NIHRDataInsights/HRCSData huggingface dataset:
Title: 2013 Doctoral Fellowship: Development of Oncostatin M inhibition as a novel treatment for Acute Lung Injury
Funder: Health and Social Care Research and Development Division (HSC R&D) of Public Health Agency, Northern Ireland

Abstract: Acute Lung Injury (ALI) has a high morbidity and mortality with no effective pharmacological intervention. Alveolar fluid leak occurs in response to inflammation with resulting endothelial and epithelial injury. Matrix Metalloproteinases (MMPs) drive inflammatory cell recruitment and extracellular matrix destruction in ALI. We have identified that Oncostatin M (OSM) is produced by neutrophils and monocytic cells in ALI and that it amplifies inflammatory cytokine and MMP production by alveolar epithelial and endothelial cells. OSM inhibition is being tested as a therapy for other inflammatory diseases including rheumatoid arthritis. This project will test the hypotheses that OSM is increased and bioactive in the lung in ALI, and that inhibiting OSM in clinically relevant human in vitro and ex vivo models of ALI, reduces injury and promotes repair. We will investigate the following - OSM bioactivity in the alveolus in ALI - OSM inhibition on inflammatory cytokine and MMP production by primary human alveolar epithelial and endothelial cells in in vitro models of ALI - effect of OSM inhibition on alveolar epithelial cell wound healing - effect of OSM inhibition on monocyte/macrophage clearance of bacterial pathogens - effect of OSM inhibition on epithelial function, endothelial damage and inflammation in response to LPS in the human ex vivo lung perfusion model. Taken together these data will confirm whether OSM inhibition might provide a safe new therapeutic option for ALI, inhibiting injury and promoting epithelial repair without compromising host defence. Data will inform the design of a clinical trial of anti-OSM therapy in ALI.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: Development, validation and application of population-based pulmonary disease models using robustness analysis and ensemble forecasting
Funder: Engineering and Physical Sciences Research Council

Abstract: Lung diseases affecting the critically ill (acute respiratory distress syndrome (ARDS), pneumonia and ventilator-associated lung injury) are acute, severe injuries affecting most or all of both lungs. Patients with these conditions experience defects in gas-exchange and tissue oxygenation and often require mechanical ventilation (life support) because of respiratory failure. While medical researchers and physiologists have been studying these disease for many years, very limited progress has been made in understanding the underlying causes and mechanisms (especially of ARDS and VALI). As a result of the explosive developments and demonstrated successes of molecular systems biology in the last decade, many researchers are now attempting to apply similar systems-based computational approaches to develop and analyse physiological simulation models at the organ level. However, the uncertainty that arises due to patient and disease heterogeneity, and the difficulty in rigorously validating simulation models which take this uncertainty into account, represent serious roadblocks to progress in applying systems approaches in a clinical setting. We propose to tackle both of these problems by adopting a highly novel and interdisciplinary approach. Using approaches from the field of Control Engineering, we will develop population-based disease models which explicitly take account of uncertainty and variability both within a single patient and between diverse members of a patient population, and rigorously validate these models using advanced robustness analysis techniques. By adapting ensemble modelling techniques from the field of climate forecasting, we will develop reliable descriptors of disease severity and novel disease-specific therapeutic strategies that are applicable to populations of individual patients, rather than a single "typical" patient. By transferring state-of-the-art technologies from control engineering and climate science into critical-care medicine, this project will deliver a significant improvement in the understanding, diagnosis and treatment of ARDS, pneumonia and VALI, and a corresponding reduction in both their impact on patients and the associated cost to the NHS.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: Device to measure lung function in children and adults
Funder: Engineering and Physical Sciences Research Council

Abstract: Patients suffering from lung diseases require lung function tests to assess the severity of their disease and to monitor the benefit of any therapy. These tests are commonly performed in specialised hospital laboratories, and require the co-operation of the patient and a rapport between the clinician and patient. Adults and babies in Intensive Care Units (ICUs) are dependent on continuous life support, and so cannot be moved to these specialised laboratories. Unfortunately therefore, those patients who would benefit most from heart-lung function tests, are the most difficult to be assessed by conventional means. This is also true for anaesthetised patients in the operating theatre, since the unconscious patient is unable to participate in volitional respiratory manoeuvres. Severely premature babies have immature lungs and mostly require ventilation. At present, there is no clear way to determine how much inflating pressure to apply to the lungs. Too little pressure results in under-aeration, and too much causes lung trauma. There is a need to continually monitor the degree of lung inflation. A great need therefore exists for a new system to measure lung functions non-invasively. The purpose of our research is to develop such a new medical device, made possible by recent advancements in gas sensors and flow control technologies. By using small perturbations in oxygen and nitrous oxide in the inhaled breath, and measuring the responses in real time, we can measure heart-lung function indirectly. An online computer model of the lung is used to convert sensor data to robust estimations of lung volume, ventilation, lung blood flow, and especially lung inhomogeneity. This approach eliminates the need for patients' cooperation, and also does not interfere with his/her breathing pattern. As no similar technology currently exists, our proposed technique and device will have a large impact on UK and global health care, especially in outpatient clinics, the ICU environment, and in the operating theatre. This new technique could significantly aid the clinicians in selecting the ventilator settings, and adjusting other therapeutic measures, to (a) "titrate" the therapy to "best effect" in any individual patient; and (b) help avoid the ever present problem of ventilator-induced lung injury worldwide. This is especially true in the early management of preterm infants who have fragile and rapidly changing lung and are at greater risk from over distension and subsequent injury.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: RESPIRATORY
Title: ROBUST REPEATABLE MONITORING WITH EIT
Funder: Engineering and Physical Sciences Research Council

Abstract: Mechanical ventilation in the intensive care unit (ICU) is often a life-saving intervention for patients suffering from acute respiratory distress syndrome (ARDS) and acute lung injury (ALI). However, in recent years, it has become clear that mechanical v


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: RESPIRATORY
Title: Characterisation and modulation of monocyte/macrophage lineage cells in idiopathic pulmonary fibrosis
Funder: Chief Scientist Office (Scotland)

Abstract: Current pharmacological interventions remain disappointingly ineffective for the treatment of many incurable inflammatory lung diseases including idiopathic pulmonary fibrosis (IPF). We have characterised a novel cell population in the inflamed human lung, with features of both peripheral blood monocytes and activated macrophages termed “small lung macrophages” (SLMs), and further identified SLM subpopulations in acute lung injury and IPF patients, which differ in phenotype, cytokine production and proliferative capacity. Using novel protocols we aim to isolate highly pure SLM subpopulations from lungs of patients with IPF, permitting functional analyses de novo. Our preliminary data indicate that SLMs represent a potential cellular target for development of future therapies for the treatment of inflammatory lung diseases. We now aim to further investigate this, including studies into the capacity of novel lipid mediators to induce a ‘pro-resolution’ switch in SLM phenotype, via our collaboration with the Lipidomics Department, University of the Highlands and Islands.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: Mannose binding lectin deficiency, bacterial infection and disease severity in chronic obstructive pulmonary disease: towards personalised medicine for COPD.
Funder: Chief Scientist Office (Scotland)

Abstract: "There are large variations in prognosis and the response to drug therapy in chronic obstructive pulmonary disease(COPD). Personalised medicine, the tailoring of therapy based on patients’ individual genetic profile, offers the hope of improved outcomes in COPD. By studying 2000 DNA samples from patients with COPD linked to a detailed clinical database we will determine if deficiency in mannose-binding lectin (MBL), a component of the innate immune system, is associated with disease severity and exacerbations. Further, we will study sputum bacteriology by novel PCR methods to determine if MBL deficiency is associated with airway bacterial colonisation. Finally, we will study the importance of MBL in resolution of airway inflammation. In-vitro, the defect in macrophage function induced by MBL deficiency can be corrected with a macrolide antibiotic- azithromycin. If MBL deficiency is associated with disease severity, this offers the prospect of the first personalised (pharmacogenetic) treatment based on genotype in COPD "


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: The effect of nanoparticles on in-vitro airway epithelial cell function in children and adults with and without asthma
Funder: Chief Scientist Office (Scotland)

Abstract: The UK Government has prioritised the quantification of risks associated with nanoparticles (NP). Potential NP adverse effects on the lungs are a cause for concern particularly in asthma. Our hypothesis is that bronchial airway epithelial cell (AEC) function in-vitro will be altered by exposure to NP, with greater effects in AEC derived from children and adults with asthma. AEC sampled from adults and children with or without asthma undergoing day-case surgery or elective bronchoscopy will be cultured and NP originating from vehicle emissions (cerium, vanadium, zinc) will be added at doses representative of ‘real-life’. Electron microscopy will characterise cellular uptake and trafficking. Cellular responses to NP (viability, proliferation, oxidative stress, pro-inflammatory cytokine and chemokine production) will be characterised. Increased understanding of NP action on AEC function would provide important information on their potential adverse effects informing risk assessments in collaboration with relevant stakeholders from the motor vehicle industry and government.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: RESPIRATORY
Title: Reprogramming Alveolar Macrophages in IPF
Funder: Chief Scientist Office (Scotland)

Abstract: Idiopathic pulmonary fibrosis (IPF) is a devastating form of chronic fibrotic lung injury of unknown aetiology. There are currently no effective therapies available for treatment of IPF patients and median survival is 3-4 years from diagnosis. Alveolar macrophages (AM) have a central role in the resolution of lung injury, promoting restoration of normal tissue architecture. However in IPF, the AM are dysfunctional and induce aberrant repair responses (fibrosis) through release of pro-fibrotic mediators, a consequence of altered transcription factor (TF) profiles. I t is now well established that phagocytosis of apoptotic cells (efferocytosis) promotes the release of mediators that facilitate resolution of inflammation and that this process is defective in IPF AM. This project aims to identify the efferocytosis-induced TF/pathway modulation necessary for acquisition of a pro-resolving macrophage phenotype, defining which are dysfunctional in IPF AM and those that could be manipulated to reverse the fibrotic IPF AM phenotype.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: THE LONDON COPD EXACERBATION COHORT (The EXCEL Cohort)
Funder: Medical Research Council

Abstract: Chronic obstructive pulmonary disease (COPD) exacerbations are acute episodes of worsening symptoms and an important cause of morbidity and mortality associated with the condition. They are also a major outcome measure for therapeutic intervention studies. The triggers and mechanisms of COPD exacerbations are still not clearly understood and more study of exacerbations is required if the economic and health burden of these disease is to be reduced. Exacerbations are heterogeneous in severity, occur unpredictably and must be sampled early before they are treated and resolve. Thus studies of COPD exacerbations must have access to patients who develop exacerbations and who are trained in detection and reporting of these exacerbations to the study team. The London COPD Exacerbation Cohort (EXCEL Cohort) is an established cohort designed to study mechanisms of COPD exacerbations and their impact on health status and disease progression. Our work has contributed greatly to the understanding of COPD exacerbations. The cohort has already participated in observational studies, proof of concept studies, both grant funded and industry funded, to reduce the frequency and severity of these important events. We will utilize our existing strengths for accurately determining exacerbation frequency and severity with robust methodology previously developed by our group. Patients will be trained to monitor their symptoms electronically and detect and report exacerbations promptly, so that their exacerbations can be sampled early after symptom onset. With the specific funding, the cohort will be increased to recruit a total of 300 COPD patients, who will be phenotyped on the basis of exacerbation frequency, usual long term therapy, lung function, health status and psychological function, airway bacterial and viral infection by quantitative molecular methods. The funding requested will allow further phenotyping by CT scanning on the basis of airway wall thickness and emphysema, novel airway and systemic inflammatory markers and cardiovascular function. The exacerbation cohort will be suitable for epidemiological studies of the natural history and mechanisms of exacerbations, interventions to reduce exacerbation severity and frequency and also studies of interventions to treat individual exacerbations. Enlargement of our cohort has received support from two multi-national drug companies as it provides them with a cost-effective resource to carry out targeted proof of concept trials on specific groups of COPD patients.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: RESPIRATORY
Title: Wessex severe asthma cohort
Funder: Medical Research Council

Abstract: This cohort of patients with persistent and severe asthma specifically responds to a significant unmet clinical need and is not duplicated within National Service Framework strategies or any Topic Specific Clinical Research Networks, as none exist for asthma. This will provide well characterised subjects that facilitate the proof of principle investigation of novel therapies with a sound rationale in this group of patients. The collection and characterisation of these patients reflects a strong partnership between NHS and academic respiratory physicians in Wessex and the close geographic localisation makes possible the potential conduct of sophisticated, mechanistic, translational, pharmacological studies that would not be possible in a widely disseminated cohort and for which Southampton has a proven track record. Three hundred patients with asthma who, despite regular maintenance therapy at level 4 or level 5 of the British Thoracic Society asthma management guidelines, remain symptomatic and have unstable disease, in that they have a history of severe exacerbation necessitating a course of oral steroids or an increased in maintenance oral steroid dose, will be recruited. Characterisation, in addition to a detailed history which will include details of smoking habit and medication use, will consist of 1) patient centered questionnaires and diary card recording of upper and lower airway symptoms, to evaluate the impact of the disease on the individual, 2) physiological measures of lung function at home and in the laboratory before and after bronchodilator therapy, to assess lung function in relationship to the norm (predicted values), the natural diurnal variation and the short term pharmacological reversibility of any impairment, 3) biological sample collection to evaluate airway inflammation within the upper and lower airways and to store samples from induced sputum, nasal lavage, peripheral blood (serum and plasma) and urine for subsequent biomarker evaluation, for which separate funding would need to be applied for. Additional assessments include documentation of atopic status, measurement of BMI and measurement of urinary cotinine to verify tobacco smoking history. A range of potential mechanistic proof of principle studies on novel therapies that could be undertaken on this cohort of patients with severe asthma are detailed, along with possible industrial collaborators. These focus on modifying the effect or exposure to trigger factors (viruses and bacteria), the underlying abnormal airway inflammation (eosinophilic and neutrophilic) or specific disease processes through molecular targeting.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: RESPIRATORY
Title: ENDOGENOUS SUPPRESSION OF LUNG INFLAMMATION
Funder: Medical Research Council

Abstract: We have new data indicating that when myeloid phagocytes in the lung deploy alpha-v integrin to bind apoptotic cells, subsequent phagocyte responses protect the lung from persistent inflammation threatened by injurious airborne stimuli. We now aim to (1) confirm preliminary data that in the lung, as already demonstrated in the gut and peritoneum, immunosuppressive myeloid phagocyte clearance of dying cells is indeed disrupted in our recently generated lineage-specific knockout mice lacking alpha-v in the myeloid line; (2) build on preliminary evidence of enhanced acute bleomycin lung injury in mice with myeloid alpha-v deficiency to investigate whether, as in the gut, there is also an increased propensity for luminal microbial stimuli to induce persistent rather than self-limited inflammation; and (3) investigate whether recipient mice are protected from microbially-induced lung inflammation by the transfer of immunoregulatory myeloid and lymphoid cells generated by TGFa1-dependent mechanisms engaged by normal clearance of apoptotic cells from lungs injured by microbial stimuli. These studies will provide important new insights into why the lungs are not normally inflammed despite exposure to inhaled microbial stimuli and what may go wrong when lungs develop persistent inflammation.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY
Title: A Life Course Approach to Investigating Asthma Pathogenesis and Progression
Funder: Medical Research Council

Abstract: Asthma is an inflammatory disorder of the airways which undergo distinct structural and functional changes leading to variable airflow obstruction. It is amongst the commonest chronic conditions in Western countries affecting 1 in 7 children and 1 in 12 adults. Despite massive investment in research, few new treatments have emerged, current treatment being aimed at suppressing inflammation and symptoms without influencing the underlying causes. The purpose of this programme is to take a life-course view of asthma, the development of sub-phenotypes and their progression over time by combining epidemiological with functional and mechanistic studies in vivo and in vitro. Fundamental to our approach is the recognition that the disease begins most frequently in the first few years, involves multiple interacting environmental stimuli (including viruses, allergens and pollutants) and has a variable natural history. Our programme places the airway epithelium and its communication with the underlying mesenchyme (Epithelial Mesenchymal Trophic Unit) at the centre of asthma. To test this, we will study three age groups: (i) young children at the onset of disease focussing on the role of multiple insults on a susceptible epithelium; ii) teenagers from our Isle of Wight cohort that has been extensively phenotyped for asthma from birth to 18 years seeking evidence for persistent activation of the EMTU; and (iii) adults with established asthma focussing on disease chronicity due to structural changes driven by the EMTU. Using biopsies and epithelial brushings from well phenotyped subjects we will apply our culture systems of epithelial monolayer, differentiated epithelium, epithelium seeded with dendritic cells and epithelium grown over (myo)fibroblasts to recapitulate the EMTU using airway cells from groups (i) and (ii). Cultures will be exposed to rhinovirus and smoke extract as the most important early life exposures linked to asthma onset, and effects on barrier function, allergen penetration and innate immunity assessed. In adults, airway wall remodelling dominates more chronic asthma. We will use endobronchial fibrepotic fluorecence microscopy combined with IHC, atomic force microscopy (stiffness) and helium ion microscopy (ultrastructure) and relate these to collagen type and cross-linking. Because remodelling is a response to repeated distortion of the airways, we will examine the effect of cyclical strain on the EMTU using cells from well phenotyped patients with differing degrees disease severity and remodelling. This integrated programme brings together epidemiological and disease cohorts with detailed phenotyping and mechanistic studies to reveal new high level targets fundamental to disease pathogenesis and progression.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY