Altered inflammatory gene expression underlies increased susceptibility to murine postoperative ileus with advancing age

Abstract

Susceptibility to postoperative ileus following abdominal surgery increases with advancing age. The mechanisms underlying this phenomenon are unknown. This study compares functional and molecular endpoints between young-adult (2 mo old), middle-aged (15 mo old), and elderly mice (26–30 mo old) to identify potential mechanisms. Susceptibility to ileus was assessed by measuring gastrointestinal transit (geometric center) 24 h after anesthesia, laparotomy, and light manipulation (LM) of the small bowel. Proinflammatory (IL-6, COX-2, inducible nitric oxide synthase) and anti-inflammatory (IL-10, heme oxygenase-1) gene and protein expressions were determined by real time RT-PCR, Western blot, and ELISA. LM did not alter gastrointestinal transit in young animals (geometric center = 8.8 ± 0.9), but transit was increasingly delayed in middle-aged (6.9 ± 0.8, P = 0.03) and elderly animals (4.7 ± 0.6, P = 0.013). Despite the lack of LM effect on transit in young mice, IL-6 and COX-2 mRNA expressions were significantly increased postoperatively (165 ± 24-fold and 2.9 ± 0.3-fold, respectively). Expressions were increased further in middle-aged mice (1,103 ± 187-fold; 4.4 ± 0.7-fold) and further still in elderly mice (1,218 ± 168-fold; 6.9 ± 0.3-fold). IL-10 and heme oxygenase-1 gene expressions were also elevated postoperatively in young mice (4.8 ± 0.5-fold and 13.0 ± 1.3-fold, respectively) and were further increased in middle-aged mice (7.5 ± 0.6-fold; 21.8 ± 3.2-fold). However, inductions in elderly mice were significantly blunted (5.8 ± 0.9-fold; 16.9 ± 0.8-fold). There is both an age-dependent increase in the proinflammatory mediator expression and an age-dependent decrease in anti-inflammatory mediator expressions following minor insult to the bowel. Such imbalances between pro- and anti-inflammatory mechanisms may form the basis for increased susceptibility to ileus and for the increased severity and duration of ileus observed in the elderly.