Isolation of Legionella pneumophila from Pluvial Floods by Amoebal Coculture

Viable Legionella pneumophila bacteria were isolated by amoebal coculture from pluvial floods after intense rainfall and from water collected at sewage treatment plants. Several isolated L. pneumophila strains belonged to sequence types that have been previously identified in patients

Prevention of progression of pulmonary hypertension by the Nur77 agonist 6-mercaptopurine: role of BMP signalling

International audiencePulmonary arterial hypertension (PAH) is a progressive fatal disease characterised by abnormal remodelling of pulmonary vessels, leading to increased vascular resistance and right ventricle failure. This abnormal vascular remodelling is associated with endothelial cell dysfunction, increased proliferation of smooth muscle cells, inflammation and impaired bone morphogenetic protein (BMP) signalling. Orphan nuclear receptor Nur77 is a key regulator of proliferation and inflammation in vascular cells, but its role in impaired BMP signalling and vascular remodelling in PAH is unknown.We hypothesised that activation of Nur77 by 6-mercaptopurine (6-MP) would improve PAH by inhibiting endothelial cell dysfunction and vascular remodelling.Nur77 expression is decreased in cultured pulmonary microvascular endothelial cells (MVECs) and lungs of PAH patients. Nur77 significantly increased BMP signalling and strongly decreased proliferation and inflammation in MVECs. In addition, conditioned medium from PAH MVECs overexpressing Nur77 inhibited the growth of healthy smooth muscle cells. Pharmacological activation of Nur77 by 6-MP markedly restored MVEC function by normalising proliferation, inflammation and BMP signalling. Finally, 6-MP prevented and reversed abnormal vascular remodelling and right ventricle hypertrophy in the Sugen/hypoxia rat model of severe angioproliferative PAH.Our data demonstrate that Nur77 is a critical modulator in PAH by inhibiting vascular remodelling and increasing BMP signalling, and activation of Nur77 could be a promising option for the treatment of PAH

Prevention of progression of pulmonary hypertension by the Nur77 agonist 6-mercaptopurine: Role of BMP signalling

Pulmonary arterial hypertension (PAH) is a progressive fatal disease characterised by abnormal remodelling of pulmonary vessels, leading to increased vascular resistance and right ventricle failure. This abnormal vascular remodelling is associated with endothelial cell dysfunction, increased proliferation of smooth muscle cells, inflammation and impaired bone morphogenetic protein (BMP) signalling. Orphan nuclear receptor Nur77 is a key regulator of proliferation and inflammation in vascular cells, but its role in impaired BMP signalling and vascular remodelling in PAH is unknown. We hypothesised that activation of Nur77 by 6-mercaptopurine (6-MP) would improve PAH by inhibiting endothelial cell dysfunction and vascular remodelling. Nur77 expression is decreased in cultured pulmonary microvascular endothelial cells (MVECs) and lungs of PAH patients. Nur77 significantly increased BMP signalling and strongly decreased proliferation and inflammation in MVECs. In addition, conditioned medium from PAH MVECs overexpressing Nur77 inhibited the growth of healthy smooth muscle cells. Pharmacological activation of Nur77 by 6-MP markedly restored MVEC function by normalising proliferation, inflammation and BMP signalling. Finally, 6-MP prevented and reversed abnormal vascular remodelling and right ventricle hypertrophy in the Sugen/hypoxia rat model of severe angioproliferative PAH. Our data demonstrate that Nur77 is a critical modulator in PAH by inhibiting vascular remodelling and increasing BMP signalling, and activation of Nur77 could be a promising option for the treatment of PAH

Nintedanib improves cardiac fibrosis but leaves pulmonary vascular remodelling unaltered in experimental pulmonary hypertension

Aims Pulmonary arterial hypertension (PAH) is associated with increased levels of circulating growth factors and corresponding receptors such as platelet derived growth factor, fibroblast growth factor and vascular endothelial growth factor. Nintedanib, a tyrosine kinase inhibitor targeting primarily these receptors, is approved for the treatment of patients with idiopathic pulmonary fibrosis. Our objective was to examine the effect of nintedanib on proliferation of human pulmonary microvascular endothelial cells (MVEC) and assess its effects in rats with advanced experimental pulmonary hypertension (PH).Methods and results Proliferation was assessed in control and PAH MVEC exposed to nintedanib. PH was induced in rats by subcutaneous injection of Sugen (SU5416) and subsequent exposure to 10% hypoxia for 4weeks (SuHx model). Four weeks after re-exposure to normoxia, nintedanib was administered once daily for 3 weeks. Effects of the treatment were assessed with echocardiography, right heart catheterization, and histological analysis of the heart and lungs. Changes in extracellular matrix production was assessed in human cardiac fibroblasts stimulated with nintedanib. Decreased proliferation with nintedanib was observed in control MVEC, but not in PAH patient derived MVEC. Nintedanib treatment did not affect right ventricular (RV) systolic pressure or total pulmonary resistance index in SuHx rats and had no effects on pulmonary vascular remodelling. However, despite unaltered pressure overload, the right ventricle showed less dilatation and decreased fibrosis, hypertrophy, and collagen type III with nintedanib treatment. This could be explained by less fibronectin production by cardiac fibroblasts exposed to nintedanib.Conclusion Nintedanib inhibits proliferation of pulmonary MVECs from controls, but not from PAH patients. While in rats with experimental PH nintedanib has no effects on the pulmonary vascular pathology, it has favourable effects on RV remodelling.Therapeutic cell differentiatio

E-C Coupling and Contractile Characteristics of Mechanically Skinned Single Fibres from Young Rats During Rapid Growth and Maturation

The postnatal growth of rats involves a developmental phase (0 to ∼3 weeks), a rapid growth phase (∼3 to ∼10 weeks), and a slower maturation phase (∼10 weeks+). In this study, we investigated the age-related changes in excitation–contraction (E–C) coupling characteristics of mammalian skeletal muscle, during rapid growth (4– 10 weeks) and maturation (10–21 weeks) phases, using single, mechanically skinned fibres from rat extensor digitorum longus (EDL) muscle. Fibres from rats aged 4 and 8 weeks produced lower maximum T-system depolarizationinduced force responses and fewer T-system depolarizationinduced force responses to 75% run-down than those produced by fibres from rats aged 10 weeks and older. The sensitivity of the contractile apparatus to Ca2+ in fibres from 4-week rats was significantly higher than that in fibres from 10-week rats; however, the maximum Ca2+-activated force per skinned fibre cross-sectional area (specific force) developed by fibres from 4-week rats was on average ∼44% lower than the values obtained for all the other age groups. In agreement with the age difference in specific force, the MHC content of EDL muscles from 4-week rats was ∼29% lower than that of 10-week rats. Thus, mechanically skinned fibres from rats undergoing rapid growth are less responsive to T-system depolarization and maximal Ca2+ activation than fibres from rats at the later stage of maturation or adult rats. These results suggest that during the rapid growth phase in rats, the structure and function of elements involved in E–C coupling in fast-twitch skeletal muscle continue to undergo significant changes

Hind limb scaling of kangaroos and wallabies (superfamily Macropodoidea): implications for hopping performance, safety factor and elastic savings

The aim of this study was to examine hind limb scaling of the musculoskeletal system in the Macropodoidea, the superfamily containing wallabies and kangaroos, to re-examine the effect of size on the locomotor mechanics and physiology of marsupial hopping. Morphometric musculoskeletal analyses were conducted of 15 species and skeletal specimens of 21 species spanning a size range from 0.8 to 80 kg that included representatives of 12 of the 16 extant genera of macropodoids. We found that unlike other groups, macropodoids are able to match force demands associated with increasing body size primarily through a combination of positive allometry in muscle area and muscle moment arms. Isometric scaling of primary hind limb bones suggests, however, that larger species experience relatively greater bone stresses. Muscle to tendon area ratios of the ankle extensors scale with strong positive allometry, indicating that peak tendon stresses also increase with increasing body size but to a lesser degree than previously reported. Consistent with previous morphological and experimental studies, large macropodoids are therefore better suited for elastic strain energy recovery but operate at lower safety factors, which likely poses an upper limit to body size. Scaling patterns for extant macropodoids suggest that extinct giant kangaroos (∼250 kg) were likely limited in locomotor capacity