Dexamethasone induces apoptosis in pulmonary arterial smooth muscle cells

BACKGROUND: Dexamethasone suppressed inflammation and haemodynamic changes in an animal model of pulmonary arterial hypertension (PAH). A major target for dexamethasone actions is NF-κB, which is activated in pulmonary vascular cells and perivascular inflammatory cells in PAH. Reverse remodelling is an important concept in PAH disease therapy, and further to its anti-proliferative effects, we sought to explore whether dexamethasone augments pulmonary arterial smooth muscle cell (PASMC) apoptosis. METHODS: Analysis of apoptosis markers (caspase 3, in-situ DNA fragmentation) and NF-κB (p65 and phospho-IKK-α/β) activation was performed on lung tissue from rats with monocrotaline (MCT)-induced pulmonary hypertension (PH), before and after day 14–28 treatment with dexamethasone (5 mg/kg/day). PASMC were cultured from this rat PH model and from normal human lung following lung cancer surgery. Following stimulation with TNF-α (10 ng/ml), the effects of dexamethasone (10(−8)–10(−6) M) and IKK2 (NF-κB) inhibition (AS602868, 0–3 μM (0-3×10(−6) M) on IL-6 and CXCL8 release and apoptosis was determined by ELISA and by Hoechst staining. NF-κB activation was measured by TransAm assay. RESULTS: Dexamethasone treatment of rats with MCT-induced PH in vivo led to PASMC apoptosis as displayed by increased caspase 3 expression and DNA fragmentation. A similar effect was seen in vitro using TNF-α-simulated human and rat PASMC following both dexamethasone and IKK2 inhibition. Increased apoptosis was associated with a reduction in NF-κB activation and in IL-6 and CXCL8 release from PASMC. CONCLUSIONS: Dexamethasone exerted reverse-remodelling effects by augmenting apoptosis and reversing inflammation in PASMC possibly via inhibition of NF-κB. Future PAH therapies may involve targeting these important inflammatory pathways

Identity crisis in pulmonary arterial hypertension

International audiencePulmonary arterial hypertension (PAH) shares many hallmarks with cancer. Cancer cells acquire their hallmarks by a pathological Darwinian evolution process built on the so-called cancer cell ''identity crisis.'' Here we demonstrate that PAH shares the most striking features of the cancer identity crisis: the ectopic expression of normally silent tissue-specific genes

Bromodomain and extra-terminal protein mimic JQ1 decreases inflammation in human vascular endothelial cells: Implications for pulmonary arterial hypertension

Background and objective Nuclear factor kappa B (NF-kB)-mediated inflammatory gene expression and vascular endothelial cell proliferation/remodelling are implicated in the pathophysiology of the fatal disease, pulmonary arterial hypertension (PAH). Bromodomain and extra-terminal (BET) proteins are essential for the expression of a subset of NF-kB-induced inflammatory genes. BET mimics including JQ1+ prevent binding of BETs to acetylated histones and down-regulate the expression of selected genes. Methods The effects of JQ1+ on the proliferation of primary human pulmonary microvascular endothelial cells (HPMECs) from healthy subjects were measured by bromodeoxyuridine (BrdU) incorporation. Cell cycle progression was assessed by flow cytometry; mRNA and protein levels of cyclin-dependent kinases (CDKs), inhibitors and cytokines were determined by reverse transcription-quantitative PCR (RT-qPCR), Western blotting or ELISA. Histone acetyltransferase (HAT) and deacetylase (HDAC) activities were determined in nuclear extracts from whole lung of PAH and control patients. Results JQ1+ significantly inhibited IL6 and IL8 (IL6 and CXCL8) mRNA and protein in HPMECs compared with its inactive enantiomer JQ1−. JQ1+ decreased NF-kB p65 recruitment to native IL6 and IL8 promoters. JQ1+ showed a concentration-dependent decrease in HPMEC proliferation compared with JQ1−-treated cells. JQ1+ induced G1 cell cycle arrest by increasing the expression of the CDK inhibitors (CDKN) 1A (p21cip) and CDKN2D (p19INK4D ) and decreasing that of CDK2, CDK4 and CDK6. JQ1+ also inhibited serum-stimulated migration of HPMECs. Finally, HAT activity was significantly increased in the lung of PAH patients. Conclusion Inhibition of BETs in primary HPMECs decreases inflammation and remodelling. BET proteins could be a target for future therapies for PAH

Hypothyroidism and type d personality:Results from E-MPATHY, a cross-sectional international online patient survey

ContextBetween 10% and 15% of people with hypothyroidism experience persistent symptoms, despite achieving biochemical euthyroidism.The underlying causes are unclear. Type D personality (a vulnerability factor for general psychological distress) is associated with poor healthstatus and symptom burden but has not been studied in people with hypothyroidism.ObjectiveTo investigate type D personality in hypothyroidism and explore associations with other characteristics and patient-reported outcomes.DesignMultinational, cross-sectional survey.SettingOnline.ParticipantsIndividuals with self-reported, treated hypothyroidism.InterventionQuestionnaire.Main Outcome MeasuresType D personality and associations with baseline characteristics, control of the symptoms of hypothyroidism bymedication, satisfaction with care and treatment of hypothyroidism, impact of hypothyroidism on everyday living.ResultsA total of 3915 responses were received, 3523 of which were valid. The prevalence of type D personality was 54.2%. Statisticallysignificant associations were found between type D personality and several respondent characteristics (age, marital status, ethnicity,household income, comorbidities, type of treatment for hypothyroidism, most recent TSH level), anxiety, depression, somatization, poorcontrol of the symptoms of hypothyroidism by medication, dissatisfaction with care and treatment of hypothyroidism, and a negative impactof hypothyroidism on everyday living).DiscussionOur study found a high prevalence of type D personality among people with hypothyroidism who responded to the survey. Type Dpersonality may be an important determinant of dissatisfaction with treatment and care among people with hypothyroidism. Our findings requireindependent confirmation. Close collaboration between the disciplines of thyroidology and psychology is likely to be key in progressing ourunderstanding in this area

Obsessive compulsive disorder as a functional interhemispheric imbalance at the thalamic level

Obsessive Compulsive Disorder (OCD) involves failures in two main inhibitory processes, namely cognitive (obsessions) and behavioral (compulsions). Recent research has supported two cortical–subcortical pathways on OCD pathogenesis: (a) the frontostriatal loop (dorsolateral-caudate–striatum–thalamus) responsible for impairments of behavioral inhibition; (b) the orbitofrontal loop (orbitofrontal, medial prefrontal and cingulate) responsible for impairments with cognitive inhibitory processes. These failures in both cognitive and motor inhibitory systems may mediate several neuropsychological deficits in these patients, namely memory, attention, planning and decision making. But are those deficits related to specific hemispheric effects, namely functional imbalance between hemispheres? In this article we hypothesize that: (1) OCD patients have an inter-hemispheric functional imbalance, probably due to inadequate filtering at the thalamic level; (2) the restoration of inter-hemispheric balance, will be correlative to symptomatic improvement

Remodeling of extra-bronchial lung vasculature following allergic airway inflammation

<p>Abstract</p> <p>Background</p> <p>We previously observed that allergen-exposed mice exhibit remodeling of large bronchial-associated blood vessels. The aim of the study was to examine whether vascular remodeling occurs also in vessels where a spill-over effect of bronchial remodeling molecules is less likely.</p> <p>Methods</p> <p>We used an established mouse model of allergic airway inflammation, where an allergic airway inflammation is triggered by inhalations of OVA. Remodeling of bronchial un-associated vessels was determined histologically by staining for α-smooth muscle actin, procollagen I, Ki67 and von Willebrand-factor. Myofibroblasts were defined as and visualized by double staining for α-smooth muscle actin and procollagen I. For quantification the blood vessels were divided, based on length of basement membrane, into groups; small (≤250 μm) and mid-sized (250–500 μm).</p> <p>Results</p> <p>We discovered marked remodeling in solitary small and mid-sized blood vessels. Smooth muscle mass increased significantly as did the number of proliferating smooth muscle and endothelial cells. The changes were similar to those previously seen in large bronchial-associated vessels. Additionally, normally poorly muscularized blood vessels changed phenotype to a more muscularized type and the number of myofibroblasts around the small and mid-sized vessels increased following allergen challenge.</p> <p>Conclusion</p> <p>We demonstrate that allergic airway inflammation in mice is accompanied by remodeling of small and mid-sized pulmonary blood vessels some distance away (at least 150 μm) from the allergen-exposed bronchi. The present findings suggest the possibility that allergic airway inflammation may cause such vascular remodeling as previously associated with lung inflammatory conditions involving a risk for development of pulmonary hypertension.</p