal Allografts

https://doi.org/10.1016/j.healun.2004.11.002Get rights and content

Background

Obliterative bronchiolitis (OB) is the histologic correlate of chronic airway rejection, which remains the most significant cause of death in long-term survivors of lung transplantation. Using an established murine heterotopic tracheal transplant model of chronic airway rejection, the effects of the oral anti-fibrotic agent pirfenidone on development of the OB-like lesion were evaluated.

Methods

Tracheas from BALB/c mice were implanted into the sub-cutaneous tissue of C57BL/6 mice, and the allografts were evaluated morphologically for airway rejection changes and immunohistochemically for transforming growth factor (TGF)-β at 16 or 28 days after transplantation. In addition, the potential additive effects of pirfenidone in combination with 2 immunosuppressive agents, cyclosporine or rapamycin, was evaluated.

Results

Compared with untreated controls, pirfenidone-fed mice showed less epithelial cell injury and luminal granulation tissue and fibrosis. Plasma TGF-β levels and local TGF-β expression based on immunohistochemistry were decreased in the pirfenidone-treated animals. Pirfenidone given on Day 9 or 16 post-transplant through Day 28 resulted in no significant improvement compared with controls. There was no significant additive effect of pirfenidone in combination with cyclosporine, whereas pirfenidone plus rapamycin demonstrated additive protection against the development of the obstructive airway lesion.

Conclusions

In aggregate, these results show that the anti-fibrotic agent pirfenidone inhibits the development of the OB-like lesion in this mouse model of human chronic airway rejection, and that these effects may be mediated by TGF-β. The results also suggest that pirfenidone may be worthy of investigation in human lung transplant recipients at high risk of developing OB.

Section snippets

Heterotopic Murine Animal Model

Sub-cutaneous tracheal transplantation was performed under general anesthesia in accordance with guidelines of the University of Florida Institutional Animal Care and Use Committee. All animals received humane care in compliance with The Principles of Laboratory Animal Care formulated by the National Society for Medical Research and the Guide for the Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources. BALB/c and C57BL/6 8-week-old female mice were used as donors

Results

Rejection-associated histologic changes for this mouse trachea transplant model12 were evident to varying degrees in each group. The severity of these changes differed significantly between the untreated mice and mice treated with pirfenidone starting 1 day before transplant to time of killing, Day 16 or 28 post-transplant (Figure 1). Isografts demonstrated normal respiratory epithelium and no intraluminal granulation tissue. The majority of the allografts from the untreated animals showed a

Discussion

Transplantation-related chronic airway rejection, manifested as the histologic lesion of OB, is a fibroproliferative disorder and a major limitation to the long-term survival of lung transplant recipients.1, 2, 3 OB represents the result of immune-mediated, and possibly non–immune-mediated, small airway injury and is characterized histologically by fibrous luminal obliteration of small airways, lymphocytic airway infiltrates and respiratory epithelial sloughing and necrosis. Current medical

References (34)

Cited by (34)

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    2019, Journal of Thoracic and Cardiovascular Surgery
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    Furthermore, pirfenidone decreased the number of apoptotic cells and proinflammatory cytokines in lung tissue. There have been some reports that pirfenidone suppresses fibrosis caused by rejection and inflammatory change in the chronic or subacute phase after lung transplantation,16-18 but there are no reports of the acute phase, especially within 72 hours, after transplantation. In this study, it was shown that administration of pirfenidone was effective before the onset of lung IRI, which is the main cause of acute lung injury after lung transplantation.

  • Update in Chronic Lung Allograft Dysfunction

    2017, Clinics in Chest Medicine
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    There are also data suggesting there may be a role for pirfenidone in lung transplant recipients. Preclinical data in animal models of transplant demonstrate a decrease in inflammation and fibrosis in animals treated with pirfenidone.139,140 There is 1 case report describing stabilization of lung function after use of pirfenidone in a patient with BOS.141

  • Pirfenidone ameliorates murine chronic GVHD through inhibition of macrophage infiltration and TGF-β production

    2017, Blood
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    Pirfenidone (5-methyl-1-phenyl-2- (1H)-pyridone) is a small molecule known for its antifibrosis properties. In bleomycin-induced lung injury and lung allotransplant models, pirfenidone decreased hydroxyproline, fibrosis, procollagen I and II, platelet-derived growth factor isoforms, transforming growth factor-beta (TGF-β), fibroblast growth factor, and IL-13.13-21 Moreover, pirfenidone increases scavenger of reactive oxygen species22 and decreases inflammation pathways that initiate fibrosis, such as nitrites, IL-623 and tumor necrosis factor-α.24

  • Hepatocyte growth factor enhances the inflammation-alleviating effect of umbilical cord-derived mesenchymal stromal cells in a bronchiolitis obliterans model

    2016, Cytotherapy
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    The histopathologic features of this experimental BO model largely reproduce the changes in human recipients who develop BO after allogeneic HSCT. By using this model, investigations have been performed to testify various new strategies for the treatment of BO, such as interleukin (IL)-10 (DNAX Corp.)[7], Tacrolimus (Astellas Pharma) [4] and Pirfenidone (Marnac, Inc., Dallas, TX) [8]. Mesenchymal stromal cells (MSCs) are adult stem cells characterized by their immune-regulation properties.

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Supported by a grant from the American Lung Association of Florida (to G.V.).

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