Responses to surgical stress after esophagectomy: Gene expression of heat shock protein 70, toll-like receptor 4, tumor necrosis factor-α and inducible nitric oxide synthase

Abstract

The progression and interrelationship of mediators that are released, activated or suppressed after major surgery appear to play an important role in responses to surgical stress. Heat shock protein 70 (HSP70) is stress-induced and acts like a cytokine to modulate pro-inflammatory mediators, such as tumor necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS), by stimulating toll-like receptor4 (TLR4) signaling. We hypothesized that this effect would occur after major surgery, such as esophagectomy. We therefore measured the expression of HSP70, TLR4, TNF-α and iNOS mRNA in peripheral blood mononuclear cells (PBMCs) from 11 patients who underwent esophagectomy with thoracoabdominal procedures at postoperative day (POD) 1 and POD3 using real-time polymerase chain reaction, and compared the results to expression levels in 6 healthy adult volunteers (controls). We also measured plasma cortisol as a well-known stress hormone. The expression of HSP70 mRNA in PBMCs was 2.1-fold higher on POD1 compared to the controls (P=0.041) and was positively correlated with TLR4 mRNA (r2=0.45, P=0.0007). The expression of TNF-α mRNA tended to be lower on POD1 (P=0.055) and was significantly decreased on POD3 (P=0.016), and iNOS mRNA were significantly lower on POD1 (P=0.0015) and POD3 (P=0.0003) compared to the controls. Moreover, there was a positive correlation between the expression of TLR4 mRNA and plasma cortisol levels (r2=0.24, P=0.021). The expression of HSP70 mRNA in PBMCs in the early postoperative period was significantly higher and positively correlated with TLR4 mRNA. This suggests that HSP70-TLR4 signaling has an important role in postoperative inflammatory responses. However, the expression of pro-inflammatory mediators, including TNF-α and iNOS mRNA, was significantly decreased postoperatively. This may be caused by the anti-inflammatory mechanism of cortisol. Our findings indicate that responses to surgical stress reflect simultaneous pro-inflammatory and anti-inflammatory responses, and are complex.