Age-associated increased inflammatory response to pulmonary bacterial challenge

Introduction

Sepsis, the systemic inflammation following infectious insult, is a major cause of morbidity and mortality particularly in older individuals. While most animal models of sepsis have studied polymicrobial or Gram-negative sepsis from an abdominal origin in young animals, the most common presentation in the medical ICU is in older individuals (median age 64 years), with Gram-positive bacteria (predominantly Staphylococcus aureus) infection in the lung. Our recent studies reveal a critical role for macrophage migration inhibitory factor (MIF) in the pathogenesis of sepsis, and thyroxine (T4), two molecules with major implications in sepsis. Therefore, we reasoned that the age-related severity of sepsis may be due to an exaggerated imbalance between MIF and its inhibitor.

Objective

To examine age-dependent differences in inflammatory responses following pulmonary staphylococcal challenge.

Methods

Lipoteichoic acid (LTA) and peptidoglycan (PGN) are major inflammatory components of the staphylococcal cell wall known to induce shock. Male Fischer 344 rats either Young (6 months) or Old (>18 months), approximately equivalent to humans of 18 and 60 years respectively, were anesthetized and LTA and PGN (1.5/5 mg/kg in 200 μl) were administered intra-tracheally. Six hours later, blood was collected from the heart, and post mortem, the lungs were lavaged for analysis of the epithelial lining fluid. Young, untreated cage control animals (Control) were also assessed.

Results

The plasma MIF concentration significantly increased with LTA/PGN challenge (Control, 24.9 ± 0.6 ng/ml; Young, 38.8 ± 5.9 ng/ml; Old, 64.2 ± 12.1 ng/ml) and the mean concentration in the old animals was significantly higher than in the young; P = 0.004. Conversely, plasma free-T4 significantly decreased with LTA/PGN challenge (Control, 2.3 ± 0.9 ng/dl; Young, 1.7 ± 0.7 ng/dl; Old, 1.0 ± 0.4 ng/dl) and the mean concentration in the old animals was significantly lower than in the young; P < 0.05. Significant age-specific differences were also noted in the response with respect to neutrophils and IL-6 within the lavage fluid.

Conclusion

Typically, critically ill patients have abnormally low plasma T4 concentrations even in the absence of thyroidal illnesses (the so-called euthyroid sick phenomenon) with the lowest values being observed in septic and/or elderly individuals, suggesting a strong negative correlation between prognosis and T4 concentration. The data suggest that an increased early inflammatory response in older compared with young animals results in an exaggerated imbalance between MIF and T4, possibly leading to development of an uncontrolled systemic response.