Cortisol-binding globulin cleavage at sites of inflammation in critically ill patients

Introduction

In vitro studies have shown that cortisol-binding globulin (CBG) can be cleaved by neutrophil elastase with a resulting reduction in affinity for cortisol [1]. Local elastase production by activated neutrophils may trigger cortisol release by CBG cleavage, providing a potential mechanism for targeted delivery of corticosteroids to inflamed tissues. We looked for evidence of this process at sites of inflammation in critically ill patients.

Methods

Sera and bronchoalveolar lavage (BAL) fluid were collected from six mechanically ventilated patients with a clinical diagnosis of ventilator-associated pneumonia or acute respiratory distress syndrome (ARDS). These samples, along with sera from six healthy controls, were subjected to gel electrophoresis (SDS-PAGE) and immunoblotting for CBG. Densitometry was used to quantify the proportion of cleaved CBG.

Results

CBG cleavage product was seen within the BAL but not the sera of patients with acute inflammatory lung disease. Figure 1 shows a typical western blot comparing control sera (C1 and C2), septic sera (S1 and S2) and BAL from the same septic patients (B1 and B2, respectively). The mean percentage of CBG in the cleaved form was 63.3% ± 21.8 in BAL compared with 0.94% ± 1.73 in sera from the same patients and 12.5% ± 11.4 from healthy controls (see Figure 2; all comparisons statistically significant).

Figure 1

SDS-PAGE and immunoblotting of CBG. MW, molecular weights (arrows mark the place of the relevant molecular weight markers).

Figure 2

Cleaved CBG as a percentage of total CBG. * P < 0.05, ** P < 0.01.

Conclusion

This study provides the first in vivo support for a mechanism of enhanced cortisol delivery to sites of inflammation that involves local CBG cleavage.