RCMV increases intimal hyperplasia by inducing inflammation, MCP-1 expression and recruitment of adventitial cells to intima

Cytomegalovirus (CMV) infection has been associated with accelerated transplant vasculopathy. In this study, we assessed the effects of acute rat CMV (RCMV) infection on vessel remodeling in transplant vasculopathy, focusing on allograft morphology, inflammation and contribution of adventitial cells to intimal hyperplasia.Infrarenal aorta was locally infected with RCMV and transplanted from female F344 rats to male Lewis rats. Graft samples were collected 2 and 8 weeks after transplantation and analyzed for intimal hyperplasia, collagen degradation and inflammation. Transplantation of aorta followed by transplantation of RCMV infected and labeled isogenic adventitia were performed to study migration of adventitial cells towards the intima.Intimal hyperplasia was increased threefold in infected allografts. RCMV induced apoptosis in the media, expression of matrix metalloproteinase 2, and decreased collagen deposits. Macrophage infiltration was increased in the infected allografts and resulted in increased production of MCP-1. RCMV-infected macrophages were observed in the adventitia and intima. Cells derived from infected adventitia migrated towards the intima of the allograft.RCMV enhances infiltration of macrophages to the allografts, and thereby increases MCP-1 production and inflammation, followed by recruitment of adventitial cells to the intima and accelerated intimal hyperplasia

Host-Derived Smooth Muscle Cells Accumulate in Cardiac Allografts: Role of Inflammation and Monocyte Chemoattractant Protein 1

Transplant arteriosclerosis is characterized by inflammation and intimal thickening caused by accumulation of smooth muscle cells (SMCs) both from donor and recipient. We assessed the relationship between clinical factors and the presence of host-derived SMCs in 124 myocardial biopsies from 26 consecutive patients who received hearts from opposite-sex donors. Clinical and demographic information was obtained from the patients' medical records. Host-derived SMCs accounted for 3.35±2.3% of cells in arterioles (range, 0.08–12.51%). As shown by linear regression analysis, an increased number of SMCs was associated with rejection grade (mean, 1.41±1.03, p = 0.034) and the number of leukocytes (19.1±12.7 per 20 high-power fields, p = 0.01). The accumulation of host-derived SMCs was associated with an increased number of leukocytes in the allografts. In vitro, monocyte chemoattractant protein 1 (MCP-1) released from leukocytes was crucial for SMC migration. After heart allotransplantion, mice treated with MCP-1-specific antibodies had significantly fewer host-derived SMCs in the grafts than mice treated with isotypic antibody controls. We conclude that the number of host-derived SMCs in human cardiac allografts is associated with the rejection grade and that MCP-1 may play pivotal role in recruiting host-derived SMCs into cardiac allografts

Immnunohistochemical analysis of mouse cardiac allograft treated anti-MCP-1 or isotypic control.

<p>(A and B) Distribution of CD45⁺ leukocytes in cardiac allografts treated with anti-MCP-1 antibodies (A) and control isotypic antibodies (B). (C and D) Distribution of CD68⁺ leukocytes in cardiac allografts treated with antibodies against MCP-1 antibodies (C) and control isotypic antibodies (D). Blue, positive signal; red, nuclear counterstaining. (E) Numbers of αSMA-positive vessels and leukocytes expressing CD45, CD68, CD3, CD4, and CD8. *p<0.05.</p

Immunohistochemical characteristic of human cardiac allografts.

<p>(A) Immunohistochemistry for αSMA (blue) followed by in situ hybridization for chromosome Y (green) and nuclear counterstaining (red). (B–K) Immunohistochemical staining of human cardiac allografts for αSMA (B), vWF (C), CD45 (D), CD14 (E), IgG (F), IgM (G), CD4 (H), and CD8 (I). Arrows indicate positive cells and staining. (J and K) Scatter plots showing the association between the number of αSMA-positive cells in the vessel and patient age (J) CD45+ cells (K).</p

Logistic linear regression analysis of the association between predicting factors and accumulation of vascular progenitor cells in arterioles.

<p>Logistic linear regression analysis of the association between predicting factors and accumulation of vascular progenitor cells in arterioles.</p

Baseline characteristic of the patients^*.

*<p>Values are numbers of patients, unless indicated otherwise.</p

Migration of SMCs <i>in vitro</i>.

<p>SMC migration was induced by leukocyte-conditioned medium and MCP-1 and inhibited by neutralizing antibodies against MCP-1 and CCR2. *p<0.05.</p