Publications
150 results found
Griffiths M, Meade S, Summers C, et al., 2022, RAND appropriateness panel to determine the applicability of international guidelines on the management of acute respiratory distress syndrome (ARDS) and other strategies in the context of the COVID-19 pandemic, Thorax, Vol: 77, Pages: 129-135, ISSN: 0040-6376
Background: COVID-19 has become the commonest cause of ARDS world-wide. Features of the pathophysiology and clinical presentation partially distinguish it from “classical” ARDS. A RAND analysis gauged the opinion of an expert panel about the management of ARDS with and without COVID-19 as the precipitating cause, using recent UK guidelines as a template. Methods: An 11-person panel comprising intensive care practitioners rated the appropriateness of ARDS management options at different times during hospital admission, in the presence or absence of, or varying severity of SARS-CoV-2 infection on a scale of 1-9 (where, 1-3 is inappropriate, 4-6 is uncertain and 7-9 is appropriate). A summary of the anonymised results was discussed at an online meeting moderated by an expert in RAND methodology. The modified online survey comprising 76 questions, subdivided into: investigations 16, non-invasive respiratory support 18, basic ICU management of ARDS 20, management of refractory hypoxaemia 8, pharmacotherapy 7, and anticoagulation 7, was completed again. Results: Disagreement between experts was significant only when addressing the appropriateness of diagnostic bronchoscopy in patients with confirmed or suspected COVID-19. Adherence to existing published guidelines for the management of ARDS for relevant evidence-based interventions was recommended. Responses of the experts to the final survey suggested that the supportive management of ARDS should be the same, regardless of a COVID-19 diagnosis. For ARDS patients with COVID-19, the panel recommended routine treatment with corticosteroids and a lower threshold for full anticoagulation based on a high index of suspicion for venous-thrombo-embolic disease.Conclusion: The expert panel found no reason to deviate from the evidence based supportive strategies for managing ARDS outlined in recent guidelines.
Proudfoot AG, Kalakoutas A, Meade S, et al., 2021, Contemporary Management of Cardiogenic Shock: A RAND Appropriateness Panel Approach, CIRCULATION-HEART FAILURE, Vol: 14, ISSN: 1941-3289
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Kim SY, Mongey S, Wang P, et al., 2021, The Acid Injury and Repair (AIR) model: A new ex vivo tool to understand lung repair, Biomaterials, Vol: 267, ISSN: 0142-9612
Research into mechanisms underlying lung injury and subsequent repair responses is currently of paramount importance. There is a paucity of models that bridge the gap between in vitro and in vivo research. Such intermediate models are critical for researchers to decipher the mechanisms that drive repair and to test potential new treatments for lung repair and regeneration. Here we report the establishment of a new tool, the Acid Injury and Repair (AIR) model, that will facilitate studies of lung tissue repair. In this model, injury is applied to a restricted area of a precision-cut lung slice using hydrochloric acid, a clinically relevant driver. The surrounding area remains uninjured, thus mimicking the heterogeneous pattern of injury frequently observed in lung diseases. We show that in response to injury, the percentage of progenitor cells (pro surfactant protein C, proSP-C and TM4SF1 positive) significantly increases in the injured region. Whereas in the uninjured area, the percentage of proSP-C/TM4SF1 cells remains unchanged but proliferating cells (Ki67 positive) increase. These effects are modified in the presence of inhibitors of proliferation (Cytochalasin D) and Wnt secretion (C59) demonstrating that the AIR model is an important new tool for research into lung disease pathogenesis and potential regenerative medicine strategies.
Kim S, Mongey R, Griffiths M, et al., 2020, An ex vivo acid injury and repair (AIR) model using precision-cut lung slices to understand lung injury and repair, Current protocols in mouse biology, Vol: 10, Pages: e85-e85, ISSN: 2161-2617
Recent advances in cell culture models like air‒liquid interface culture and ex vivo models such as organoids have advanced studies of lung biology; however, gaps exist between these models and tools that represent the complexity of the three‐dimensional environment of the lung. Precision‐cut lung slices (PCLS) mimic the in vivo environment and bridge the gap between in vitro and in vivo models. We have established the acid injury and repair (AIR) model where a spatially restricted area of tissue is injured using drops of HCl combined with Pluronic gel. Injury and repair are assessed by immunofluorescence using robust markers, including Ki67 for cell proliferation and prosurfactant protein C for alveolar type 2/progenitor cells. Importantly, the AIR model enables the study of injury and repair in mouse lung tissue without the need for an initial in vivo injury, and the results are highly reproducible. Here, we present detailed protocols for the generation of PCLS and the AIR model. We also describe methods to analyze and quantify injury in AIR‐PCLS by immunostaining with established early repair markers and fluorescence imaging. This novel ex vivo model is a versatile tool for studying lung cell biology in acute lung injury and for semi‐high‐throughput screening of potential therapeutics. © 2020 Wiley Periodicals LLC.
Cheong SS, Akram K, Metellan C, et al., 2020, The planar polarity component Vangl2 is a key regulator of mechanosignaling, Frontiers in Cell and Developmental Biology, Vol: 8, ISSN: 2296-634X
VANGL2 is a component of the planar cell polarity (PCP) pathway, which regulates tissue polarity and patterning. The Vangl2Lp mutation causes lung branching defects due to dysfunctional actomyosin-driven morphogenesis. Since the actomyosin network regulates cell mechanics, we speculated that mechanosignaling could be impaired when VANGL2 is disrupted. Here, we used live-imaging of precision-cut lung slices (PCLS) from Vangl2Lp/+ mice to determine that alveologenesis is attenuated as a result of impaired epithelial cell migration. Vangl2Lp/+ tracheal epithelial cells (TECs) and alveolar epithelial cells (AECs) exhibited highly disrupted actomyosin networks and focal adhesions (FAs). Functional assessment of cellular forces confirmed impaired traction force generation in Vangl2Lp/+ TECs. YAP signaling in Vangl2Lp airway epithelium was reduced, consistent with a role for VANGL2 in mechanotransduction. Furthermore, activation of RhoA signaling restored actomyosin organization in Vangl2Lp/+, confirming RhoA as an effector of VANGL2. This study identifies a pivotal role for VANGL2 in mechanosignaling, which underlies the key role of the PCP pathway in tissue morphogenesis.
Kemp P, Paul R, Neil D, et al., 2020, Metabolic profiling shows pre-existing mitochondrial dysfunction contributes to muscle loss in a model of ICU acquired weakness, Journal of Cachexia, Sarcopenia and Muscle, Vol: 11, Pages: 1321-1335, ISSN: 2190-6009
Background:Surgery can lead to significant muscle loss,which increasesrecovery time and associateswith increased mortality. Muscle lossis not uniform,with some patients losing significant muscle mass and others losing relatively little, andis likely to be accompanied by marked changes in circulating metabolitesand proteins. Determining these changes may help understand the variability and identify novel therapeutic approachesor markers of muscle wasting.Methods:To determine the association between muscle loss and circulating metabolites we studied 20 male patients (median age,70.5, inter-quartile range,62.5-75)undergoing aortic surgery. Muscle mass was determined before and 7 days after surgery and blood samples were taken before surgery, and 1, 3 and 7 days after surgery. The circulating metabolome and proteome were determined using commercial services (Metabolon and SOMAlogic). Results:Ten patients lost more than 10% of the cross-sectional area of the rectus femoris (RFCSA) and were defined as wasting. Metabolomic analysisshowed 557 circulatingmetabolites were altered following surgery (q<0.05) in the whole cohort and 104 differed between wasting and non-wasting patients (q<0.05).Weighted genome co-expression network analysis,identified clusters of metabolites, both before and after surgery, that associated with muscle mass and function(r=-0.72, p=6x10-4with RFCSAon day 0, p=3x10-4with RFCSAon day 7 and r=-0.73, p=5x10-4with hand-grip strength on day 7). These clusters were mainly composed of acyl carnitines and dicarboxylates indicating that pre-existing mitochondrial dysfunction contributes to muscle loss following surgery. Surgery elevated cortisolto the same extent in wasting and non-wasting patients but the cortisol:cortisone ratio was higher in the wasting patients (day 3 p=0.043 and day 7 p=0.016).Wasting patients also showed a greater increase in circulating nucleotides3 days after surgery. Comparison of the metabolome with inflammatory markers
Upton PD, Park JES, De Souza PM, et al., 2020, The endothelial protective factors, BMP9 and BMP10, inhibit CCL2 release by human vascular endothelial cells, Journal of Cell Science, Vol: 133, ISSN: 0021-9533
Bone morphogenetic protein (BMP)-9 and BMP10 are circulating ligands that mediate endothelial cell (EC) protection via complexes of the type I receptor, ALK1, and the type II receptors, the activin type-IIA and bone morphogenetic type II receptors. We previously demonstrated that BMP9 induces the expression of interleukin-6, interleukin-8 and E-selectin in ECs and may influence their interactions with monocytes and neutrophils. We asked whether BMP9 and BMP10 regulate the expression of Chemokine (C-C motif) ligand 2 (CCL2), a key chemokine involved in monocyte-macrophage chemoattraction. Here, we show that BMP9 and BMP10 repress basal CCL2 expression and release from human pulmonary artery ECs and aortic ECs. This was dependent on ALK1 and co-dependent on ACTR-IIA and BMPR-II. Assessment of canonical Smad signalling indicated a reliance of this response on Smad4. Of note, Smad1/5 signalling contributed only at BMP9 concentrations similar to those in the circulation. In the context of inflammation, BMP9 did not alter the induction of CCL2 by TNF-α. As CCL2 promotes monocyte/macrophage chemotaxis and endothelial permeability, these data support the concept that BMP9 preserves basal endothelial integrity.
Powell N, 2020, Adaptation of the British Society of Gastroenterology guidelines on the management of acute severe ulcerative colitis in the context of the COVID-19 pandemic: a RAND appropriateness panel, Gut, Vol: 69, Pages: 1769-1777, ISSN: 0017-5749
ObjectiveManagement of acute severe ulcerative colitis (ASUC) during the novel coronavirus2019 (COVID-19) pandemic presents significant dilemmas. We aimed to provideCOVID-19-specific guidance using current British Society of Gastroenterology (BSG)guidelines as a reference point.DesignWe convened a RAND appropriateness panel comprising 14 gastroenterologists andan IBD nurse consultant supplemented by surgical and COVID-19 experts. Panellistsrated the appropriateness of interventions for ASUC in the context of severe acuterespiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Median scores anddisagreement index (DI) were calculated. Results were discussed at a moderatedmeeting prior to a second survey.ResultsPanellists recommended that patients with ASUC should be isolated throughout theirhospital stay and should have a SARS-CoV-2 swab performed on admission. Patientswith a positive swab should be discussed with COVID-19 specialists.As per BSG guidance, intravenous hydrocortisone was considered appropriate asinitial management; only in patients with COVID-19 pneumonia was their use deemeduncertain. In patients requiring rescue therapy, infliximab with continuing steroidswas recommended. Delaying colectomy because of COVID-19 was deemedinappropriate.Steroid tapering as per BSG guidance, was deemed appropriate for all patients apartfrom those with COVID-19 pneumonia in whom a 4-6-week taper was preferred. Post-ASUC maintenance therapy was dependent on SARS-CoV-2 status but, in general,biologics were more likely to be deemed appropriate than azathioprine or tofacitinib.Panellists deemed prophylactic anticoagulation post-discharge to be appropriate inpatients with a positive SARS-CoV-2 swab.ConclusionWe have suggested COVID-19-specific adaptations to the BSG ASUC guideline using aRAND Panel.
Ujma S, Carse S, Chetty A, et al., 2019, Surfactant Protein A Impairs Genital HPV16 Pseudovirus Infection by Innate Immune Cell Activation in A Murine Model, PATHOGENS, Vol: 8
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Akram K, Yates L, Mongey R, et al., 2019, Time-lapse imaging of alveologenesis in mouse precision-cut lung slices, Bio-protocol, Vol: 9, ISSN: 2331-8325
Alveoli are the gas-exchange units of lung. The process of alveolar development,alveologenesis, is regulated by a complex network of signaling pathways that act on various cell typesincluding alveolar type I and II epithelial cells, fibroblasts and the vascular endothelium. Dysregulatedalveologenesis results in bronchopulmonary dysplasia in neonates and in adults, disrupted alveolarregeneration is associated with chronic lung diseases including COPD and pulmonary fibrosis.Therefore, visualizing alveologenesis is critical to understand lung homeostasis and for thedevelopment of effective therapies for incurable lung diseases. We have developed a technique tovisualize alveologenesis in real-time using a combination of widefield microscopy and imagedeconvolution of precision-cut lung slices. Here, we describe this live imaging technique in step-by-stepdetail. This time-lapse imaging technique can be used to capture the dynamics of individual cells withintissue slices over a long time period (up to 16 h), with minimal loss of fluorescence or cell toxicity.
Griffiths M, Fan E, Baudouin SV, 2019, New UK guidelines for the management of adult patients with ARDS, Thorax, Vol: 74, Pages: 931-933, ISSN: 0040-6376
Kim SY, Mongey R, Wang P, et al., 2019, LSC-2019-A novel ex-vivo approach to study lung injury and repair, European-Respiratory-Society (ERS) International Congress, Publisher: European Respiratory Society, ISSN: 0903-1936
Ng-Blichfeldt J-P, Gosens R, Dean C, et al., 2019, Regenerative pharmacology for COPD: breathing new life into old lungs, Thorax, Vol: 74, Pages: 890-897, ISSN: 1468-3296
Chronic obstructive pulmonary disease (COPD) is a major global health concern with few effective treatments. Widespread destruction of alveolar tissue contributes to impaired gas exchange in severe COPD, and recent radiological evidence suggests that destruction of small airways is a major contributor to increased peripheral airway resistance in disease. This important finding might in part explain the failure of conventional anti-inflammatory treatments to restore lung function even in patients with mild disease. There is a clear need for alternative pharmacological strategies for patients with COPD/emphysema. Proposed regenerative strategies such as cell therapy and tissue engineering are hampered by poor availability of exogenous stem cells, discouraging trial results, and risks and cost associated with surgery. An alternative therapeutic approach is augmentation of lung regeneration and/or repair by biologically active factors, which have potential to be employed on a large scale. In favour of this strategy, the healthy adult lung is known to possess a remarkable endogenous regenerative capacity. Numerous preclinical studies have shown induction of regeneration in animal models of COPD/emphysema. Here, we argue that given the widespread and irreversible nature of COPD, serious consideration of regenerative pharmacology is necessary. However, for this approach to be feasible, a better understanding of the cell-specific molecular control of regeneration, the regenerative potential of the human lung and regenerative competencies of patients with COPD are required.
Griffiths MJD, McAuley DF, Perkins GD, et al., 2019, Guidelines on the management of acute respiratory distress syndrome, BMJ Open Respiratory Research, Vol: 6, Pages: 1-27, ISSN: 2052-4439
The Faculty of Intensive Care Medicine and Intensive Care Society Guideline Development Group have used GRADE methodology to make the following recommendations for the management of adult patients with acute respiratory distress syndrome (ARDS). The British Thoracic Society supports the recommendations in this guideline. Where mechanical ventilation is required, the use of low tidal volumes (<6 ml/kg ideal body weight) and airway pressures (plateau pressure <30 cmH2O) was recommended. For patients with moderate/severe ARDS (PF ratio<20 kPa), prone positioning was recommended for at least 12 hours per day. By contrast, high frequency oscillation was not recommended and it was suggested that inhaled nitric oxide is not used. The use of a conservative fluid management strategy was suggested for all patients, whereas mechanical ventilation with high positive end-expiratory pressure and the use of the neuromuscular blocking agent cisatracurium for 48 hours was suggested for patients with ARDS with ratio of arterial oxygen partial pressure to fractional inspired oxygen (PF) ratios less than or equal to 27 and 20 kPa, respectively. Extracorporeal membrane oxygenation was suggested as an adjunct to protective mechanical ventilation for patients with very severe ARDS. In the absence of adequate evidence, research recommendations were made for the use of corticosteroids and extracorporeal carbon dioxide removal.
Kemp P, Griffiths M, Polkey M, 2019, Muscle wasting in the presence of disease, why is it so variable?, Biological Reviews, Vol: 94, Pages: 1038-105, ISSN: 1464-7931
Skeletal muscle wasting is a common clinical feature of many chronic diseases and also occurs in response to single acute events. The accompanying loss of strength can lead to significant disability, increased care needs and have profound negative effects on quality of life. As muscle is the most abundant source of amino acids in the body, it appears to function as a buffer for fuel and substrates that can be used to repair damage elsewhere and to feed the immune system. In essence, the fundamentals of muscle wasting are simple: less muscle is made than is broken down. However, although well‐described mechanisms modulate muscle protein turnover, significant individual differences in the amount of muscle lost in the presence of a given severity of disease complicate the understanding of underlying mechanisms and suggest that individuals have different sensitivities to signals for muscle loss. Furthermore, the rate at which muscle protein is turned over under normal conditions means that clinically significant muscle loss can occur with changes in the rate of protein synthesis and/or breakdown that are too small to be measurable. Consequently, the changes in expression of factors regulating muscle turnover required to cause a decline in muscle mass are small and, except in cases of rapid wasting, there is no consistent pattern of change in the expression of factors that regulate muscle mass. MicroRNAs are fine tuners of cell phenotype and are therefore ideally suited to cause the subtle changes in proteome required to tilt the balance between synthesis and degradation in a way that causes clinically significant wasting. Herein we present a model in which muscle loss as a consequence of disease in non‐muscle tissue is modulated by a set of microRNAs, the muscle expression of which is associated with severity of disease in the non‐muscle tissue. These microRNAs alter fundamental biological processes including the synthesis of ribosomes and mitochondria leading to reduce
Akram K, Yates L, Mongey R, et al., 2019, Live imaging of alveologenesis in precision-cut lung slices reveals dynamic epithelial cell behaviour, Nature Communications, Vol: 10, Pages: 1-16, ISSN: 2041-1723
Damage to alveoli, the gas-exchanging region of the lungs, is a component of many chronic and acute lung diseases. In addition, insufficient generation of alveoli results in bronchopulmonary dysplasia, a disease of prematurity. Therefore visualising the process of alveolar development (alveologenesis) is critical for our understanding of lung homeostasis and for the development of treatments to repair and regenerate lung tissue. Using long-term, time-lapse imaging of precision-cut lung slices, we show alveologenesis for the first time. We reveal that during this process, epithelial cells are highly mobile and we identify specific cell behaviours that contribute to alveologenesis: cell clustering, hollowing and cell extension. Using the cytoskeleton inhibitors blebbistatin and cytochalasin D, we showed that cell migration is a key driver of alveologenesis. This study reveals important novel information about lung biology and provides a new system in which to manipulate alveologenesis genetically and pharmacologically.
Dunning J, Blankley S, Hoang LT, et al., 2019, Author Correction: Progression of whole-blood transcriptional signatures from interferon-induced to neutrophil-associated patterns in severe influenza., Nature Immunology, Vol: 20, Pages: 373-373, ISSN: 1529-2908
In the version of this article initially published, a source of funding was not included in the Acknowledgements section. That section should include the following: P.J.M.O. was supported by EU FP7 PREPARE project 602525. The error has been corrected in the HTML and PDF version of the article.
Proudfoot A, Bayliffe A, O'Kane CM, et al., 2018, Novel anti-tumour necrosis factor receptor-1 (TNFR1) domain antibody prevents pulmonary inflammation in experimental acute lung injury, Thorax, Vol: 73, Pages: 723-730, ISSN: 1468-3296
BACKGROUND: Tumour necrosis factor alpha (TNF-α) is a pleiotropic cytokine with both injurious and protective functions, which are thought to diverge at the level of its two cell surface receptors, TNFR1 and TNFR2. In the setting of acute injury, selective inhibition of TNFR1 is predicted to attenuate the cell death and inflammation associated with TNF-α, while sparing or potentiating the protective effects of TNFR2 signalling. We developed a potent and selective antagonist of TNFR1 (GSK1995057) using a novel domain antibody (dAb) therapeutic and assessed its efficacy in vitro, in vivo and in a clinical trial involving healthy human subjects. METHODS: We investigated the in vitro effects of GSK1995057 on human pulmonary microvascular endothelial cells (HMVEC-L) and then assessed the effects of pretreatment with nebulised GSK1995057 in a non-human primate model of acute lung injury. We then tested translation to humans by investigating the effects of a single nebulised dose of GSK1995057 in healthy humans (n=37) in a randomised controlled clinical trial in which subjects were subsequently exposed to inhaled endotoxin. RESULTS: Selective inhibition of TNFR1 signalling potently inhibited cytokine and neutrophil adhesion molecule expression in activated HMVEC-L monolayers in vitro (P<0.01 and P<0.001, respectively), and also significantly attenuated inflammation and signs of lung injury in non-human primates (P<0.01 in all cases). In a randomised, placebo-controlled trial of nebulised GSK1995057 in 37 healthy humans challenged with a low dose of inhaled endotoxin, treatment with GSK1995057 attenuated pulmonary neutrophilia, inflammatory cytokine release (P<0.01 in all cases) and signs of endothelial injury (P<0.05) in bronchoalveolar lavage and serum samples. CONCLUSION: These data support the potential for pulmonary delivery of a selective TNFR1 dAb as a novel therapeutic approach for the prevention of acute respiratory distress syndrome. TRI
Dunning J, Blankley S, Hoang LT, et al., 2018, Progression of whole-blood transcriptional signatures from interferon-induced to neutrophil-associated patterns in severe influenza, Nature Immunology, Vol: 19, Pages: 625-635, ISSN: 1529-2916
Transcriptional profiles and host-response biomarkers are used increasingly to investigate the severity, subtype and pathogenesis of disease. We now describe whole-blood mRNA signatures and concentrations of local and systemic immunological mediators in 131 adults hospitalized with influenza, from whom extensive clinical and investigational data were obtained by MOSAIC investigators. Signatures reflective of interferon-related antiviral pathways were common up to day 4 of symptoms in patients who did not require mechanical ventilator support; in those who needed mechanical ventilation, an inflammatory, activated-neutrophil and cell-stress or death (‘bacterial’) pattern was seen, even early in disease. Identifiable bacterial co-infection was not necessary for this ‘bacterial’ signature but was able to enhance its development while attenuating the early ‘viral’ signature. Our findings emphasize the importance of timing and severity in the interpretation of host responses to acute viral infection and identify specific patterns of immune-system activation that might enable the development of novel diagnostic and therapeutic tools for severe influenza.
Alcada J, Shao D, Griffiths MJ, et al., 2018, Retinoic Acid Upregulates Endothelial-Derived Angiocrine Factors to Promote Human Alveolar Epithelial Repair, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Kemp P, Connolly, Paul R, et al., 2017, miR-424-5p reduces ribosomal RNA and protein synthesis in muscle wasting, Journal of Cachexia, Sarcopenia and Muscle, Vol: 9, Pages: 400-416, ISSN: 2190-6009
Background: A loss of muscle mass occurs as a consequence of a range of chronic and acute diseases as well as in older age. This wasting results from an imbalance of protein synthesis and degradation with a reduction in synthesis and resistance to anabolic stimulation often reported features. Ribosomes are required for protein synthesis so changes in the control of ribosome synthesis is a potential contributor to muscle wasting. MicroRNAs (miRNAs) are known regulators of muscle phenotype and have been shown to modulate components of the protein synthetic pathway. One miRNA that is predicted to target a number of components of protein synthetic pathway is miR-424-5p, which is elevated in the quadriceps of patients with chronic obstructive pulmonary disease (COPD).Methods: Targets of miR-424-5p were identified by Ago2 pull-down and the effects of the miRNA on RNA and protein expression were determined by qPCR and western blotting in muscle cells in vitro. Protein synthesis was determined by puromycin incorporation in vitro. The miRNA was over-expressed in the tibialis anterior muscle of mice by electroporation and the effects quantified. Finally, quadriceps expression of the miRNA was determined by qPCR in patients with COPD, intensive care unit acquired weakness (ICUAW), and in patients undergoing aortic surgery as well as in individuals from the Hertfordshire Sarcopenia Study.Results: Pull-down assays showed that miR-424-5p bound to mRNAs encoding proteins associated with muscle protein synthesis. The most highly enriched mRNAs encoded proteins required for the Pol I RNA pre-initiation complex (PIC) required for rRNA transcription, (PolR1A and Upstream binding transcription factor, UBTF). In vitro, miR-424-5p reduced expression of these RNAs, reduced rRNA levels and inhibited protein synthesis. In mice, over-expression of miR-322 (rodent miR-424 orthologue) caused fibre atrophy and reduced UBTF expression and rRNA levels. In humans elevated miR-424-5p as
Alcada J, Shao DS, Griffiths MJD, et al., 2017, MECHANISMS OF REGENERATION: RETINOIC ACID ACTS VIA THE ENDOTHELIUM TO DRIVE HUMAN LUNG REPAIR, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A106-A107, ISSN: 0040-6376
Kemp P, paul R, lee J, et al., 2017, miR-422a suppresses SMAD4 protein expression and promotes resistance to muscle loss, Journal of Cachexia Sarcopenia and Muscle, Vol: 9, Pages: 119-128, ISSN: 2190-5991
BackgroundLoss of muscle mass and strength are important sequelae of chronic disease, but the response of individuals is remarkably variable, suggesting important genetic and epigenetic modulators of muscle homeostasis. Such factors are likely to modify the activity of pathways that regulate wasting, but to date, few such factors have been identified.MethodsThe effect of miR-422a on SMAD4 expression and transforming growth factor (TGF)-β signalling were determined by western blotting and luciferase assay. miRNA expression was determined by qPCR in plasma and muscle biopsy samples from a cross-sectional study of patients with chronic obstructive pulmonary disease (COPD) and a longitudinal study of patients undergoing aortic surgery, who were subsequently admitted to the intensive care unit (ICU).ResultsmiR-422a was identified, by a screen, as a microRNA that was present in the plasma of patients with COPD and negatively associated with muscle strength as well as being readily detectable in the muscle of patients. In vitro, miR-422a suppressed SMAD4 expression and inhibited TGF-beta and bone morphogenetic protein-dependent luciferase activity in muscle cells. In male patients with COPD and those undergoing aortic surgery and on the ICU, a model of ICU-associated muscle weakness, quadriceps expression of miR-422a was positively associated with muscle strength (maximal voluntary contraction r = 0.59, P < 0.001 and r = 0.51, P = 0.004, for COPD and aortic surgery, respectively). Furthermore, pre-surgery levels of miR-422a were inversely associated with the amount of muscle that would be lost in the first post-operative week (r = −0.57, P < 0.001).ConclusionsThese data suggest that differences in miR-422a expression contribute to the susceptibility to muscle wasting associated with chronic and acute disease and that at least part of this activity may be mediated by reduced TGF-beta signalling in skeletal muscle.
Mason C, Dooley N, Griffiths M, 2017, Acute respiratory distress syndrome, CLINICAL MEDICINE, Vol: 17, Pages: 439-443, ISSN: 1470-2118
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farre garros, paul R, connolly M, et al., 2017, miR-542 promotes mitochondrial dysfunction and SMAD activity and is raised in ICU Acquired Weakness, American Journal of Respiratory and Critical Care Medicine, Vol: 196, Pages: 1-12, ISSN: 1073-449X
Rationale: Loss of skeletal muscle mass and function is a common consequence of critical illness and a range of chronic diseases but the mechanisms by which this occurs are unclear. Objectives: We aimed to identify miRNAs that were increased in the quadriceps of patients with muscle wasting and to determine the molecular pathways by which they contributed to muscle dysfunction. Methods: miR-542-3p/-5p were quantified in the quadriceps of patients with COPD and intensive care unit acquired weakness (ICUAW). The effect of miR-542-3p/5p was determined on mitochondrial function and TGF-β signaling in vitro and in vivo. Measurements and main results: miR-542-3p/5p were elevated in patients with COPD but more markedly in patients with ICUAW. In vitro, miR-542-3p suppressed the expression of the mitochondrial ribosomal protein MRPS10, and reduced 12S rRNA expression suggesting mitochondrial ribosomal stress. miR-542-5p increased nuclear phospho-SMAD2/3 and suppressed expression of SMAD7, SMURF1 and PPP2CA, proteins that inhibit or reduce SMAD2/3 phosphorylation suggesting that miR-542-5p increased TGF-β signaling. In mice, miR-542 over-expression caused muscle wasting, reduced mitochondrial function, 12S rRNA expression and SMAD7 expression, consistent with the effects of the miRNAs in vitro. Similarly, in patients with ICUAW, the expression of 12S rRNA and of the inhibitors of SMAD2/3 phosphorylation were reduced, indicative of mitochondrial ribosomal stress and increased TGF-β signaling. In patients undergoing aortic surgery, pre-operative levels of miR-542-3p/5p were positively correlated with muscle loss following surgery. Conclusion; Elevated miR-542-3p/5p may cause muscle atrophy in ICU patients through the promotion of mitochondrial dysfunction and activation of SMAD2/3 phosphorylation.
Thakuria L, Romano R, Goss V, et al., 2017, Surfactant Metabolism During Normothermic Ex Vivo Lung Perfusion, 37th Annual Meeting and Scientific Sessions of the International-Society-for-Heart-and-Lung-Transplantation (ISHLT), Publisher: ELSEVIER SCIENCE INC, Pages: S91-S91, ISSN: 1053-2498
Poobalasingam T, Yates LL, Walker SA, et al., 2017, Heterozygous Vangl2 looptail mice reveal novel roles for the planar cell polarity pathway in adult lung homeostasis and repair, Disease Models & Mechanisms, Vol: 10, Pages: 409-423, ISSN: 1754-8403
Lung diseases impose a huge economic and health burden worldwide. A key aspect of several adult lung diseases, such as Idiopathic pulmonary fibrosis (IPF) and Chronic Obstructive pulmonary Disease (COPD), including emphysema, is aberrant tissue repair, which leads to an accumulation of damage and impaired respiratory function. Currently, there are few effective treatments available for these diseases and their incidence is rising.The Planar Cell Polarity (PCP) pathway is critical for the embryonic development of many organs, including kidney and lung. We have previously shown that perturbation of the PCP pathway impairs tissue morphogenesis, which disrupts the number and shape of epithelial tubes formed within these organs during embryogenesis. However, very little is known about the role of the PCP pathway beyond birth, partly due to the perinatal lethality of many PCP mouse mutant lines.Here we have investigated heterozygous Looptail (Lp) mice, in which a single copy of the core PCP gene, Vangl2, is disrupted. We show that these mice are viable but display severe airspace enlargement and impaired adult lung function. Underlying these defects, we find that Vangl2Lp/+ lungs exhibit altered distribution of actin microfilaments and abnormal regulation of the actin modifying protein cofilin. In addition, we show that Vangl2Lp/+ lungs exhibit many of the hallmarks of tissue damage including an altered macrophage population, abnormal elastin deposition and elevated levels of the elastin-modifying enzyme, Mmp12, all of which are observed in the lung disease, emphysema.In vitro, VANGL2 disruption impairs directed cell migration and reduces the rate of repair following scratch wounding of human alveolar epithelial cells. Moreover, using population data from a birth cohort of young adults, all aged 31, we found evidence of an interactive effect between VANGL2 and smoking (a tissue damaging insult) on lung function. Finally, we show that that PCP genes VANGL2 and SCRIBBLE (SC
Ng-Blichfeldt JP, Alçada J, Montero MA, et al., 2017, Deficient retinoid-driven angiogenesis may contribute to failure of adult human lung regeneration in emphysema, Thorax, Vol: 72, Pages: 510-521, ISSN: 0040-6376
BACKGROUND: Molecular pathways that regulate alveolar development and adult repair represent potential therapeutic targets for emphysema. Signalling via retinoic acid (RA), derived from vitamin A, is required for mammalian alveologenesis, and exogenous RA can induce alveolar regeneration in rodents. Little is known about RA signalling in the human lung and its potential role in lung disease. OBJECTIVES: To examine regulation of human alveolar epithelial and endothelial repair by RA, and characterise RA signalling in human emphysema. METHODS: The role of RA signalling in alveolar epithelial repair was investigated with a scratch assay using an alveolar cell line (A549) and primary human alveolar type 2 (AT2) cells from resected lung, and the role in angiogenesis using a tube formation assay with human lung microvascular endothelial cells (HLMVEC). Localisation of RA synthetic (RALDH-1) and degrading (cytochrome P450 subfamily 26 A1 (CYP26A1)) enzymes in human lung was determined by immunofluorescence. Regulation of RA pathway components was investigated in emphysematous and control human lung tissue by quantitative real-time PCR and Western analysis. RESULTS: RA stimulated HLMVEC angiogenesis in vitro; this was partially reproduced with a RAR-α agonist. RA induced mRNA expression of vascular endothelial growth factor A (VEGFA) and VEGFR2. RA did not modulate AT2 repair. CYP26A1 protein was identified in human lung microvasculature, whereas RALDH-1 partially co-localised with vimentin-positive fibroblasts. CYP26A1 mRNA and protein were increased in emphysema. CONCLUSIONS: RA regulates lung microvascular angiogenesis; the endothelium produces CYP26A1 which is increased in emphysema, possibly leading to reduced RA availability. These data highlight a role for RA in maintenance of the human pulmonary microvascular endothelium.
McNamee J, Gillies M, Barrett N, et al., 2016, pRotective vEntilation with veno-venouS lung assisT in respiratory failure: A protocol for a multicentre randomised controlled trial of extracorporeal carbon dioxide removal in patients with acute hypoxaemic respiratory failure, Journal of the Intensive Care Society, Vol: 18, Pages: 159-169, ISSN: 1751-1437
One of the few interventions to demonstrate improved outcomes for acute hypoxaemic respiratory failure is reducing tidal volumes when using mechanical ventilation, often termed lung protective ventilation. Veno-venous extracorporeal carbon dioxide removal (vv-ECCO2R) can facilitate reducing tidal volumes. pRotective vEntilation with veno-venouS lung assisT (REST) is a randomised, allocation concealed, controlled, open, multicentre pragmatic trial to determine the clinical and cost-effectiveness of lower tidal volume mechanical ventilation facilitated by vv-ECCO2R in patients with acute hypoxaemic respiratory failure. Patients requiring intubation and mechanical ventilation for acute hypoxaemic respiratory failure will be randomly allocated to receive either vv-ECCO2R and lower tidal volume mechanical ventilation or standard care with stratification by recruitment centre. There is a need for a large randomised controlled trial to establish whether vv-ECCO2R in acute hypoxaemic respiratory failure can allow the use of a more protective lung ventilation strategy and is associated with improved patient outcomes.
Mason C, Dooley N, Griffiths M, 2016, Acute respiratory distress syndrome, Clinical Medicine, Vol: 16, Pages: s66-s70, ISSN: 1470-2118
Acute respiratory distress syndrome is a common cause of acute respiratory failure that is underdiagnosed both inside and outside of intensive care units. Progression to the most severe forms of the syndrome confers a mortality rate greater than 40% and is associated with often severe functional disability and psychological sequelae in survivors. While there are no disease-modifying pharmacotherapies for the syndrome, this progression may be prevented through the institution of quality improvement measures that minimise iatrogenic injury associated with acute severe illness.
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