Now showing 1 - 7 of 7
  • 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
      329Scopus© Citations 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.
      1156Scopus© Citations 62
  • Publication
    Shear Stress Markedly Alters the Proteomic Response to Hypoxia in Human Pulmonary Endothelial Cells
    Blood flow produces shear stress that homeostatically regulates the phenotype of pulmonary endothelial cells, exerting antiinflammatory and antithrombotic actions and maintaining normal barrier function. Hypoxia due to diseases, such as chronic obstructive pulmonary disease (COPD), causes vasoconstriction, increased vascular resistance, and pulmonary hypertension. Hypoxia-induced changes in endothelial function play a central role in the development of pulmonary hypertension. However, the interactive effects of hypoxia and shear stress on the pulmonary endothelial phenotype have not been studied. Human pulmonary microvascular endothelial cells were cultured in normoxia or hypoxia while subjected to physiological shear stress or in static conditions. Unbiased proteomics was used to identify hypoxia-induced changes in protein expression. Using publicly available single-cell RNA sequencing datasets, differences in gene expression between the alveolar endothelial cells from COPD and healthy lungs were identified. Sixty proteins were identified whose expression changed in response to hypoxia in conditions of physiological shear stress but not in static conditions. These included proteins that are crucial for endothelial homeostasis (e.g., JAM-A [junctional adhesion molecule A], ERG [ETS transcription factor ERG]) or implicated in pulmonary hypertension (e.g., thrombospondin-1). Fifty-five of these 60 have not been previously implicated in the development of hypoxic lung diseases. mRNA for 5 of the 60 (ERG, MCRIP1 [MAPK regulated corepressor interacting protein 1], EIF4A2 [eukaryotic translation initiation factor 4A2], HSP90AA1 [heat shock protein 90 alpha family class A member 1], and DNAJA1 [DnaJ Hsp40 (heat shock protein family) member A1]) showed similar changes in the alveolar endothelial cells of COPD compared with healthy lungs in females but not in males. These data show that the proteomic responses of the pulmonary microvascular endothelium to hypoxia are significantly altered by shear stress and suggest that these shear-hypoxia interactions are important in the development of hypoxic pulmonary vascular disease.
      42Scopus© Citations 5
  • 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.
      394Scopus© Citations 25
  • 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.
      251Scopus© Citations 5
  • Publication
    Transcriptomics and proteomics revealed sex differences in human pulmonary microvascular endothelial cells
    Marked sexual dimorphism is displayed in the onset and progression of pulmonary hypertension (PH). Females more commonly develop pulmonary arterial hypertension (PAH), yet females with PAH and other types of PH have better survival than males. Pulmonary microvascular endothelial cells play a crucial role in the pulmonary vascular remodelling and increased pulmonary vascular resistance in PH. Given this background, we hypothesized that there are sex differences in the pulmonary microvascular endothelium basally and in response to hypoxia that are independent of the sex hormone environment. Human pulmonary microvascular endothelial cells (HPMECs) from healthy male and female donors, cultured under physiological shear stress, were analysed using RNA sequencing and label-free quantitative proteomics. Gene set enrichment analysis identified a number of sex different pathways both in normoxia and hypoxia, including pathways that regulate cell proliferation. In vitro, rate of proliferation in female HPMECs was lower than in male HPMECs, a finding that supports the omics results. Interestingly, thrombospondin1, an inhibitor of proliferation, was more highly expressed in female than in male cells. These results demonstrate for the first time important differences between female and male HPMECs that persist in the absence of sex hormone differences and identify novel pathways for further investigation that may contribute to sexual dimorphism in pulmonary hypertensive diseases.
  • Publication
    Gremlin 1 is required for macrophage M2 polarization
    Pro-proliferative, M2-like polarization of macrophages is a critical step in the development of fibrosis and remodeling in chronic lung diseases such as pulmonary fibrosis and pulmonary hypertension. Macrophages in healthy and diseased lungs express gremlin 1 (Grem1), a secreted glycoprotein that acts in both paracrine and autocrine manners to modulate cellular function. Increased Grem1 expression plays a central role in pulmonary fibrosis and remodeling, however, the role of Grem1 in M2-like polarization of macrophages has not previously been explored. The results reported here show that recombinant Grem1 potentiated M2-like polarization of mouse macrophages and bone marrow-derived macrophages (BMDMs) in response to the Th2 cytokines IL4 and IL13. Genetic depletion of Grem1 in BMDMs inhibited M2 polarization while exogenous gremlin 1 could partially rescue this effect. Taken together, these findings reveal that gremlin 1 is required for M2-like polarization of macrophages. We show here that gremlin 1 potentiated M2 polarization of mouse bone marrow-derived macrophages (BMDMs) in response to the Th2 cytokines IL4 and IL13. Genetic depletion of Grem1 in BMDMs inhibited M2 polarization while exogenous gremlin 1 partially rescued this effect. Taken together, these findings reveal a previously unknown requirement for gremlin 1 in M2 polarization of macrophages and suggest a novel cellular mechanism promoting fibrosis and remodeling in lung diseases.