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The role of vascular endothelial growth factor (VEGF) in repair and recovery from acute respiratory distress syndrome (ARDS)

2013-04-17T13:17:42Z

Title: The role of vascular endothelial growth factor (VEGF) in repair and recovery from acute respiratory distress syndrome (ARDS) Authors: Medford, Andrew R.L Abstract: Acute Respiratory Distress Syndrome (ARDS) is the most extreme form of acute lung injury and continues to have a significant morbidity and mortality. Unfortunately, the mechanisms involved in the recovery and repair of the lung following ARDS remain poorly understood. An understanding of these is pivotal to improving outcome from acute lung injury. Several observational studies have suggested a potential relationship between Vascular Endothelial Growth Factor (VEGF) in the lung and the development/outcome of ARDS. In this thesis, three potential mechanisms underlying these observations have been explored: 1. What is the anatomical distribution of VEGF receptor and isoform expression in normal and ARDS lung? How does this change at early and later time points following acute lung injury? 2. Are human type 2 alveolar epithelial (ATII) cells a source of and target for VEGF? How does exposure to a pro-inflammatory milieu modify their expression of VEGF isoforms and receptors? 3. Is there a relationship between a functional VEGF polymorphism and susceptibility to developing and severity of ARDS? I have demonstrated VEGF receptor expression on both sides of the alveolarcapillary membrane with upregulation in later ARDS. All three principal isoforms (VEGF121, VEGF165 and VEGF189) are expressed in normal human lung with uniform downregulation of all three in early ARDS, which normalises with increasing time following injury. I have not found any evidence of VEGF isoform switching. I have also demonstrated human ATII cells are both a significant cellular source of and a target for VEGF (via VEGF receptor expression) confirming autocrine VEGF activity in the lung. VEGF is an ATII cell survival factor. ATII cells differentially respond to pro-inflammatory stimuli by increasing VEGF isoform but not receptor expression, which may serve as a regulatory control mechanism. Finally, I have demonstrated the VEGF 936 T allele increases susceptibility to and the severity of lung injury. The T allele is associated with an increase in plasma VEGF level in ARDS patients but intra-alveolar levels are unaffected.

Inhibition of phosphodiesterase type 5 in cardiovascular disease

2013-02-27T13:48:12Z

Title: Inhibition of phosphodiesterase type 5 in cardiovascular disease Authors: Oliver, James John Abstract: Nitric oxide is released from the endothelium and causes relaxation of vascular smooth muscle by stimulating guanylate cyclase to produce guanosine 3’,5’-cyclic monophosphate (cGMP) which, in turn, is degraded by phosphodiesterase type 5 (PDE5). Inhibition of PDE5, with drugs like sildenafil citrate, promotes NOstimulated relaxation of vascular smooth muscle. The overall aim of the work contained within this thesis was to further characterise the systemic vascular effects of PDE5 inhibition. Four clinical studies were performed. The aims of the first study were to investigate in healthy men the effect of smoking on endothelium-dependent vasomotor function measured as the change in peripheral arterial wave reflection with inhaled salbutamol, and the effect of acute sildenafil 100 mg on this response. Smokers (n=12) exhibited a reduced response to inhaled salbutamol compared to non-smokers (n=11) [mean(standard deviation) area under the curve of the change in central augmentation index following salbutamol 400 μg: -29(143) AU in smokers vs -159(124) AU in non-smokers, P=0.03]. In the smokers, there was a trend to an improvement in the response to salbutamol following sildenafil [-96(266) AU vs -29(143) AU with matched placebo; P=0.2]. The co-administration of glyceryl trinitrate (GTN) and sildenafil is absolutely contraindicated because of the potential for profound hypotension. The aim of the second study was to characterise the time course of this interaction. Twenty men with stable angina, maintained on their usual medicines, were administered sublingual GTN 400 μg 1, 4, 6 and 8 hours after sildenafil 100 mg or matched placebo. Compared to the combination of GTN and placebo, the combination of GTN and sildenafil resulted in greater mean maximum reductions from baseline in sitting systolic blood pressure (BP) at 1, 4 and 8 hours, and in sitting diastolic BP at all time points (all P<0.05). Compared to placebo, sildenafil alone reduced systolic BP at 1, 4, 6 and 8 hours (P<0.01 at 1 hour and P<0.05 at 4, 6, and 8 hours) and diastolic BP at 4, 6, and 8 hours (all P<0.01). Analysis of the change in BP from the measures taken before each GTN challenge suggested that the interaction on BP might be synergistic at 1 hour after sildenafil, but no more than additive at 6 and 8 hours after sildenafil. Symptoms consistent with hypotension occurred following GTN in 6 subjects at 1 hour and 3 subjects at 4 hours after sildenafil, but in no subjects at 6 and 8 hours after sildenafil or at any time after placebo. In the third study, 25 otherwise untreated hypertensives were given sildenafil 50 mg or matched placebo three times daily for 16 days and the effects on ambulatory BP, clinic BP, arterial wave reflection, carotid-femoral pulse wave velocity and brachial artery flow-mediated dilatation were measured. Three subjects were withdrawn because of side effects and the data from the remaining 22 subjects were analysed. Sildenafil reduced ambulatory BP [change from baseline in average daytime BP: systolic -8(9) mmHg vs 2(9) mmHg with placebo, P<0.01; diastolic -6(5) mmHg vs 0(6) mmHg, P<0.01] and clinic BP [change from baseline to 1 hour after drug administration on day 16: systolic -5(11) mmHg vs 4(10) mmHg, P<0.01; diastolic -5(5) mmHg vs 2(7) mmHg, P<0.01]. Sildenafil, but not placebo, reduced arterial wave reflection [central augmentation index from 32(9)% at baseline to 30(10)% at 1 hour after administration on day 16, P<0.05; radial augmentation index from 88(13)% to 84(13)%, P<0.01], but the change in arterial wave reflection was not statistically significant compared to the change with placebo. Sildenafil did not affect pulse wave velocity or flow-mediated dilatation. The fourth study investigated the potential of combined PDE5 inhibition and organic nitrate for the management of treatment-resistant hypertension (TRH). In 6 patients with TRH, maintained on their usual antihypertensives sildenafil 50 mg alone, isosorbide mononitrate (ISMN) 10 mg alone and co-administered sildenafil and ISMN all acutely reduced systolic BP and diastolic BP compared to placebo (quantified as the area under the curve of the change from baseline to 4 hours after drug administration; all P≤0.01). The combination produced a greater reduction in systolic BP than did either sildenafil alone (P=0.03) or ISMN alone (P=0.01) and a greater reduction in diastolic BP than did sildenafil alone (P=0.02). Compared to placebo, from 1 to 3 hours after drug administration BP was on average 13/10 mmHg lower with sildenafil alone, 18/14 mmHg lower with ISMN alone and 26/18 mmHg lower with the combination. The following conclusions were made. (1) Smokers exhibit impaired vascular responsiveness to inhaled salbutamol, indicating systemic endothelial dysfunction, which may be improved by sildenafil. (2) In men with stable angina there is an interaction on BP reduction between sildenafil 100 mg and sublingual GTN 400 μg for at least 8 hours after sildenafil administration, but this interaction is no more than additive from 6 hours after sildenafil administration. (3) Regular sildenafil monotherapy reduces BP in hypertension. (4) In patients with TRH maintained on their usual antihypertensives sildenafil alone and ISMN alone both acutely reduce BP and there is additional BP reduction when these drugs are given in combination.

Cigarette smoking and schizophrenia

2013-02-27T13:47:53Z

Title: Cigarette smoking and schizophrenia Authors: Patrick, Jon Alan Abstract: Section 1 Introduction Cigarette smoking is anecdotally seen more often amongst schizophrenic than well subjects. Research has suggested a variety of explanations which are discussed; the role of genetics, psychosocial explanations and smoking as selfmedication. The financial, physical health and treatment options of and for nicotine dependence are also examined with reference to schizophrenia. Section 2 Systematic Review of Cigarette Smoking and Schizophrenia 50 studies were identified with a mean prevalence rate of smoking in schizophrenic populations of 66%. Male schizophrenics had a significantly higher (p=0.04) rate of smoking and smoked more heavily (p=0.01) than females. Different settings were also examined. Section 3 Meta-Analysis of Case-Control Studies examining the Prevalence of Smoking in Schizophrenia 11 studies were identified that could be examined in a meta-analysis comparing prevalence rates of smoking. Schizophrenic patients were found to be nearly 3 times more likely to smoke than controls. Section 4 Investigation into Patterns of Cigarette Smoking in Schizophrenia Using Data from the Edinburgh High-Risk Study (EHRS) At first interview there was a tendency (p=0.18) for high-risk group members with psychotic symptoms to have ever smoked compared to other high-risk and control subjects. Schizophrenic controls had a significantly higher prevalence of ever smoking compared to the high-risk and control groups (p=0.01). At the fourth interview there was a trend for high-risk subjects showed a nonsignificant difference in the rates of ever smoking compared with the controls (p=0.16). Those subjects who developed schizophrenia showed a clear trend (p=0.07) towards ever smoking Sections 5/6 Synthesis and Discussion of Results/Conclusion Explanations for the findings are presented. Although schizophrenia and cigarette smoking are inextricably linked, further studies are necessary if we are to more fully understand the nature of this association.

Role of 11βHSD2 in salt and water homeostasis

2012-11-15T15:22:41Z

Title: Role of 11βHSD2 in salt and water homeostasis Authors: Evans, Louise Christine Abstract: 11β-Hydroxysteroid Dehydrogenase Type 2 (11βHSD2) catalyses the inactivation of cortisol. In aldosterone target tissues co-expression of 11βHSD2 and mineralocorticoid receptors (MR) protects the receptor from activation by glucocorticoids. In the syndrome of Apparent Mineralocorticoid Excess, mutations in the HSD11B2 gene cause hypertension, which is thought to be driven by volume expansion secondary to sodium retention. 11βHSD2 mice are indeed hypertensive but paradoxically volume contracted, suggestive of a urine-concentrating defect. The current studies were designed to evaluate sodium and water homeostasis in 11βHSD2-/- mice. 11βHSD2-/- mice developed a severe and progressive polyuric-polydipsic phenotype. Despite basal polyuria, at <100 days 11βHSD2-/- mice had a functional concentration response when challenged with 24 hours water deprivation. At >180 days the exacerbated polyuria was associated with severe medullary injury in the null mice. Basal aquaporin 2 (AQP2) abundance was reduced in the 11βHSD2-/- mice at both <100 and >180 days. Moreover, vasopressin 2 receptor (V2R) stimulation failed to normalize the impaired response to water deprivation in >180 day null mice. Consequently, a renal origin to the polyuria was postulated. Indeed, mice in which 11βHSD2 had been selectively targeted in the brain had a normal water turnover. A key finding from these studies is that functional deletion of 11βHSD2 in the brain, specifically the nucleus of the solitary tract (NTS), resulted in an increased salt appetite. Moreover, the mice displayed a preference for 1.5% NaCl over water. Blockade of mineralocorticoid receptors (MR) significantly reduced NaCl intake. This is the first demonstration of an increased salt appetite in a model with normal renal function and in the absence of sodium depletion. These data implicate activation of MR on 11βHSD2 positive neurons in the NTS in the behavioural drive to consume sodium.