Biology subjects

McAuley, D. F.

Publications and source records attributed to McAuley, D. F..

3 recordsLinked to original sources

bioRxiv2022

E-cigarette vapour from base components propylene glycol and vegetable glycerine inhibits inflammatory response in macrophages and epithelial cells

E-cigarettes are a highly popular nicotine replacement therapy in the process of smoking cessation. Despite this, research on the effects of E-vapours to human health remains limited. The popularity of vaping and mass production of cheap E-liquids has led to compromised safety regulations, with contaminants such as heavy metals and alkaloids detected in multiple liquids. Vaporised E-liquids increase cellular ROS generation and inflammatory cytokine release from pulmonary macrophages. This suggests that E-cigarette usage might activate inflammasomes. Common food additives vegetable glycerine (VG) and propylene glycol (PG) form the base of all E-liquids, but little is known about their inflammatory potential once inhaled. Here, the effect of base components PG and VG on inflammasome activation and cytokine release was investigated in macrophages and epithelial cells exposed to E-liquids and vaporised E-liquid extract (E-vapour). Base E-liquid and E-vapour did not induce cellular cytotoxicity and non-vapourised E-liquid had no effect on IL-8 release. However, basic PG/VG E-vapour inhibited both IL-8 release and conventional inflammasome activation by known inflammatory activators in macrophages and epithelial cells. These results propose a novel inhibitory effect of basic E-vapour components to inflammatory challenges.

immunology↗

bioRxiv2020

Characterising pre-clinical sub-phenotypic models of Acute Respiratory Distress Syndrome: an experimental ovine study.

The Acute Respiratory Distress Syndrome (ARDS) describes a heterogenous population of patients with acute severe respiratory failure. However, contemporary advances have begun to identify distinct sub-phenotypes that exist within its broader envelope. These sub-phenotypes have varied outcomes and respond differently to several previously studied interventions. A more precise understanding of their pathobiology and an ability to prospectively identify them, may allow for the development of precision therapies in ARDS. Historically, animal models have played a key role in translational research, although few studies have so far assessed either the ability of animal models to replicate these sub-phenotypes or investigated the presence of sub-phenotypes within animal models. Here, in three ovine models of ARDS, using combinations of oleic acid and intravenous, or intratracheal lipopolysaccharide, we demonstrate the presence of sub-phenotypes which qualitatively resemble those found in clinical cohorts. Principal Components Analysis and partitional clustering reveal two clusters, differentiated by markers of shock, inflammation, and lung injury. This study provides the first preliminary evidence of ARDS phenotypes in pre-clinical models and develops a methodology for investigating this phenomenon in future studies.

physiology↗

bioRxiv2019

A porcine ex vivo lung perfusion model to investigate bacterial pathogenesis

The use of animal infection models is essential to understand microbial pathogenesis and to develop and test treatments. Insects, and 2D and 3D tissue models are increasingly being used as surrogate for mammalian models. However, there are concerns whether these models recapitulate the complexity of host-pathogen interactions. Here, we developed the ex vivo lung perfusion (EVLP) model of infection using porcine lungs to investigate Klebsiella pneumoniae-triggered pneumonia as model of respiratory infections. The porcine EVLP model recapitulates features of K. pneumoniae-induced pneumonia lung injury. This model is also useful to assess the pathogenic potential of K. pneumoniae as we observed that the attenuated Klebsiella capsule mutant strain caused less pathological tissue damage with a concomitant decrease in the bacterial burden compare to lungs infected with the wild type. The porcine EVLP model allows assessment of inflammatory responses following infection; similar to the mouse pneumonia model, we observed an increase of il-10 in the lungs infected with the wild type and an increase of ifn-{gamma} in lungs infected with the capsule mutant. This model also allows monitoring phenotypes at the single-cell level. Wild-type K. pneumoniae skews macrophages towards an M2-like state. In vitro experiments probing pig bone marrow-derived macrophages uncovered the role of the M2 transcriptional factor STAT6, and that Klebsiella-induced il10 expression is controlled by p38 and ERK. Klebsiella-induced macrophage polarization is dependent on the capsule. Altogether, this study support the utility of the EVLP model using pig lungs as platform to investigate the infection biology of respiratory pathogens.\n\nIMPORTANCEThe implementation of infection models that approximate human disease is essential to understand infections and for testing new therapies before they enter into clinical stages. Rodents are used in most of pre-clinical studies, although the differences between mouse and man have fuelled the conclusion that murine studies are unreliable predictors of human outcomes. Here, we have developed a whole lung porcine model of infection using the established ex vivo lung perfusion (EVLP) system established to re-condition human lungs for transplant. As a proof-of-principle, we provide evidence demonstrating that infection of the porcine EVLP with the human pathogen K. pneumoniae recapitulates the known features of Klebsiella-triggered pneumonia. Moreover, our data revealed the porcine EVLP model is useful to reveal features of the virulence of K. pneumoniae including the manipulation of immune cells. Altogether, this study supports the utility of the EVLP model using pig lungs as surrogate host for assessing respiratory infections.

microbiology↗