Patients who received infusions of fentanyl for at least 5 days were just as likely to complete a low-dose methadone taper as a high-dose methadone taper. Because of the risks of both withdrawal and oversedation with any fixed methadone schedule, the methadone dose must be adjusted according to each patient's response.
A defining characteristic of pulmonary hypertension (PH) is the extensive remodeling of pulmonary arteries (PAs), which results in progressive increases in vascular resistance and stiffness and eventual failure of the right ventricle. There is no cure for PH and identification of novel molecular mechanisms that underlie increased proliferation, reduced apoptosis, and excessive extracellular matrix production in pulmonary artery smooth muscle cells (PASMCs) is a vital objective. Galectin-3 (Gal-3) is a chimeric lectin and potent driver of many aspects of fibrosis, but its role in regulating PASMC behavior in PH remains poorly understood. Herein, we evaluated the importance of increased Gal-3 expression and signaling on PA vascular remodeling and cardiopulmonary function in experimental models of PH. Gal-3 expression was quantified by qRT-PCR, immunoblotting, and immunofluorescence imaging, and its functional role was assessed by specific Gal-3 inhibitors and CRISPR/Cas9-mediated knockout of Gal-3 in the rat. In rat models of PH, we observed increased Gal-3 expression in PASMCs, which stimulated migration and resistance to apoptosis, whereas silencing or genetic deletion reduced cellular migration and PA fibrosis and increased apoptosis. Gal-3 inhibitors attenuated and reversed PA remodeling and fibrosis, as well as hemodynamic indices in monocrotaline (MCT)-treated rats in vivo. These results were supported by genetic deletion of Gal-3 in both MCT and Sugen Hypoxia rat models. In conclusion, our results suggest that elevated Gal-3 levels contribute to inappropriate PA remodeling in PH by enhancing multiple profibrotic mechanisms. Therapeutic strategies targeting Gal-3 may be of benefit in the treatment of PH.
Non-technical summary It is now known that adverse events in the womb leading to fetal growth impairment increase the risk of cardiovascular disease (CVD) in adulthood. We show perturbed arterial development in sheep fetuses subjected to oxygen deprivation by placental dysfunction, which accounts for the majority of fetal growth restriction in developed countries. The altered structure and composition of the vascular wall exhibited by growth restricted sheep fetuses are akin to those changes present in the preclinical stage of CVD. Therefore, we reveal a plausible mechanism of CVD susceptibility in individuals growth restricted by placental dysfunction. In addition, we identified molecular factors involved in aberrant arterial formation and thus highlight the need for further investigation into these molecular pathways and possible prenatal interventions such as antioxidants.Abstract This study explored arterial remodelling in fetuses growth restricted by hypoxia. Chronically catheterized fetal sheep were made moderately or severely hypoxic by placental embolization for 15 days starting at gestational age 116-118 (term ∼147 days). Cross-sections of the aorta were analysed for collagen and elastin content using histological procedures, while immunofluorescence was applied to measure markers of vascular smooth muscle cell (VSMC) type. In frozen aortae quantitative PCR was used to measure mRNA levels of extracellular matrix (ECM) precursor proteins as well as molecular regulators of developmental and pathological remodelling. Relative to Control (n = 6), aortic wall thickness was increased by 23% in the Moderate group (n = 5) and 33% (P < 0.01) in the Severe group (n = 5). Relative to Control, the Severe group exhibited a 5-fold increase in total collagen content (P < 0.01) that paralleled increases in mRNA levels of procollagen I (P < 0.05) and III and transforming growth factor β (TGF-β 1 ) (P < 0.05). The percentage area stained for α-actin was inversely related to fetal arterial oxygen saturation (P < 0.05) and total α-actin content was 45% higher in the Moderate group and 65% (P < 0.05) higher in the Severe group, compared to Control. A 12% and 39% (P < 0.05) reduction in relative elastic fibre content was observed in Moderate and Severe fetuses, respectively. mRNA levels of the elastolytic enzyme, matrix metalloproteinase-2 (MMP-2) were inversely correlated with fetal arterial oxygen saturation (P < 0.05) (Fig. 7) and mRNA levels of its activator, membrane-type MMP (MTI-MMP), were elevated in the Severe group (P < 0.05). Marked neointima formation was apparent in Severe fetuses (P < 0.05) concomitant with an increase in E-selectin mRNA expression (P < 0.05). Thus, aberrant aortic formation in utero mediated by molecular regulators of arterial growth occurs in response to chronic hypoxaemia. Abbreviations CVD, cardiovascular disease; ECM, extracellular matrix; IUGR, intrauterine growth restriction; MHC-B, non-muscle myosin heavy chain B; MMP, matrix metalloproteinase; MTI-MMP, membrane-type metalloproteinase; ...
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