Acute Respiratory Distress Syndrome: Response

The epistolic response to other letters published in The New England Journal of Medicine 337 (2017), no. 19, pp. 1903-1905, as a result of the Review Article: B. Taylor Thompson, Rachel C. Chambers, Kathleen D. Liu, Acute Respiratory Distress Syndrome, The New England of Medicine 377, no. 6, (2017), pp. 562-572

Training response inhibition to reduce food consumption: Mechanisms, stimulus specificity and appropriate training protocols.

Published onlineJournal ArticleThis is the final version of the article. Available from Elsevier via the DOI in this record.Training individuals to inhibit their responses towards unhealthy foods has been shown to reduce food intake relative to a control group. Here we aimed to further explore these effects by investigating the role of stimulus devaluation, training protocol, and choice of control group. Restrained eaters received either inhibition or control training using a modified version of either the stop-signal or go/no-go task. Following training we measured implicit attitudes towards food (Study 1) and food consumption (Studies 1 and 2). In Study 1 we used a modified stop-signal training task with increased demands on top-down control (using a tracking procedure and feedback to maintain competition between the stop and go processes). With this task, we found no evidence for an effect of training on implicit attitudes or food consumption, with Bayesian inferential analyses revealing substantial evidence for the null hypothesis. In Study 2 we removed the feedback in the stop-signal training to increase the rate of successful inhibition and revealed a significant effect of both stop-signal and go/no-go training on food intake (compared to double-response and go training, respectively) with a greater difference in consumption in the go/no-go task, compared with the stop-signal task. However, results from an additional passive control group suggest that training effects could be partly caused by increased consumption in the go control group whereas evidence for reduced consumption in the inhibition groups was inconclusive. Our findings therefore support evidence that inhibition training tasks with higher rates of inhibition accuracy are more effective, but prompt caution for interpreting the efficacy of laboratory-based inhibition training as an intervention for behaviour change.This project was supported by a PhD studentship from the School of Psychology, Cardiff University (to R. Adams) and a Biotechnology and Biological Sciences Research Council Grant (BB/K008277/1) to C. Chambers and F. Verbruggen. F Verbruggen is supported by a starting grant from the European Research Council (ERC) under the European Union’s Seventh Framework Programme (FP7/2007–2013)/ERC Grant Agreement No. 312445. R. Adams was principally responsible for all parts of the paper. N. Lawrence, F. Verbruggen and C. Chambers made substantial contributions to all parts of the paper. C. Chambers was senior author and oversaw the project

Fibrometabolism-An emerging therapeutic frontier in pulmonary fibrosis

Fibrosis is the final pathological outcome and major cause of morbidity and mortality in many common and chronic inflammatory, immune-mediated, and metabolic diseases. Despite the growing incidence of fibrotic diseases and extensive research efforts, there remains a lack of effective therapies that improve survival. The application of omics technologies has revolutionized our approach to identifying previously unknown therapeutic targets and potential disease biomarkers. The application of metabolomics, in particular, has improved our understanding of disease pathomechanisms and garnered a wave of scientific interest in the role of metabolism in the biology of myofibroblasts, the key effector cells of the fibrogenic response. Emerging evidence suggests that alterations in metabolism not only are a feature of but also may play an influential role in the pathogenesis of fibrosis, most notably in idiopathic pulmonary fibrosis (IPF), the most rapidly progressive and fatal of all fibrotic conditions. This review will detail the role of key metabolic pathways, their alterations in myofibroblasts, and the potential this new knowledge offers for the development of antifibrotic therapeutic strategies

Ligation of protease-activated receptor 1 enhances alpha(v)beta(6) integrin-dependent TGF-beta activation and promotes acute lung injury

Activation of latent TGF-beta by the alpha(v)beta(6) integrin is a critical step in the development of acute lung injury. However, the mechanism by which a alpha(v)beta(6)-mediated TGF-beta activation is regulated has not been identified. We show that thrombin, and other agonists of protease-activated receptor 1(PAR1), activate TGF-beta in an alpha(v)beta(6) integrin-specific manner. This effect is PART specific and is mediated by RhoA and Rho kinase. Intratracheal instillation of the PART-specific peptide TFLLRN increases lung edema during high-tidal-volume ventilation, and this effect is completely inhibited by a blocking antibody against the alpha(v)beta(6) integrin. Instillation of TFLLRN during high-tidal-volume ventilation is associated with increased pulmonary TGF-beta activation; however, this is not observed in Itgb6(-/-) mice. Furthermore, Itgb6(-/-) mice are also protected from ventilator-induced lung edema. We also demonstrate that pulmonary edema and TGF-beta activity are similarly reduced in Par1(-/-) mice following bleomycin-induced lung injury. These results suggest that PART-mediated enhancement of a alpha(v)beta(6)-dependent TGF-beta activation could be one mechanism by which activation of the coagulation cascade contributes to the development of acute lung injury, and they identify PART and the alpha(v)beta(6) integrin as potential therapeutic targets in this condition

Food addiction: Implications for the diagnosis and treatment of overeating

This is the final version. Available from MDPI via the DOI in this record. With the obesity epidemic being largely attributed to overeating, much research has been aimed at understanding the psychological causes of overeating and using this knowledge to develop targeted interventions. Here, we review this literature under a model of food addiction and present evidence according to the fifth edition of the Diagnostic and Statistical Manual (DSM-5) criteria for substance use disorders. We review several innovative treatments related to a food addiction model ranging from cognitive intervention tasks to neuromodulation techniques. We conclude that there is evidence to suggest that, for some individuals, food can induce addictive-type behaviours similar to those seen with other addictive substances. However, with several DSM-5 criteria having limited application to overeating, the term ‘food addiction’ is likely to apply only in a minority of cases. Nevertheless, research investigating the underlying psychological causes of overeating within the context of food addiction has led to some novel and potentially effective interventions. Understanding the similarities and differences between the addictive characteristics of food and illicit substances should prove fruitful in further developing these interventions.Biotechnology and Biological Sciences Research CouncilEuropean Research Counci

Intrinsic defence capacity and therapeutic potential of natriuretic peptides in pulmonary hypertension associated with lung fibrosis

This work was supported by the British Lung Foundation. C.J.S. is supported by a Medical Research Council Fellowship

Regulation of neutrophilic inflammation by proteinase-activated receptor 1 during bacterial pulmonary infection

Neutrophils are key effector cells of the innate immune response to pathogenic bacteria, but excessive neutrophilic inflammation can be associated with bystander tissue damage. The mechanisms responsible for neutrophil recruitment to the lungs during bacterial pneumonia are poorly defined. In this study, we focus on the potential role of the major high-affinity thrombin receptor, proteinase-activated receptor 1 (PAR-1), during the development of pneumonia to the common lung pathogen Streptococcus pneumoniae. Our studies demonstrate that neutrophils were indispensable for controlling S. pneumoniae outgrowth but contributed to alveolar barrier disruption. We further report that intra-alveolar coagulation (bronchoalveolar lavage fluid thrombin-antithrombin complex levels) and PAR-1 immunostaining were increased in this model of bacterial lung infection. Functional studies using the most clinically advanced PAR-1 antagonist, SCH530348, revealed a key contribution for PAR-1 signaling in influencing neutrophil recruitment to lung airspaces in response to both an invasive and noninvasive strain of S. pneumoniae (D39 and EF3030) but that PAR-1 antagonism did not impair the ability of the host to control bacterial outgrowth. PAR-1 antagonist treatment significantly decreased pulmonary levels of IL-1β, CXCL1, CCL2, and CCL7 and attenuated alveolar leak. Ab neutralization studies further demonstrated a nonredundant role for IL-1β, CXCL1, and CCL7 in mediating neutrophil recruitment in response to S. pneumoniae infection. Taken together, these data demonstrate a key role for PAR-1 during S. pneumoniae lung infection that is mediated, at least in part, by influencing multiple downstream inflammatory mediators