Is Vitamin D deficiency a mechanistic driver of Acute Lung Injury (ALI)?

Lead Research Organisation: University of Warwick
Department Name: Warwick Medical School

Abstract

Sunlight is the major natural source of vitamin D and therefore vitamin D deficiency is common in the UK. Vitamin D deficiency can cause many health problems, particulary relating to reduced immunity and increasing susceptibility to infections. Studies have shown that vitamin D has effects on many different aspects of the immune system.

Acute Lung Injury (ALI) is a condition that causes respiratory failure in critically ill people. It occurs when the immune system damages the lungs. It can occur as a result of direct injury to the lungs, such as pneumonia, or through indirect damage such septicaemia, trauma or surgery. However, not all patients who have these problems go on to develop ALI.

ALI is of considerable public health importance as it has a high mortality rate (40-50%) and leads to a similar number of deaths per year in the UK as breast cancer or AIDS. ALI also has major impact upon patients who survive with 40-50% of those of working age unable to return to work within 12 months.

The question we are looking to address is, why do some people develop ALI when others in the same cirumstances do not? Is this linked to their Vitamin D level and it's effect on the immune system?

ALI affects 1 in 4 people requiring a surgical operation to remove the gullet (oesphagectomy). We have identified that deficiency of vitamin D may be an important risk factor for developing ALI in this group of people.

We will look at the effects of vitamin D on different types of immune cells isolated from samples from blood and lung in patients undergoing oesophagectomy and with ALI. We will also use mouse models that are vitamin D deficient to investigate the effects of vitamin D deficiency and whether its replacment can prevent the onset of acute lung injury.

This research will determine the role of vitamin D deficiency as a major contributing factor to the development of ALI and also help define the underlying mechanisms by which it occurs. We will test the effects of treatment with vitamin D as a strategy for preventing lung injury which may lead to the use of vitamin D supplementation in patients with, and at risk of, ALI as a means of preventing and treating the condition.

Technical Summary

Acute Lung Injury (ALI) is the final common pathway of immunological response to a variety of direct and indirect pulmonary insults. Vitamin D has been shown to have profound effects on human immunity as a result of its actions on both the innate and adaptive immune systems. By acting as an immune system modulator, preventing excessive expression of inflammatory cytokines and increasing the 'oxidative burst' potential of macrophages and therefore enhancing bacterial killing.

Transthoracic oesophagectomy involves an extended period of one lung ventilation and has been suggested as a model with which to study the development of lung injury as there is a high postoperative incidence (28%) of ALI

Using archived clinical samples we have measured 25-OH vitamin D levels in 50 patients with ALI and 50 patients undergoing oesophagectomy. All ALI cases and 48/50 oesophagectomy cases had deficient levels of vitamin D. Very low 25-OH vitamin D levels in the oesophagectomy cohort were associated with elevated plasma levels of IL-6, sRAGE (a type I epithelial cell marker) and HMGB-1 in the immediate post-operative period.

Sequential plasma and bronchoalveolar lavage fluid (BALF) will be obtained from patients undergoing one lung ventilation for oesophagectomy and ALI as well as murine models that are genetically and dietarily vitamin D deficient to investigate the effects of vitamin D deficiency and its replacement on acute lung injury.

This translational work aims to confirm if vitamin D deficiency is of mechanistic importance in the development of ALI by determining the influence of vitamin D levles upon primary alveolar epithelial cell dysfunction, antibacterial peptide release and phagocytosis/efferocytosis. Combining this with murine studies and complimenting the MRC DCS study we intend the results from this study to form the scientific rationale for a randomised controlled trial of vitamin D replacement in patients with ALI.

Planned Impact

Patients with ALI, even if previously functional and without other significant organ dysfunction at baseline, incur high hospital costs, consume a large proportion of the NHS ITU capacity and resource use due to extended hospital stays and experience significant mortality (not only in the first month), require substantial post discharge support, are often re-hospitalised, report poor quality of life over the following months, and have not returned to baseline activity at 1 year. Therefore, it is of considerable public health importance. There are no current readily available tests that can clearly identify those who are at high risk of ALI, and no therapeutic interventions proven to prevent or treat it. Clearly this represents a major unmet health need. Thus this research will not only potentially impact on the health and quality of life of patients but also the NHS and health care providing organisations.

The role of vitamin D as an immune modulator and its involvement in other respiratory conditions (TB, COPD, lung development) is being investigated by other researcher. Therefore, increased insight into the mechanisms of vitamin D at a cellular level of immunity and inflammation in ALI will translate to other inflammatory conditions of the lung and impact the wider academic community. It will also provide, by complimenting the MRC DCS funded Trial, a rationale for a randomised controlled trial of vitamin D treatment in ALI, thus providing bench to bedside impact.

Due to the heterogeneity of aetiologies of ALI and this study in at risk surgical patients the potential impact of the results encompasses a breadth of patients, academic and clinical peers across specialities including critical care, respiratory medicine, surgery, and translational inflammation.

Within the research group and in collaboration with the Universities of Warwick and Birmingham we endeavour to use the fellow's research output to enthuse the next generation by actively participating in the Researcher in Residence scheme, where they discuss their research with A-level students at local schools and assist in the training of work experience and BMedSci students, several of whom spend time in our laboratories every year to learn about the structure of research in an academic setting. I will be expected to take part in all of these outreach activities during my tenure.

Publications

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Grudzinska FS (2017) Statin therapy in patients with community-acquired pneumonia. in Clinical medicine (London, England)

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Grudzinska FS (2017) Statin therapy in patients with community-acquired pneumonia. in Clinical medicine (London, England)

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Howells PA (2017) ARDS following oesophagectomy: a comparison of two trials. in BMJ open respiratory research

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Parekh D (2013) Vitamin D deficiency and acute lung injury. in Inflammation & allergy drug targets

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Parekh D (2013) Vitamin D Deficiency and Acute Lung Injury in Inflammation & Allergy-Drug Targets

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Parekh D (2017) Vitamin D Deficiency in Human and Murine Sepsis. in Critical care medicine

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Parekh D (2014) Alternatives to animal research in acute lung injury. in BMJ (Clinical research ed.)

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Sapey E (2017) Pulmonary Infections in the Elderly Lead to Impaired Neutrophil Targeting, Which Is Improved by Simvastatin. in American journal of respiratory and critical care medicine

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Sapey E (2017) Pulmonary Infections in the Elderly Lead to Impaired Neutrophil Targeting, Which Is Improved by Simvastatin. in American journal of respiratory and critical care medicine

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Zheng S (2018) ResolvinD stimulates epithelial wound repair and inhibits TGF-ß-induced EMT whilst reducing fibroproliferation and collagen production. in Laboratory investigation; a journal of technical methods and pathology

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Zheng S (2018) ResolvinD stimulates epithelial wound repair and inhibits TGF-ß-induced EMT whilst reducing fibroproliferation and collagen production. in Laboratory investigation; a journal of technical methods and pathology

 
Description ATS International Trainee Scholarship
Amount $1,000 (USD)
Organisation American Thoracic Society 
Sector Learned Society
Country United States
Start 05/2014 
End 05/2014
 
Description BLF/NAPP ERS Travelling Fellowship
Amount £750 (GBP)
Organisation British Lung Foundation (BLF) 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2013 
End 09/2015
 
Description Chief Investigator Development Award
Amount £104,000 (GBP)
Organisation National Institute for Health Research 
Department NIHR Clinical Research Network West Midlands
Sector Public
Country United Kingdom
Start 06/2017 
End 06/2019
 
Description ERS Lung Science Conference Bursary
Amount € 600 (EUR)
Organisation European Respiratory Society (ERS) 
Sector Charity/Non Profit
Country European Union (EU)
Start 03/2016 
End 03/2016
 
Description VITDALIZE UK - a randomised placebo controlled trial of vitamin D therapy in critically ill patients
Amount £950,000 (GBP)
Organisation NIHR Evaluation, Trials and Studies Coordinating Centre (NETSCC) 
Sector Academic/University
Country United Kingdom
Start 06/2019 
End 05/2023
 
Description Belfast - Taggart 
Organisation Queen's University Belfast
Country United Kingdom 
Sector Academic/University 
PI Contribution Contributed patient samples and data as well as reviewing of scientific paper/intellectual input
Collaborator Contribution Expertise and intellectual input - protocols for biological analysis of samples
Impact Multi-disciplinary
Start Year 2013
 
Description Chemokine synergy/neutrophil activation in ARDS 
Organisation University College London
Department Centre for Inflammation and Tissue Repair
Country United Kingdom 
Sector Academic/University 
PI Contribution Intellectual contribution, sample analysis and asaays
Collaborator Contribution Intellectual contribution and shared patient samples
Impact Publication
Start Year 2014
 
Description DUSP1_TTP 
Organisation University of Birmingham
Department Institute of Inflammation and Ageing
Country United Kingdom 
Sector Academic/University 
PI Contribution Intellectual, samples and analysis. Hypothesis generation. Murine studies.
Collaborator Contribution Intellectual
Impact Application to Wellcome and MRC fellowships; PhD studentship
Start Year 2016
 
Description HEFT - PPI 
Organisation Birmingham Heartlands Hospital
Department Academic Department of Anaesthesia, Critical Care, Pain and Resuscitation
Country United Kingdom 
Sector Hospitals 
PI Contribution Intellectual input, training of staff, running of translational studies Setting up of Clinical Research Ambassador Group which is a patient involvement in research initiative
Collaborator Contribution Administrative and research support. Access to patients for clinical/translational studies.
Impact Multidisciplinary -Nursing, medical, physios, research staff
Start Year 2011
 
Description SepTIC Platform trial collaboration 
Organisation Imperial College London
Department Faculty of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Sepsis research group. Leading experts. Design of clinical trial in sepsis - platform trial of 3 interventions. NIHR HTA funding recommended. Intellectual , regional lead.
Collaborator Contribution Co-ordination, CI, intellectual and trials unit
Impact NIHR HTA grant.
Start Year 2018
 
Description UHB 
Organisation Queen Elizabeth Hospital Birmingham
Country United Kingdom 
Sector Hospitals 
PI Contribution Expertise and intellectual input
Collaborator Contribution Access to patients for clinical/translational studies
Impact Multidisciplinary - Surgical teams, Critical Care and Anaesthesia, Respiratory medicine, clinical research nurses
Start Year 2011
 
Description UoB 
Organisation University of Birmingham
Department Institute of Inflammation and Ageing
Country United Kingdom 
Sector Academic/University 
PI Contribution Expertise, Intellectual input, supporting recruitment of patients, laboratory work and analysis of data, training of staff and supervising medical/BMedSci students
Collaborator Contribution Expertise and intellectual input. Research training. Access to laboratory space and equipment ad facilities
Impact Publications Presentations Prizes Bmedsci Student Projects PhD Supervision
Start Year 2012
 
Description VITDALIZE Trial 
Organisation University of Birmingham
Department Birmingham Clinical Trials Unit
Country Unknown 
Sector Academic/University 
PI Contribution CI application currently in process for HTA trial
Collaborator Contribution BCTU - clinical trials training component, mentorship and sponsorship of trial/
Impact N/a
Start Year 2018
 
Description VITDALIZE Trial 
Organisation University of Graz
Country Austria 
Sector Academic/University 
PI Contribution Intellectual, trial development
Collaborator Contribution Trial co-ordination, intellectual
Impact N/A
Start Year 2017
 
Description Vitamin D Metabolome 
Organisation University of Birmingham
Department Institute of Metabolism and Systems Research (IMSR)
Country United Kingdom 
Sector Academic/University 
PI Contribution Measurements of Vitamin D Metabolomics in patient samples. Collaboration together to hypothesis generation and application to Clinician Scientist Fellowship programmes
Collaborator Contribution Measurements of Vitamin D Metabolomics in patient samples. Collaboration together to hypothesis generation and application to Clinician Scientist Fellowship programmes
Impact N/A
Start Year 2015
 
Description AAGBI Thoracic Update 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Update in the management of patients undergoing thoracic surgery.
Year(s) Of Engagement Activity 2014
URL http://www.aagbi.org/sites/default/files/thoracic%20anaesthesia_0.pdf
 
Description ATS Congress San Diego 2014 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presentation the the ATS Meeting of 2 abstracts.

Discussions with potential collaborators in the USA
Year(s) Of Engagement Activity 2014
 
Description Academy of Medical Sciences Oral Presentaion at the Spring Meeting for Clinical Scientists in Training 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact 1 of 4 abstracts chosen to present as an oral presentaion the meeting. The talk raised some debate and qustions. Live feed on twitter and social media.

The abstract was publised in a special supplement addition of the Lancet in Feb 2014
Year(s) Of Engagement Activity 2014
URL http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)60278-6/fulltext#article_upsell
 
Description BTS 2012 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact British Thoracic Society Winter Meeting 2012 - London
Oral Presentation x 2

The Role of Vitamin D Deficiency in Regulating the Severity and Duration of Murine Lung Injury
S. Lax, D. Parekh, R. Dancer, D. Thickett

High Dose Vitamin D Supplementation Improves Extravascular Lung Water Index and in-Vivo Treg and Ll37 Responses Post-Oesophagectomy
R. C. A. Dancer, D. Parekh, A. R. Martineau, G. D. Perkins, D. R. Thickett


N/A
Year(s) Of Engagement Activity 2013
 
Description BTS 2013 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Due to present at the British Thoracic Winter Meeting London 2013

Oral presentation

Vitamin D deficiency increases bacterial load in a murine model of sepsis-induced lung injury
Dhruv Parekh, Sian Lax, Rachel Dancer, Gavin Perkins, David Thickett


N/A
Year(s) Of Engagement Activity 2013
 
Description BTS 2015 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presentation of the results of phase 2 clinical trial
Year(s) Of Engagement Activity 2015
 
Description Clinical Research Ambassador Group/ Patient Public Involvement (Heart of England NHS trust) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Have set up and on the steering committee of a local patient and public involvement group of Critical Care, Respiratory and Thoracic patients, relatives and carers to aid and facilitate our research activities at Heart of England NHS Trust. We have had a formal networking events. Engaging the public, patients and carers

Group is being involved in guiding further research ideas.
Year(s) Of Engagement Activity 2013,2014,2015
URL http://www.invo.org.uk/clinical-research-ambassador-group/
 
Description ERS 2013 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact European Respiratory Society Congress 2013 Barcelona
Oral Presentation x 2

Effects of high dose vitamin D supplementation in patients undergoing oesophagectomy
R. Dancer, D. Parekh, A. Martineau, G. Perkins, D. Thickett

Salmeterol prevents pneumonia and reduces biomarkers of inflammation/epithelial damage but not acute lung injury following oesophagectomy-the results of BALTI-prevention trial
D. Parekh, R. Dancer, D. Park, G. Perkins, D. Thickett


N/A
Year(s) Of Engagement Activity 2013
 
Description ERS Lung Science Meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Research presentation
Year(s) Of Engagement Activity 2016