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The growth of neointima and neointimal smooth muscle cells in baboon polytetrafluoroethylene grafts is regulated by blood flow. Because neointimal smooth muscle cells express both platelet-derived growth factor receptor-alpha and -beta (PDGFR-alpha and -beta), we designed this study to test the hypothesis that inhibiting either PDGFR-alpha or PDGFR-beta with a specific mouse/human chimeric antibody will modulate flow-induced neointimal formation. Bilateral aortoiliac grafts and distal femoral arteriovenous fistulae were placed in 17 baboons. After 8 weeks, 1 arteriovenous fistulae was ligated, normalizing flow through the ipsilateral graft while maintaining high flow in the contralateral graft. The experimental groups received a blocking antibody to PDGFR-alpha (Ab-PDGFR-alpha; 10 mg/kg; n=5) or PDGFR-beta (Ab-PDGFR-beta; 10 mg/kg; n=6) by pulsed intravenous administration 30 minutes before ligation and at 4, 8, 15, and 22 days after ligation. Controls received carrier medium alone (n=8). Serum antibody concentrations were followed. Grafts were harvested after 28 days and analyzed by videomorphometry. Serum Ab-PDGFR-alpha concentrations fell rapidly after day 7 to 0, whereas serum Ab-PDGFR-beta concentrations were maintained at the target levels (>50 microg/mL). Compared with controls (3.7+/-0.3), the ratio of the intimal areas (normalized flow/high flow) was significantly reduced in Ab-PDGFR-beta (1.2+/-0.2, P<0.01) but not in Ab-PDGFR-alpha (2.2+/-0.4). Ab-PDGFR-alpha decreased significantly the overall smooth muscle cell nuclear density of the neointima (P<0.01) compared with either the control or Ab-PDGFR-beta treated groups. PDGFR-beta is necessary for flow-induced neointimal formation in prosthetic grafts. Targeting PDGFR-beta may be an effective pharmacological strategy for suppressing graft neointimal development.

To understand the role of interleukin-1 (IL-1) as a mediator of the sepsis-induced skeletal muscle catabolism, we investigated the effects of a specific IL-1 receptor antagonist (IL-1ra) on skeletal muscle protein metabolism in a rodent model of chronic abdominal sepsis. A constant infusion of IL-1ra (2 mg.kg-1.h-1) or saline was begun immediately after the induction of sepsis and continued for 5 days. The effect of IL-1ra on protein metabolism was examined in individual muscles (gastrocnemius, soleus, heart) containing different fiber types. Infusion of IL-1ra in control animals did not alter protein metabolism in any of the muscles examined. Muscle weight, protein content, and the rate of protein synthesis in gastrocnemius were reduced by sepsis, whereas none of these parameters were affected in soleus or heart. Infusion of IL-1ra prevented the sepsis-induced loss of muscle protein and inhibition of protein synthesis in gastrocnemius but was without effect in soleus or heart. IL-1ra infusion restored translational efficiency in the gastrocnemius of septic rats and was without effect on the RNA content. These results provide evidence for a role of IL-1 as a mediator of the sepsis-induced abnormalities in skeletal muscle protein metabolism.