Changes in MIF and thyroxine, in a clinically relevant large animal model of sepsis

Introduction

Critically ill patients often have abnormally low plasma thyroxine (T4) concentrations even in the absence of thyroidal illnesses, with the lowest T4 values being observed in patients (particularly older individuals) with sepsis. Staphylococcal infection of the lung is the most common presentation of sepsis in the medical ICU setting, and is associated with a much higher mortality in older individuals than in younger. In studies where the lungs of rats are challenged with staphylococcal components lipoteichoic acid and peptidoglycan, we have noted negative correlations between plasma MIF and T4.

Objective

To examine the dynamics of MIF and T4 in a clinically relevant, large animal model of sepsis.

Methods

Adult female sheep (30 to 40 kg) with age approximately equivalent to humans of 55 years were surgically prepared for chronic study. After 5 days recovery, approximately 2.5 × 10¹¹ CFU methicillin-resistant Staphylococcus aureus (ATCC 4300, a clinical isolate) were instilled into the lung via a bronchoscope. The animals were ventilated, and hemodynamics were monitored continuously for 24 hours post instillation. Blood and lymph samples were collected at baseline and at 3, 6, 12, 18, and 24 hours. MIF was measured by semiquantitative western blot and free-T4 by ELISA.

Results

The plasma concentration of MIF increased from 24.9 ± 4.5 ng/ml at baseline to 30.1 ± 2.5 ng/ml in the first 6 hours post instillation of the bacteria. During this time period, free-T4 concentration decreased from 1.6 ± 0.5 ng/dl to 0.4 ± 0.3 ng/dl. The concentration of MIF in the pulmonary lymph was approximately 10% of the plasma level, and showed no time-dependent decrease, although the lymph flow increased approximately fourfold over the course of the study.

Conclusion

We have found that intratracheal instillation of staphylococcal cell wall components in rats results in an imbalance of plasma MIF and free-T4, and that pulmonary-derived MIF in sepsis induces cardiocirculatory depression. Here we show that, in a clinically relevant, large animal model of sepsis induced by pulmonary infection with methicillin-resistant S. aureus, increased plasma concentration of MIF and decreased free-T4 occurred in a similar manner to our rat studies, and that the total amount of MIF in the lymph also increased. Since strong negative correlations exist between prognosis and levels of T4 or MIF in patients with sepsis, our findings underscore interest in possible interactions between the MIF and T4 molecules that may be critical for the outcome of the disease.