Ronan Astin

Renin-angiotensin system blockade: a novel therapeutic approach in chronic obstructive pulmonary disease

ACE (angiotensin-converting enzyme) inhibitors and ARBs (angiotensin II receptor blockers) are already widely used for the treatment and prevention of cardiovascular disease and their potential role in other disease states has become increasingly recognized. COPD (chronic obstructive pulmonary disease) is characterized by pathological inflammatory processes involving the lung parenchyma, airways and vascular bed. The aim of the present review is to outline the role of the RAS (renin-angiotensin system) in the pathogenesis of COPD, including reference to results from fibrotic lung conditions and pulmonary hypertension. The review will, in particular, address the emerging evidence that ACE inhibition could have a beneficial effect on skeletal muscle function and cardiovascular co-morbidity in COPD patients. The evidence to support the effect of RAS blockade as a novel therapeutic approach in COPD will be discussed.

Anaemia secondary to critical illness: an unexplained phenomenon

Almost all patients suffering critical illness become anaemic during their time in intensive care. The cause of this anaemia and its management has been a topic of debate in critical care medicine for the last two decades. Packed red cell transfusion has an associated cost and morbidity such that decreasing the number of units transfused would be of great benefit. Our understanding of the aetiology and importance of this anaemia is improving with recent and ongoing work to establish the cause, effect and best treatment options. This review aims to describe the current literature whilst suggesting that the nature of the anaemia should be considered with reference to the time point in critical illness. Finally, we suggest that using haemoglobin concentration as a measure of oxygen-carrying capacity has limitations and that ways of measuring haemoglobin mass should be explored.

No evidence for a local renin-angiotensin system in liver mitochondria

The circulating, endocrine renin-angiotensin system (RAS) is important to circulatory homeostasis, while ubiquitous tissue and cellular RAS play diverse roles, including metabolic regulation. Indeed, inhibition of RAS is associated with improved cellular oxidative capacity. Recently it has been suggested that an intra-mitochondrial RAS directly impacts on metabolism. Here we sought to rigorously explore this hypothesis. Radiolabelled ligand-binding and unbiased proteomic approaches were applied to purified mitochondrial sub-fractions from rat liver, and the impact of AngII on mitochondrial function assessed. Whilst high-affinity AngII binding sites were found in the mitochondria-associated membrane (MAM) fraction, no RAS components could be detected in purified mitochondria. Moreover, AngII had no effect on the function of isolated mitochondria at physiologically relevant concentrations. We thus found no evidence of endogenous mitochondrial AngII production, and conclude that the effects of AngII on cellular energy metabolism are not mediated through its direct binding to mitochondrial targets.

How is physical activity measured in lung cancer?A systematic review of outcome measures and their psychometric properties.

Physical activity (PA) levels are low in patients with lung cancer. Emerging evidence supports the use of interventions to increase PA in this population. We aimed to (1) identify and synthesize outcome measures which assess PA levels in patients with lung cancer and (2) to evaluate, synthesize and compare the psychometric properties of these measures. A systematic review of articles from searches was conducted of five electronic databases and personal records. Eligible studies were those which assessed PA using either performance‐based or patient‐reported measures. For aim 2, studies identified in aim 1 reporting on at least one psychometric property (validity, reliability, responsiveness or measurement error) were included. Two independent reviewers assessed eligibility and risk of bias with the COnsensus‐based Standards for the selection of health status Measurement INstruments.

Metabolic phenotype of skeletal muscle in early critical illness

Objectives To characterise the sketetal muscle metabolic phenotype during early critical illness. Methods Vastus lateralis muscle biopsies and serum samples (days 1 and 7) were obtained from 63 intensive care patients (59% male, 54.7±18.0 years, Acute Physiology and Chronic Health Evaluation II score 23.5±6.5). Measurements and main results From day 1 to 7, there was a reduction in mitochondrial beta-oxidation enzyme concentrations, mitochondrial biogenesis markers (PGC1α messenger mRNA expression (−27.4CN (95% CI −123.9 to 14.3); n=23; p=0.025) and mitochondrial DNA copy number (−1859CN (IQR −5557–1325); n=35; p=0.032). Intramuscular ATP content was reduced compared tocompared with controls on day 1 (17.7mmol/kg /dry weight (dw) (95% CI 15.3 to 20.0) vs. 21.7 mmol/kg /dw (95% CI 20.4 to 22.9); p<0.001) and decreased over 7 days (−4.8 mmol/kg dw (IQR −8.0–1.2); n=33; p=0.001). In addition, the ratio of phosphorylated:total AMP-K (the bioenergetic sensor) increased (0.52 (IQR −0.09–2.6); n=31; p<0.001). There was an increase in intramuscular phosphocholine (847.2AU (IQR 232.5–1672); n=15; p=0.022), intramuscular tumour necrosis factor receptor 1 (0.66 µg (IQR −0.44–3.33); n=29; p=0.041) and IL-10 (13.6 ng (IQR 3.4–39.0); n=29; p=0.004). Serum adiponectin (10.3 µg (95% CI 6.8 to 13.7); p<0.001) and ghrelin (16.0 ng/mL (IQR −7–100); p=0.028) increased. Network analysis revealed a close and direct relationship between bioenergetic impairment and reduction in muscle mass and between intramuscular inflammation and impaired anabolic signaling. ATP content and muscle mass were unrelated to lipids delivered. Conclusions Decreased mitochondrial biogenesis and dysregulated lipid oxidation contribute to compromised skeletal muscle bioenergetic status. In addition, intramuscular inflammation was associated with impaired anabolic recovery with lipid delivery observed as bioenergetically inert. Future clinical work will focus on these key areas to ameliorate acute skeletal muscle wasting. Trial registration number NCT01106300.