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

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 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.

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.