Abstract 1680: Mechanisms Underlying Interleukin-10-Mediated Anti-Remodeling Effects on Monocrotaline-Induced Pulmonary Arterial Hypertension
Introduction: Inflammatory and proliferative responses are important therapeutic targets for vascular remodeling in pulmonary arterial hypertension (PAH). We reported that adeno-associated virus (AAV) vector-mediated expression of interleukin (IL)-10, a pleiotropic anti-inflammatory cytokine, prevented progression of monocrotaline (MCT)-induced PAH. Hemeoxygenase-1 (HO-1) plays a crucial role in anti-inflammatory signals triggered by IL-10. Here we investigated the anti-inflammatory and anti-proliferative effects of IL-10 on vascular remodeling, and seeked to determine the role of HO-1 in rat MCT-PAH.
Method: Three-week-old male Wistar rats were intramuscularly injected with 6x1010 genome copies of AAV type1-based vector expressing rat IL-10 (AAV1-IL-10, n=5) or control vector (AAV1-eGFP, n=5), followed by MCT injection 4 weeks later. Four weeks after MCT injection, we performed immunohistochemical analysis of the pulmonary vessels using anti-ED1 or anti-PCNA antibody. We also estimated the levels of IL-6, active TGF-β1, and HO-1 in the lung homogenates using ELISA.
Results: Eight weeks after vector injection, the IL-10-transduced rats exhibited a significant decrease in % medial thickness of the peripheral pulmonary arteries, the number of ED1-positive perivascular macrophages, and the percentages of PCNA-positive smooth muscle cells in the medial wall compared to those of the eGFP-tranduced controls (12.9 ± 0.3 vs. 21.4 ± 0.4%, p<0.01; 713.8 ± 41.9 vs. 1263.4 ± 71.2 cells/mm2, p<0.001; 6.5 ± 1.2 vs. 12.3 ± 4.2 %, p<0.01, respectively). IL-10 also decreased pulmonary tissue levels of IL-6 and TGF-β1 which correlated with the degree of % medial thickness (r =0.80, p<0.01; r =0.84, p<0.01, respectively). In addition, IL-10 increased pulmonary tissue levels of HO-1 which negatively correlated with the IL-6 levels (r =−0.85, p<0.001).
Conclusion: Induction of HO-1 as well as reduced expression of IL-6 and TGF-β1 would be involved in IL-10-mediated anti-remodeling effects on MCT-PAH. Further studies on these mechanisms would provide new insights into anti-inflammation therapy of PAH.