The role of adipokines in age-related sensitivity to systemic inflammation and sepsis

Aging is characterized by an altered stress response that underlies a compromised resistance to disease or injury. Activation of inflammatory and coagulant pathways is a frequent consequence of severe critical illnesses and results in the progression of the systemic inflammatory response syndrome (SIRS). Recent evidence suggests that adipokines, adipose tissue-derived signaling proteins, including cytokines, coagulation factors, and hormones, may contribute substantially to the inflammatory response. The major objective of this project was to identify and evaluate the expression of adipokines, particularly interleukin-6 (IL-6) and others highly involved with inflammatory and coagulant process, which differ by aging upon severe inflammatory stress. My central hypothesis is that expression patterns of cytokines and coagulation factors from the adipose tissue are significantly altered with age and that this alteration contributes to age-related sensitivity to systemic inflammation and sepsis. My long-term goals are to identify the mechanisms by which adipokines contribute to the age-dependent severity of SIRS and to develop therapeutic strategies for decreasing vulnerability to inflammatory disorders. For these studies I used two widely accepted mouse models of sepsis: acute endotoxemia induced by injection with bacterial endotoxin lipopolysaccharide and an intra-abdominal sepsis model induced by surgical cecal ligation and puncture. To test my hypothesis, I pursued the following four specific aims: (1) To determine the levels of age-associated mortality, coagulation, and inflammation during SIRS and sepsis and to characterize interleukin-6 (IL-6) over-expression in aged adipose tissue during SIRS, (2) To determine which adipokines show age-associated differences in expression during SIRS and sepsis using microarray and qRT-PCR, (3) To determine the mechanisms of IL-6 over-expression in aged adipose tissue during inflammatory stress using ex-vivo culture of adipose tissues, (4) To test interventions for improving age-related vulnerability to SIRS through decreases in adipose tissue mass by either surgical removal or dietary restriction. These studies have provided significant insight into the role of age-related changes in adipose tissue during the inflammatory response to critical illnesses.