Now showing 1 - 4 of 4
  • Publication
    Hypoxic pulmonary hypertension in chronic lung diseases: novel vasoconstrictor pathway
    Pulmonary hypertension is a well recognised complication of chronic hypoxic lung diseases, which are among the most common causes of death and disability worldwide. Development of pulmonary hypertension independently predicts reduced life expectancy. In chronic obstructive pulmonary disease, long-term oxygen therapy ameliorates pulmonary hypertension and greatly improves survival, although the correction of alveolar hypoxia and pulmonary hypertension is only partial. Advances in understanding of the regulation of vascular smooth muscle tone show that chronic vasoconstriction plays a more important part in the pathogenesis of hypoxic pulmonary hypertension than previously thought, and that structural vascular changes contribute less. Trials of existing vasodilators show that pulmonary hypertension can be ameliorated and systemic oxygen delivery improved in carefully selected patients, although systemic hypotensive effects limit the doses used. Vasoconstrictor pathways that are selective for the pulmonary circulation can be blocked to reduce hypoxic pulmonary hypertension without causing systemic hypotension, and thus provide potential targets for novel therapeutic strategies.
      841Scopus© Citations 47
  • Publication
    Elevated plasma CXCL12a is associated with a poorer prognosis in pulmonary arterial hypertension
    Recent work in preclinical models suggests that signalling via the pro-angiogenic and pro-inflammatory cytokine, CXCL12 (SDF-1), plays an important pathogenic role in pulmonary hypertension (PH). The objective of this study was to establish whether circulating concentrations of CXCL12a were elevated in patients with PAH and related to mortality. Plasma samples were collected from patients with idiopathic pulmonary arterial hypertension (IPAH) and PAH associated with connective tissue diseases (CTD-PAH) attending two pulmonary hypertension referral centres (n = 95) and from age and gender matched healthy controls (n = 44). Patients were subsequently monitored throughout a period of five years. CXCL12a concentrations were elevated in PAH groups compared to controls (P<0.05) and receiver-operating-characteristic analysis showed that plasma CXCL12a concentrations discriminated patients from healthy controls (AUC 0.80, 95% confidence interval 0.73-0.88). Kaplan Meier analysis indicated that elevated plasma CXCL12a concentration was associated with reduced survival (P<0.01). Multivariate Cox proportional hazards model showed that elevated CXCL12a independently predicted (P<0.05) earlier death in PAH with a hazard ratio (95% confidence interval) of 2.25 (1.01-5.00). In the largest subset by WHO functional class (Class 3, 65% of patients) elevated CXCL12a independently predicted (P<0.05) earlier death, hazard ratio 2.27 (1.05-4.89). Our data show that elevated concentrations of circulating CXCL12a in PAH predicted poorer survival. Furthermore, elevated circulating CXCL12a was an independent risk factor for death that could potentially be included in a prognostic model and guide therapy.
      327Scopus© Citations 21
  • Publication
    Obesity and lung disease: a toxic mix
    (Wiley, 2015-04)
    Obesity is associated with an increased incidence of lung diseases including such common conditions as asthma, COPD, ARDS, sleep apnoea syndrome and pulmonary hypertension. The adverse effects of obesity on the respiratory system are mediated by a number of mechanisms including the production of pro-inflammatory cytokines by adipose tissue, mechanical restriction of thoracic volumes and obesity-induced hypoventilation
      207Scopus© Citations 4
  • Publication
    Hypoxic pulmonary hypertension: the paradigm is changing
    We began in the early 2000s to explore the hypothesis that vasoconstrictor mechanisms, selectively altered in the lung, were significant contributors to the increase in pulmonary vascular resistance in pulmonary hypertension. We found that in the normal rat pulmonary circulation the RhoA-ROCK pathway is a greater contributor to vasoconstriction than it is in systemic vessels, demonstrating an important phenotypic difference in the regulation of vascular tone in the two circulations.
      211Scopus© Citations 5