Pulmonary macrophage migration inhibitory factor: an important contributor to age-dependent inflammation in sepsis

Background

Sepsis, the progressive, systemic host response to infection, kills over 215,000 individuals annually in the United States, and the mortality rate increases greatly with age. A recent ICU survey of sepsis occurrence in acutely ill patients identified the major site of infection as the lung (68%), Staphylococcus aureus as the most common infecting agent (30%), and the median patient age as 64 years. We therefore developed a rodent model using S. aureus cell wall components lipoteichoic acid (LTA) and peptidoglycan G (PGN) instilled into the lungs to study age-related changes in pulmonary infection and sepsis.

Materials

Male Fischer 344 rats (Harlan Inc., Indianapolis, IN, USA); C57Bl/6 mice, wild-type (mif^+/+) and migration inhibitory factor (MIF) gene-deficient (mif^-/-) (Feinstein Institute for Medical Research, Manhasset, NY, USA); LTA and PGN (Sigma-Aldrich Co., St Louis, MO, USA); ELISA Assays (R&D Systems, Minneapolis, MN, USA); high-density oligonucleotide expression microarrays (GeneChips; Affymetrix Inc., Santa Clara, CA, USA).

Methods

Saline alone (control) or LTA 1.5 mg/kg and PGN 5 mg/kg were instilled intratracheally into Fischer 344 rats 6, 18, or 24 months old (equating approximately to humans of 18, 45 and 60 years). After 6 hours, the animals were euthanized, blood collected from the left atrium, and the lungs lavaged with saline (bronchoalveolar lavage (BAL)). To further characterize the contributions of MIF following LTA-PGN challenge, we used GeneChips to obtain a description of the global transcriptomic response of lungs from mif^+/+ and mif^-/- mice 6 hours post LTA-PGN.

Results

There were significant age-related increases in lung compliance and BAL protein content (sham, 0.2 ± 0.01; 6 months, 1.2 ± 1.4; 18 months, 5.2 ± 0.7; 24 months, 4.8 ± 0.4 mg/ml), suggesting a more severe injury in the older age groups. BAL concentrations of GRO-KC (CXCL1) (sham, 0.13 ± 0.03; 6 months, 2.46 ± 0.79; 18 months, 2.89 ± 0.50; 24 months, 4.02 ± 1.54 ng/ml) and IL-6 (sham, 0.1 ± 0.1; 6 months, 5.2 ± 5.6; 18 months, 14.2 ± 2.3; 24 months, 13.0 ± 6.8 ng/ml), and blood MIF concentrations around threefold higher in the older rats suggest an age-dependent increase in inflammatory response. Comparative analysis of lung transcriptomes (~8,500 mRNAs) of the mice suggested a larger response in mif^-/- mice of genes regulated by NFκB.

Conclusion

These observations suggest, for the first time, a role for MIF–NFκB molecular circuitry modulating cardiopulmonary system responses following pulmonary infection. Since MIF can cause cardiac dysfunction, the increased MIF response during sepsis in the older individual may be responsible for an increased mortality in this patient population.