NF-κB inhibitor improves pulmonary vascular remodeling by reversing LPS-induced down-regulation of BMPRII / 生理学报

The occurrence and development of pulmonary arterial hypertension (PAH) is closely related to the genetic mutation of bone morphogenetic protein receptor type II (BMPRII) encoding gene and the inflammatory response mediated by nuclear factor κB (NF-κB) pathway. This paper was aimed to investigate the effect of NF-κB pathway inhibitors on lipopolysaccharide (LPS)-induced pulmonary artery endothelial cell injury. Human pulmonary artery endothelial cells were treated with 1 μg/mL of LPS. The expression levels of BMPRII and interleukin-8 (IL-8) were detected by Western blot and qPCR. The rat PAH model was established by intraperitoneal (i.p.) injection of monocrotaline (MCT). The expression levels of BMPRII and IL-8 in pulmonary artery endothelial cells were detected by immunofluorescence staining. Cardiac hemodynamic changes and pulmonary vascular remodeling were detected in the MCT-PAH model rats. The results showed that LPS caused down-regulation of BMPRII expression and up-regulation of IL-8 expression in human pulmonary artery endothelial cells. NF-κB inhibitor BAY11-7082 (10 μmol/L) reversed the effect of LPS. In the pulmonary artery endothelial cells of MCT-PAH model, BMPRII expression was down-regulated, IL-8 expression was up-regulated, weight ratio of right ventricle to left ventricle plus septum [RV/(LV+S)] and right ventricular systolic pressure (RVSP) were significantly increased, cardiac output (CO) and tricuspid annular plane systolic excursion (TAPSE) were significantly reduced, and pulmonary vessel wall was significantly thickened. BAY11-7082 (5 mg/kg, i.p., 21 consecutive days) reversed the above changes in the MCT-PAH model rats. These results suggest that LPS down-regulates the expression level of BMPRII through NF-κB signaling pathway, promoting the occurrence and development of PAH. Therefore, the NF-κB pathway can be used as a potential therapeutic target for PAH.

Efficacy of internalized RGD-modified echogenic liposomes in diagnosis and treatment in a mouse model of rheumatoid arthritis / 南方医科大学学报

<p><b>OBJECTIVE</b>To prepare internalized RGD (iRGD) modified echogenic liposomes containing methotrexate (MTX) and indocyanine green (ICG) (iRGD MTX ICG ELIP) and evaluate its targeting efficiency and inhibitory effect combined with ultrasound on synovial cells.</p><p><b>METHODS</b>iRGD MTX ICG ELIP was prepared by the thin film rehydration and freeze-lyophilization method and its general characteristics and acoustic responsiveness were assessed. The targeting effect of the prepared liposome was observed by assessing its cell uptake in vitro. In a mouse model of rheumatiod arthritis, the targeting effect of the prepared liposome was determined by detecting the fluorescence intensity of the drug in arthrosis. The inhibitory effect of iRGD MTX ICG ELIP combined with ultrasound on synovial MH7A cells in vitro were investigated using CCK8 test.</p><p><b>RESULTS</b>The average diameter and zeta potential of iRGD MTX ICG ELIP was 134.4∓17.61 nm and 10.07∓4.28 mV, and the entrapment efficiency of MTX and ICG was (62.56∓0.77)% and (95.13∓0.82)%, respectively. With ultrasound exposure, the release of MTX and ICG from iRGD MTX ICG ELIP increased with the ultrasound intensity and with the exposure time. In HUVECs, the uptake efficiency of iRGD MTX ICG ELIP was 1.89 times higher than that of non targeted MTX ICG ELIP (P<0.05). In vivo imaging of mouse joint with rheumatiod arthritis showed that the fluorescence intensity of iRGD MTX ICG ELIP was significantly stronger than that of the non targeted liposome. CCK8 assay showed that iRGD MTX ICG ELIP combined with ultrasound resulted in a survival rate of MH7A cells of (32.49∓3.04)%, significantly lower than the rate of cells treated with iRGD MTX ICG ELIP but without ultrasound (P<0.05).</p><p><b>CONCLUSIONS</b>iRGD MTX ICG ELIP has a suitable particle size and can effectively target HUVECs and the joints with rheumatiod arthritis. With a good drug entrapment efficiency and acoustic responsiveness, the drug loaded liposome shows enhanced inhibitory effect on MH7A cells combined with ultrasound in vitro, suggesting its potential in the treatment of rheumatoid arthritis.</p>