ISCHEMIA INDUCED MYOCARDIAL INJURY IS ACCENTUATED IN TRANSGENIC MICE OVEREXPRESSING FGF-2 AND IS LINKED TO A T-CELL DEPENDENT PROCESS.

Abstract

118 Recent studies of chronic rejection have highlighted the importance of immune and non-immune mediated injury in activating endothelial programs (i.e. growth factors) that in turn support tissue proliferation and fibrosis. Fibroblast growth factor-2 (FGF-2) stimulates proliferation of endothelial cells, vascular smooth muscle cells and fibroblasts. The current study investigated whether increased FGF-2 levels in the heart induced intra-myocardial fibrosis after non-immune injury. Ischemic myocardial injury was induced in (a) CD-1 transgenic (TG) mice, expressing the 18kD isoform of rat FGF-2, under the control of the Rous sarcoma virus promotor, solely in cardiac muscle, and (b) control CD-1 (non-TG) mice by i.p. injection of isoproterenol (IsP) (80 or 160 mg/kg) or vehicle. Histological assessment was at 24h and 4 days post-injury. Histopathological evaluation yielded higher pathology scores (tissue damage and fibrosis) in the TG as compared to the non-TG counterpart, in response to IsP. At 24h, TG hearts displayed significantly more cellular infiltration than non-TG hearts, which correlated with higher pathology scores on day 4. At 24h immunohistology showed the presence of PMNs, CD4+ and CD8+ T-cells, and macrophages. Infiltrating cells were PCNA+, and CD4+ T-cells costained for FGFR1, a finding consistent with the notion that these recruited cells are expanded by FGF-2 released from injured cardiac muscle. To determine if the enhanced pathology scores (i.e. fibrosis) in the presence of FGF-2 were dependent on the cellular infiltration, the following experiments were carried out. First, no cardiac lesions were observed in SCID mice (lacking T and B cells) 24h after IsP injection. Secondly, the cardiac lesions on day 4 were significantly reduced and the pathology scores equalized in TG and non-TG treated daily from day −4 to +4 with oral cyclosporine (75mg/kg) or anti-CD3 (50ug i.p.). The current model demonstrates that tissue damage in response to non-immune injury is enhanced in the presence of excess FGF-2 and that this effect appears to be via stimulation of an immune response (i.e. CD3+ cells). FGF-2 may be a key element that can intensify an immune response at the site of tissue injury independent of the cause of the injury (alloimmune vs non-immune).