Targeting HIF2α-ARNT hetero-dimerisation as a novel therapeutic strategy for pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a destructive disease of the pulmonary vasculature often leading to right heart failure and death. Current therapeutic intervention strategies only slow disease progression. The role of aberrant hypoxia-inducible factor (HIF)2α stability and function in the initiation and development of pulmonary hypertension (PH) has been an area of intense interest for nearly two decades.Here we determine the effect of a novel HIF2α inhibitor (PT2567) on PH disease initiation and progression, using two pre-clinical models of PH. Haemodynamic measurements were performed, followed by collection of heart, lung and blood for pathological, gene expression and biochemical analysis. Blood outgrowth endothelial cells from idiopathic PAH patients were used to determine the impact of HIF2α-inhibition on endothelial function.Global inhibition of HIF2a reduced pulmonary vascular haemodynamics and pulmonary vascular remodelling in both su5416/hypoxia prevention and intervention models. PT2567 intervention reduced the expression of PH-associated target genes in both lung and cardiac tissues and restored plasma nitrite concentration. Treatment of monocrotaline-exposed rodents with PT2567 reduced the impact on cardiovascular haemodynamics and promoted a survival advantage. In vitro, loss of HIF2α signalling in human pulmonary arterial endothelial cells suppresses target genes associated with inflammation, and PT2567 reduced the hyperproliferative phenotype and overactive arginase activity in blood outgrowth endothelial cells from idiopathic PAH patients. These data suggest that targeting HIF2α hetero-dimerisation with an orally bioavailable compound could offer a new therapeutic approach for PAH. Future studies are required to determine the role of HIF in the heterogeneous PAH population.

C5a anaphylatoxin and its role in critical illness-induced organ dysfunction.

Critical illness is an aetiologically and clinically heterogeneous syndrome that is characterised by organ failure and immune dysfunction. Mortality in critically ill patients is driven by inflammation-associated organ damage and a profound vulnerability to nosocomial infection. Both factors are influenced by the activated complement protein C5a, released by unbridled activation of the complement system during critical illness. C5a exerts deleterious effects on organ systems directly and suppresses antimicrobial functions of key immune cells. Whilst several recent reports have added key knowledge of the cellular signalling pathways triggered by C5a, there remain a number of areas that are incompletely understood and therapeutic opportunities are still being evaluated. In this review, we summarise the cellular basis for C5a-induced vulnerability to nosocomial infection and organ dysfunction. We focus on cells of the innate immune system, highlighting the major areas in need of further research and potential avenues for targeted therapies.

Regulation of ICAM-1 in human neutrophils.

Intercellular cell adhesion molecule 1 (ICAM-1) is a cell surface glycoprotein with a vital role in the immune response to pathogens. The expression pattern of ICAM-1 is wide-ranging, encompassing endothelial cells, epithelial cells and neutrophils. Recent work has characterized the role of ICAM-1 in murine neutrophils, but the function of human neutrophil ICAM-1 is incompletely understood. Herein, we investigated the expression and role of ICAMs in human neutrophils in vitro and in vivo. Our findings show clear expression of ICAM-1, -3 and -4 on peripheral blood-derived neutrophils and demonstrate that the pathogen-associated molecular pattern (PAMP) lipoteichoic acid (LTA) is an inducer of ICAM-1 expression in vitro. In vivo, neutrophils obtained from the pleural cavity of patients with a parapneumonic effusion display enhanced expression of ICAM-1 compared to peripheral blood- and oral cavity-derived neutrophils. Moreover, migration of peripheral blood-derived neutrophils across endothelial cells can upregulate neutrophil ICAM-1 expression. These findings indicate that PAMPs and/or cytokines, alongside transmigration, enhance neutrophil ICAM-1 expression at sites of inflammation. Mechanistically we observed that ICAM-1high neutrophils display elevated S. aureus phagocytic capacity. However, unlike murine neutrophils, ICAM-1 intracellular signaling in human neutrophils was not essential for phagocytosis of S. aureus and reactive oxygen species (ROS) generation. Taken together, these results have important implications for the regulation of neutrophil-mediated pathogen clearance.

Burn patients, parents and doctors; are we in agreement?

BACKGROUND: Burns in children present a serious challenge for patients, parents and doctors. This study aimed to investigate differences in desire for burn reconstruction in paediatric patient, parent and surgeon groups. METHODS: This study is a case series (n=21). Questionnaires were administered to patients, their parents and surgeons. Medical records were also reviewed. Data were analysed to ascertain how different factors affected desire for reconstruction between parents, patients and surgeons. RESULTS: Surgeons and parents were more likely to desire surgery than paediatric patients (76.2 vs 61.9 vs 52.4% respectively). Surgeons were more likely to recommend surgery for pre-pubescent patients (81.8 vs 70%). All groups were more likely to desire surgery for female patients. Patients and parents desired surgery more for hidden scars. Higher VSS scores were associated with a higher desire for surgery in all groups. Agreement between patients and parents was highest (Kappa=0.81) with poor-moderate agreement between surgeons, patients and parents (Kappa=0.12-0.24). CONCLUSIONS: This study suggests that paediatric patients are less likely to want burn reconstruction compared to parents and surgeons. Gender and age may impact on desire for surgery. Opportunities for improving patient, parent and surgeon agreement may exist. Further research is warranted to validate these results.