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AB0245 Recombinant human tumor necrosis factor-α receptorII:IGG FC fusion protein attenuates monocrotaline-induced pulmonary arterial hypertension via the suppression of TNF-α expression and NF-κB pathway in rats
  1. Q. Wang,
  2. M. Zhang
  1. Rheumatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China

Abstract

Background The pathogenesis and progression of PAH is still unknown. There is substantial evidence suggesting that inflammation plays a significant role in various types of human pulmonary arterial hypertension (PAH), which supported by finding of inflammation cells, such as macrophages and T and B lymphocytes, and dendritic cells around the plexiform lesions of PAH.TNF-α is a proinflammatory cytokine with potent modulatory effects on the pulmonary circulation. In animal studies, TNF-α was shown to increase pulmonary vascular reactivity, to decrease prostacyclin production in pulmonary artery smooth muscle cells, and to potentiate platelet-activating factor-induced pulmonary vasoconstriction. Overexpression of TNF-α resulted in severe pulmonary hypertension and emphysema in mice. Suppression of TNF production by high doses of pentoxyfylline reduces both systemic and pulmonary vascular resistance. These data provide strong experimental evidence that TNF-α plays an important role in pulmonary vascular physiology.

Objectives The aim of this study was to investigate the effect of Recombinant Human Tumor Necrosis Factor-α ReceptorII:IgG Fc Fusion Protein (rhTNFRFc), a TNF-α antagonist, on monocrotaline (MCT)-induced PAH in rats

Methods MCT-induced PAH was established in Sprague-Dawley rats. Rats were divided into saline-treated control, rhTNFRFc-treated (0.4mg/kg), MCT-exposed group (60mg/kg), MCT-exposed and rhTNFRFc-treated group (0.4mg/kg). 3 weeks post MCT, pulmonary hemodynamic parameters, right ventricular hypertrophy, morphometry and the expression of the inflammatory cytokines tumor necrosis factor-α (TNF-α) in lung tissues were assayed. The pulmonary protein levels of NF-κB (total and phosphorylated form) were analyzed by Western blot.

Results Mean pulmonary pressures (mPAP) was attenuated at 3weeks after MCT exposure (20.53±3.14 mm Hg) after rhTNFRFc treatment compared with MCT group (16.25±2.08mmHg, P<0.05 vs MCT). RV hypertrophy index (RVHI) showed a similar trend as mPAP,the values of RVHI were decreased (0.32±0.03,P<0.05 vs MCT) after rhTNFRFc treatment compared with MCT group (0.44±0.03). The elevated medial wall thickness induced by MCT could be diminished by rhTNFRFc treatment (37.74±4.97% for MCT, 27.63±5.48% for MCT+ rhTNFRFc). ELISA showed that the concentrations of TNF-α in lung tissue were markedly increased in the MCT group (4.22±0.65pg/ml). rhTNFRFc displayed a significant reduced TNF-α at week 3 (2.55±0.34pg/ml). At mRNA level, the markedly increased TNF-α mRNA was observed in lung from MCT treated group. It was noted that rhTNFRFc administration significantly decreased the TNF-α mRNA expression in MCT-treated animals. IHC studies were performed to identify the pattern of cellular expression of TNF-α in the lung. Positive staining for TNF-α was significantly higher in lungs and pulmonary artierals from MCT exposure group compared with control animals in IHC studies.Furthermore,rhTNFRFc showed markedly diminished expression of cytokine TNF-α via inhibition of the activity of NF-κB in rat lungs.

Conclusions These results demonstrated that rhTNFRFc attenuated the process of MCT-induced PAH through its anti-inflammatory property and rhTNFRFc might provide therapeutic benefit for PAH patients, although more studies are needed to define the appropriate treatment regimen.

Disclosure of Interest None Declared

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