Elsevier

Transplantation Proceedings

Volume 42, Issue 7, September 2010, Pages 2763-2766
Transplantation Proceedings

Bone marrow/stem cell transplantation
Eotaxin/CCL11 Levels Correlate With Myocardial Fibrosis and Mast Cell Density in Native and Transplanted Rat Hearts

https://doi.org/10.1016/j.transproceed.2010.05.152Get rights and content

Abstract

Introduction

Myocardial fibrosis contributes to hemodynamic and cardiac functional alterations commonly observed posttransplantation. Cardiac mast cells (MC) have been linked to fibrosis in posttransplantation hearts. Eotaxin, which has been shown to be involved in fibrogenesis, has been demonstrated to be increased in production in cardiac macrophages. The aim of our study was to correlate myocardial fibrosis during heart transplant rejection in the rat with eotaxin/chemokine [c-c motif] ligand 11 (CCL11) expression, and with various subtypes of infiltrating cardiac MC, namely connective-type MC (CTMC) and mucosa-type MC (MMC).

Methods

We used tissues from 2 previous studies of ongoing acute rejection in allogeneic Brown-Norway to Lewis rat and an isogeneic Brown-Norway to Brown-Norway heterotopic heart transplantation models under cyclosporin/prednisolone immunosuppression. Collagen fibrils were stained with Masson's trichrome with myocardial fibrosis expressed as percent fibrotic area per total section area. Eotaxin/CCL11 previously measured in heart tissue using enzyme-linked immunosorbent assay (ELISA) was correlated with the extent of myocardial fibrosis. We compared values from native hearts (n = 4) as well as transplants on days 5, 16, and 28 (n = 4 in each group).

Results

The area of myocardial fibrosis was significantly increased in the allogeneic compared with the isogeneic group at day 16 (38% vs 21%) and at day 28 (49% vs 22%) after transplantation. Myocardial fibrosis correlated significantly with eotaxin/CCL11 concentrations and the density of MMC, but not with CTMC in heart tissue.

Conclusions

Eotaxin-triggered MC infiltration of the heart may contribute to myocardial fibrosis after transplantation. Targeting eotaxin/CCL11 with monoclonal antibodies, such as bertilimumab, could reduce MC infiltration, possibly resulting in decreased myocardial fibrosis and improved contractile function after heart transplantation.

Section snippets

Materials and Methods

For this study we used paraformaldhyde-fixed and paraffin-embedded rat heart tissues from previous work.15, 23 To determine myocardial fibrosis, collagen fibrils were stained with Masson's trichrome reagent. For co-localization of RMCP-1 and -2, we performed immunofluorescence double staining using a polyclonal sheep antibody to RMCP-1 (0.625 μg/mL) and a monoclonal mouse antibody to RMCP-2 (1.25 μg/mL; Moredun Scientific Ltd., Midlothian, Scotland, United Kingdom) followed by a mixture of

Results

The area of myocardial fibrosis was significantly increased in the allogeneic compared with the isogeneic group on day 16 (38% vs 21%) and on day 28 (49% vs 22%) after transplantation (Fig 1A). The isogeneic transplants showed increased fibrosis compared with native hearts (4%), which remained constant (between 22% and 24%) over all time points. All hearts were beating at the time of harvest.

A significant correlation was observed between the levels of myocardial fibrosis and eotaxin/CCL11

Discussion

Compared with isografts at 28 days after transplantation, myocardial fibrosis significantly increases in rat heart allografts during ongoing acute rejection. This change correlates with eotaxin/CCL11 concentrations and the density of MMC, but not CTMC in heart tissue. Myocardial fibrosis and histological changes in the transplanted heart, as well described in long-term surviving patients, are likely to affect short-term and long-term cardiac function. The fibrotic response occurs as early as 1

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    This work was supported by the Katharina Huber-Steiner Foundation.

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