Regulation of Fas-mediated apoptosis in neutrophils after surgery-induced acute inflammation

Masayasu Iwase, Gen Kondo, Hitoshi Watanabe, Sayaka Takaoka, Makiko Uchida, Masaru Ohashi, Masao Nagumo
Journal of Surgical Research 2006, 134 (1): 114-23

BACKGROUND: Neutrophils undergo rapid Fas-mediated apoptosis during in vitro culture. The purpose of this study was to investigate the effects of surgical stress upon the Fas-mediated apoptotic response in circulating neutrophils.

MATERIALS AND METHODS: Blood samples were drawn from eight patients with a mandibular prognathism, and who had undergone a bilateral sagittal split ramus osteotomy, at 2 days before, and at 1 and 5 days after surgery. The circulating neutrophils in each blood sample were then evaluated for their susceptibility to Fas-mediated apoptosis in either the presence or the absence of autogenous plasma.

RESULTS: Fas-induced apoptosis in the neutrophils of these surgically treated patients was found to be slightly accelerated at 1 day postoperatively in the presence of FBS, compared with 2 days preoperatively and 5 days postoperatively. However, we obtained different results for these experiments in the presence of autogenous plasma. The Fas-induced apoptotic response levels in the neutrophils at day 1 postsurgery following exposure to autogenous plasma were significantly suppressed compared with the levels at both 2 days preoperatively and 5 days postoperatively. The Fas expression levels on the cell surface of the neutrophils were not altered, but the levels of soluble Fas (sFas) in the plasma were reduced to almost inverse levels during the postoperative periods. The levels of granulocyte-macrophage colony-stimulating factor, interleukin-6, and interleukin-8 levels in the plasma were also markedly raised in the plasma from each of these patients at 1 day postoperatively. However, the anti-apoptotic effects of the plasma on the Fas-mediated neutrophil apoptosis were not influenced by the addition of their neutralizing antibodies for these cytokines. The suppressive effects of postoperative plasma on Fas-mediated neutrophil apoptosis were blocked by the phosphatidylinositol 3-kinase (PI 3-K) inhibitors, LY294002, and wortmannin. Additionally, these effects were also abrogated by the extracellular signal-regulated kinase (ERK) inhibitor, PD98059, but not by the p38 mitogen-activated protein kinase inhibitor, SB203580.

CONCLUSIONS: The increase in sFas levels in the plasma of patients with acute inflammation may lead to the inhibition of Fas-mediated neutrophil apoptosis. Moreover, the activation of the PI 3-K and ERK signaling-dependent pathways may, in part, also contribute to the down-regulation of the Fas-mediated apoptotic response in neutrophils.

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