sirolimus and Pulmonary-Embolism

An increasing number of studies have suggested that oxidative stress and inflammation play momentous roles in acute pulmonary embolism (APE). Honokiol, a bioactive biphenolic phytochemical substance, is known for its strong anti-oxidative and anti-inflammatory effects, and it served as an activator of sirtuin3 (SIRT3) in the present study. The purposes of the study were to explore the effects of honokiol on APE rats and investigate whether the function of honokiol is mediated by SIRT3 activation. In the study, the rats received a right femoral vein injection of dextran gel G-50 particles (12 mg/kg) to establish the APE model and were subsequently administered honokiol and/or a selective SIRT3 inhibitor 3-(1H-1,2,3-triazol-4-yl)pyridine (3-TYP; 5 mg/kg) intraperitoneally. The results showed that SIRT3 activation by honokiol attenuated the loss in lung function, ameliorated the inflammatory response and oxidative damage, and inhibited apoptosis in lung tissues of the rats with APE but that this was reversed by 3-TYP. In addition, we found that the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway might be activated by honokiol but restrained by 3-TYP. These results indicated that honokiol was capable of suppressing the adverse effects of APE and that this was diminished by SIRT3 suppression, implying that activation of SIRT3 might serve as a therapeutic method for APE.

Topics: AMP-Activated Protein Kinases; Animals; Anti-Inflammatory Agents; Hominidae; Mammals; Oxidative Stress; Pulmonary Embolism; Rats; Signal Transduction; Sirolimus; Sirtuin 3; TOR Serine-Threonine Kinases

A novel drug eluting retrievable vena cava filter (RVCF) with a heparin-modified poly(ε-caprolactone) (hPCL) coating containing rapamycin was prepared by electrospraying. The in vitro drug release pattern showed that the encapsulated rapamycin in the coating can be sustainably released within one month, whereas activated partial thromboplastin time (APTT) and in vitro cell culture showed that the drug eluting RVCF can effectively extend blood clotting time and inhibit smooth muscle cell (SMC) and endothelial cell (EC) proliferation, respectively. The as-prepared drug eluting RVCF and corresponding commercial RVCF were implanted into the vena cava of sheep. The retrieval operation at a predetermined time point showed that the drug eluting RVCF had a much higher retrieval rate than the commercial RVCF. Comprehensive investigations, including histological, immunohistological and immunofluorescence analyses, on explanted veins were carried out. The results demonstrated that the as-prepared RVCF possessed excellent antihyperplasia properties in vivo, significantly improving the retrieval rate and extending the in vivo dwelling time in sheep. Consequently, the drug eluting RVCF has promising potential for application in the clinic to improve RVCF retrieval rates.

Topics: Animals; Device Removal; Heparin; Hyperplasia; Pulmonary Embolism; Retrospective Studies; Sheep; Sirolimus; Treatment Outcome; Vena Cava Filters

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by intravascular thrombus formation in the pulmonary arteries.Recently, it has been shown that a myofibroblast cell phenotype was predominant within endarterectomized tissues from CTEPH patients. Indeed, our recent study demonstrated the existence of not only myofibroblast-like cells (MFLCs), but also endothelial-like cells (ELCs). Under in vitro conditions, a few transitional cells (co-expressing both endothelial- and SM-cell markers) were observed in the ELC population. We hypothesized that MFLCs in the microenvironment created by the unresolved clot may promote the endothelial-mesenchymal transition and/or induce endothelial cell (EC) dysfunction.. We isolated cells from these tissues and identified them as MFLCs and ELCs. In order to test whether the MFLCs provide the microenvironment which causes EC alterations, ECs were incubated in serum-free medium conditioned by MFLCs, or were grown in co-culture with the MFLCs.. Our experiments demonstrated that MFLCs promoted the commercially available ECs to transit to other mesenchymal phenotypes and/or induced EC dysfunction through inactivation of autophagy, disruption of the mitochondrial reticulum, alteration of the SOD-2 localization, and decreased ROS production. Indeed, ELCs included a few transitional cells, lost the ability to form autophagosomes, and had defective mitochondrial structure/function. Moreover, rapamycin reversed the phenotypic alterations and the gene expression changes in ECs co-cultured with MFLCs, thus suggesting that this agent had beneficial therapeutic effects on ECs in CTEPH tissues.. It is possible that the microenvironment created by the stabilized clot stimulates MFLCs to induce EC alterations.

Topics: Autophagy; Cell Communication; Cells, Cultured; Chronic Disease; Coculture Techniques; Culture Media, Conditioned; Endarterectomy; Endothelial Cells; Epithelial-Mesenchymal Transition; Gene Expression Profiling; Humans; Hypertension, Pulmonary; Microtubule-Associated Proteins; Mitochondria; Myofibroblasts; Phenotype; Polymerase Chain Reaction; Protein Serine-Threonine Kinases; Pulmonary Embolism; Reactive Oxygen Species; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta; Sirolimus; Smad Proteins; Superoxide Dismutase; Time Factors