Vitamin D deficiency contributes directly to the acute respiratory distress syndrome (ARDS)

Abstract

Rationale: Vitamin D deficiency has been implicated as a pathogenic factor in sepsis and intensive therapy unit mortality but has not been assessed as a risk factor for acute respiratory distress syndrome (ARDS). Causality of these associations has never been demonstrated.

Objectives: To determine if ARDS is associated with vitamin D deficiency in a clinical setting and to determine if vitamin D deficiency in experimental models of ARDS influences its severity.

Methods: Human, murine and in vitro primary alveolar epithelial cell work were included in this study.

Findings: Vitamin D deficiency (plasma 25(OH)D levels <50 nmol/L) was ubiquitous in patients with ARDS and present in the vast majority of patients at risk of developing ARDS following oesophagectomy. In a murine model of intratracheal lipopolysaccharide challenge, dietary-induced vitamin D deficiency resulted in exaggerated alveolar inflammation, epithelial damage and hypoxia. In vitro, vitamin D has trophic effects on primary human alveolar epithelial cells affecting >600 genes. In a clinical setting, pharmacological repletion of vitamin D prior to oesophagectomy reduced the observed changes of in vivo measurements of alveolar capillary damage seen in deficient patients.

Conclusions: Vitamin D deficiency is common in people who develop ARDS. This deficiency of vitamin D appears to contribute to the development of the condition, and approaches to correct vitamin D deficiency in patients at risk of ARDS should be developed.

Trial registration: UKCRN ID 11994.

Keywords: ARDS; Innate Immunity.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Figures

Figure 1

Plasma 25(OH)D3 levels in acute respiratory distress syndrome (ARDS) versus at risk and normal controls. The horizontal bar represents the median, and the boxes represent IQRs. Vertical lines show minimum–maximum range. Fifty-two patients with ARDS, 57 at-risk patients undergoing oesophagectomy, 18 healthy controls.

Figure 2

Risk of postoperative acute respiratory distress syndrome in severe 25(OH)D3 deficiency versus less severe deficiency. Severe deficiency (n=25), less severe (n=32).

Figure 3

Plasma 1,25(OH)2D was significantly higher in patients with acute respiratory distress syndrome who survived at least 28 days following admission than those who died. The horizontal bar represents the median, and the boxes represent IQRs. Vertical lines show minimum–maximum range. Died (n=32), survived (n=20).

Figure 4

Plasma vitamin D binding protein measured by ELISA in acute respiratory distress syndrome (ARDS) versus at risk and normal controls. Fifty-two patients with ARDS, 57 at-risk patients undergoing oesophagectomy, 18 healthy controls.

Figure 5

Changes in extravascular lung water index (EVLWI) at the end of oesophagectomy and on the morning of postoperative day 1. EVLWI was measured using Pulse Contour Cardiac Output Monitoring II catheter at the end of the operation and on the morning after the operation (day 1). Severe deficient (n=25), moderate (n=32) and supplemented (n=8).

Figure 6

Changes in Pulse Contour Cardiac Output Monitoring pulmonary vascular permeability index (PVPI) at the end of oesophagectomy and the morning of postoperative day 1. Severe deficient (n=25), moderate (n=32) and supplemented (n=8).

Figure 7

Lung injury and inflammation was significantly higher in vitamin D-deficient mice compared with wild-type (WT) following intra-tracheal (IT)-lipopolysaccharide (LPS). Levels of tumour necrosis factor-α and CXCL1/KC in UTCs were below the detection threshold of the assays performed. UTC, untreated control; N.D., not detected.

Figure 8

Scratch wound repair response of primary human alveolar type II cells to 25(OH)D3. Wound area after 24 h was compared with baseline and expressed as fold change in wound area. Data represents experiments using cells from six separate lung resection specimens. Analysis of variance p=0.001.

Figure 9

Proliferation of primary human ATII cells in response to physiological doses of 25(OH)D3 by bromodeoxyuridine incorporation. Experiments were performed using cells from four donors. Analysis of variance p=0.001.

Figure 10

Cellular response to soluble Fas ligand (sFasL) 10 ng/mL induced cell death. Experiments were performed using ATII cells from four donors. 100 nmol/L 25(OH)D3 was added at the time of addition of sFasL.