Reduction of recipient macrophages by gadolinium chloride prevents development of obliterative airway disease in a rat model of heterotopic tracheal transplantation.

Abstract

Recent studies have shown the possible role of growth factors and the involvement of macrophages as a source of them in the pathogenesis of bronchiolitis obliterans (BO) after lung transplantation. The authors intended to determine whether depletion of recipient macrophages by gadolinium chloride (GdCl3) resulted in decreased obliterative airway disease (OAD) in a rat model of heterotopic tracheal transplantation. A tracheal segment of donor rats (Brown Norway) was transplanted into a subcutaneous pouch of fully major histocompatibility complex-incompatible recipient rats (Lewis). Recipients were injected intravenously with 80 mg/kg of GdCl3.6H2O or saline on days 0, 7, and 14 posttransplant. Allografts were harvested on days 7, 14, 17, and 21 and the degree of OAD resulting from fibroproliferative tissue was pathologically scored on a scale of 0 to 4. A portion of allografts was submitted to reverse-transcriptase polymerase chain reaction analysis to examine mRNA expression for platelet-derived growth factor (PDGF), basic fibroblast growth factor, and transforming growth factor-beta1. Immunohistochemical studies confirmed reduction in the number of ED2+ macrophages in tracheal allografts by GdCl3 injection. GdCl3 treatment significantly decreased OAD of allografts, with the histologic score of 1.4+/-0.3 in the treated animals compared with 3.0+/-0.5 in the controls (mean+/-SE, P=0.02) at day 21 posttransplant, and this was accompanied by decreased PDGF-A and PDGF-B gene expression in the GdCl3 group at day 17 posttransplant. Macrophage reduction by GdCl3 resulted in significantly decreased OAD development and reduced PDGF mRNA expression in allografts. This suggests a potential effectiveness of therapies targeting recipient macrophages in preventing BO after lung transplantation.