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.
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.
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.
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.
Organisations
- University of Warwick (Lead Research Organisation)
- University College London (Collaboration)
- Queen Elizabeth Hospital Birmingham (Collaboration)
- UNIVERSITY OF BIRMINGHAM (Collaboration)
- University of Graz (Collaboration)
- QUEEN'S UNIVERSITY BELFAST (Collaboration)
- Birmingham Heartlands Hospital (Collaboration)
- University of Birmingham (Fellow)
People |
ORCID iD |
Dhruv Parekh (Principal Investigator / Fellow) |
Publications
Amrein K
(2018)
Vitamin D and critical illness: what endocrinology can learn from intensive care and vice versa
in Endocrine Connections
Dancer RC
(2015)
Vitamin D deficiency contributes directly to the acute respiratory distress syndrome (ARDS).
in Thorax
Grudzinska FS
(2017)
Statin therapy in patients with community-acquired pneumonia.
in Clinical medicine (London, England)
Howells PA
(2017)
ARDS following oesophagectomy: a comparison of two trials.
in BMJ open respiratory research
Lugg ST
(2019)
Dysregulated alveolar function and complications in smokers following oesophagectomy.
in ERJ open research
Mahida RY
(2021)
Assessment of Alveolar Macrophage Dysfunction Using an in vitro Model of Acute Respiratory Distress Syndrome.
in Frontiers in medicine
Mahida RY
(2021)
Acute respiratory distress syndrome is associated with impaired alveolar macrophage efferocytosis.
in The European respiratory journal
Martucci G
(2019)
Trying to identify who may benefit most from future vitamin D intervention trials: a post hoc analysis from the VITDAL-ICU study excluding the early deaths.
in Critical care (London, England)
Muthuri SG
(2014)
Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data.
in The Lancet. Respiratory medicine
Muthuri SG
(2016)
Impact of neuraminidase inhibitors on influenza A(H1N1)pdm09-related pneumonia: an individual participant data meta-analysis.
in Influenza and other respiratory viruses
Parekh D
(2014)
Alternatives to animal research in acute lung injury.
in BMJ (Clinical research ed.)
Parekh D
(2017)
Vitamin D Deficiency in Human and Murine Sepsis.
in Critical care medicine
Parekh D
(2018)
Vitamin D to Prevent Lung Injury Following Esophagectomy-A Randomized, Placebo-Controlled Trial.
in Critical care medicine
Parekh D
(2014)
Vitamin D deficiency and bacterial load in a murine model of sepsis-induced lung injury
in The Lancet
Parekh Dhruv
(2015)
Is Vitamin D deficiency a mechanistic driver of acute lung injury?
Patel JM
(2018)
Sepsis Induces a Dysregulated Neutrophil Phenotype That Is Associated with Increased Mortality.
in Mediators of inflammation
Scott A
(2018)
Pro-inflammatory effects of e-cigarette vapour condensate on human alveolar macrophages.
in Thorax
Thein OS
(2023)
Raised FGF23 Correlates to Increased Mortality in Critical Illness, Independent of Vitamin D.
in Biology
Wang Q
(2014)
S102 Lipoxin A4 Improves Efferocytosis Via Inhibition Of The Hmgb1 In Human Alveolar Macrophages
in Thorax
Williams AE
(2017)
Evidence for chemokine synergy during neutrophil migration in ARDS.
in Thorax
Zheng S
(2020)
Vitamin D attenuates lung injury via stimulating epithelial repair, reducing epithelial cell apoptosis and inhibits TGF-ß induced epithelial to mesenchymal transition.
in Biochemical pharmacology
Zheng S
(2016)
Lipoxin A4 promotes lung epithelial repair whilst inhibiting fibroblast proliferation.
in ERJ open research
Description | ATS International Trainee Scholarship |
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Description | VITDALIZE UK - a randomised placebo controlled trial of vitamin D therapy in critically ill patients |
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Description | Belfast - Taggart |
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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 |
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PI Contribution | Intellectual contribution, sample analysis and asaays |
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Description | DUSP1_TTP |
Organisation | University of Birmingham |
Department | Institute of Inflammation and Ageing |
Country | United Kingdom |
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Collaborator Contribution | Intellectual |
Impact | Application to Wellcome and MRC fellowships; PhD studentship |
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Description | HEFT - PPI |
Organisation | Birmingham Heartlands Hospital |
Department | Academic Department of Anaesthesia, Critical Care, Pain and Resuscitation |
Country | United Kingdom |
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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 |
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Start Year | 2011 |
Description | UHB |
Organisation | Queen Elizabeth Hospital Birmingham |
Country | United Kingdom |
Sector | Hospitals |
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Impact | Multidisciplinary - Surgical teams, Critical Care and Anaesthesia, Respiratory medicine, clinical research nurses |
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Description | UoB |
Organisation | University of Birmingham |
Department | Institute of Inflammation and Ageing |
Country | United Kingdom |
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Impact | Publications Presentations Prizes Bmedsci Student Projects PhD Supervision |
Start Year | 2012 |
Description | VITDALIZE Trial |
Organisation | University of Graz |
Country | Austria |
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PI Contribution | Intellectual, trial development |
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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 |
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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 |
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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 |
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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 |
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Geographic Reach | International |
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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) |
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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 |
Description | Meeting with Deputy CMO and COVID therapeutics taskforce |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Policymakers/politicians |
Results and Impact | Invited to meet with the Deputy CMO (Prof Van Tam) and the COVID19 therapeutics taskforce to provide expert opinion, update on trial status, discuss the potential for vitamin D therapy as a treatment for COVID19. We were asked if we would consider VITDALIZE becoming a COVID19 trial. |
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Year(s) Of Engagement Activity | 2020,2021,2022,2023 |