Pentraxin 3 deficiency enhances features of chronic rejection in a mouse orthotopic lung transplantation model.

Mitsuteru Yoshida,Junichi Sugihara,David M Hwang,Christina Lua,Hisashi Oishi,Zehong Guana,Tereza Martinu,Trevor D Mckee,Mingyao Liu,Xiaohui Bai,Hiromitsu Takizawa,Shaf Keshavjee,Stephen Juvet,Hae-Ra Cho,Marcelo Cypel

doi:10.18632/oncotarget.23902

Mitsuteru Yoshida, Junichi Sugihara + Show 13 more

Open Access

https://doi.org/10.18632/oncotarget.23902

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Abstract

Chronic lung allograft dysfunction (CLAD) is a serious complication after lung transplantation and thought to represent chronic rejection. Increased expression of Pentraxin 3 (PTX3), an acute phase protein, was associated with worse outcome in lung transplant patients. To determine the role of recipient PTX3 in development of chronic rejection, we used a minor alloantigen-mismatched murine orthotopic single lung transplant model. Male C57BL/10 mice were used as donors. Male PTX3 knockout (KO) mice and their wild type (WT) littermates on 129/SvEv/C57BL6/J background were used as recipients. In KO recipients, 7/13 grafted lungs were consolidated without volume recovery on CT scan, while only 2/9 WT mice showed similar graft consolidation. For grafts where lung volume could be reliably analyzed by CT scan, the lung volume recovery was significantly reduced in KO mice compared to WT. Interstitial inflammation, parenchymal fibrosis and bronchiolitis obliterans scores were significantly higher in KO mice. Presence of myofibroblasts and lymphoid aggregation was significantly enhanced in the grafts of PTX3 KO recipients. Recipient PTX3 deficiency enhanced chronic rejection-like lesions by promoting a fibrotic process in the airways and lung parenchyma. The underlying mechanisms and potential protective role of exogenous PTX3 as a therapy should be further explored.

Highlights

Chronic lung allograft dysfunction (CLAD), with an incidence of approximately 50% at 5 years after lung transplantation, is the biggest impediment to longterm survival [1]
In the present study, using Pentraxin 3 (PTX3) KO mice, we demonstrate that the presence of PTX3 in lung transplant recipients plays a protective role against the development of chronic rejection-like pathology by reducing fibrotic lesions in small airways and lung parenchyma, which may be mediated through the inhibition of lymphocyte infiltration and aggregation in the lung
The development of a mouse lung transplant model [26, 29] is a significant breakthrough in lung transplant research, which allows the use of transgenic mice for mechanistic studies

Summary

Introduction

Chronic lung allograft dysfunction (CLAD), with an incidence of approximately 50% at 5 years after lung transplantation, is the biggest impediment to longterm survival [1]. Through allogeneic immune response-induced lymphatic infiltration and lymphoid tissue formation in the lung grafts, is considered the most important contributing factor [3,4,5,6]. Increasing evidence suggests that inflammation mediated by innate immune responses during ischemiareperfusion in the lung allograft [7, 8] and activation of autoimmunity [9] are involved in the pathogenesis of CLAD. Primary graft dysfunction (PGD), acute lung injury during the first 72 h after lung transplant, is associated with the development of CLAD [10,11,12]. Identification of biomarkers of PGD may help to predict, and possibly prevent, PGD as well as CLAD

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