Background: Intestinal adaptation following massive small bowel resection (SBR) is associated with greater rates of enterocyte programmed cell death (apoptosis) by unknown mechanisms. Proinflammatory cytokines may activate epithelial apoptosis via an extrinsic, death receptor-regulated pathway. The purpose of the present study was to delineate the role of tumor necrosis factor-alpha (TNFa)and its recptor (TNFR1) in the activation of enterocyte apoptosis after massive SBR.
Methods: Male ICR mice (n=52) underwent a 50% proximal SBR or sham operation. After 12 hours, 1, 3, and 7 days the remnant ileum was removed and the expression of TNFa was measured by ELISA. In a separate experiment, SBR or sham operations (n=18) were performed in TNFR1-null mice or background strain (C57BL/6) and rates of enterocyte apoptosis (# apoptotic bodies/crypt), proliferation (by proliferating nuclear cell antigen expression immunostaining), and parameters of adaptation (ileal wet weight and villus height) were recorded after 3 days. Statistical significance was set at p<0.05 and determined by Student's t test.
Results: There was no increase in TNFa expression in the SBR group at any time point (Figure 1). Intestinal adaptation occurred normally in the TNFR1-null mice with significant increases in ileal wet weight and villus height (data not shown). Rates of apoptosis (Figure 2) and proliferation (data not shown) were also increased after SBR in both TNFR1-null and C57BL/6 mice.
Conclusion: Following massive SBR, there are no changes in intestinal expression of TNFa. Further, intestinal adaptation and rates of enterocyte apoptosis and proliferation occur normally despite absent TNFR1. The activation of enterocyte apoptosis during intestinal adaptation does not likely occur via an extrinsic, TNFa-mediated death receptor pathway.