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Cellular stress results in the release of damage-associated molecular pattern (DAMP) molecules that promote inflammatory responses. Here Ping Wang and colleagues show that cold-inducible RNA-binding protein (CIRP) is a DAMP that is released into the circulation in response to hemorrhagic shock and sepsis. It promotes proinflammatory cytokine release by binding to the TLR4-MD2 complex. Blockade of CIRP reduces inflammation, organ injury and mortality in animal models of hemorrhage and sepsis, suggesting that CIRP may be targeted therapeutically in these conditions. A systemic inflammatory response is observed in patients undergoing hemorrhagic shock and sepsis. Here we report increased levels of cold-inducible RNA-binding protein (CIRP) in the blood of individuals admitted to the surgical intensive care unit with hemorrhagic shock. In animal models of hemorrhage and sepsis, CIRP is upregulated in the heart and liver and released into the circulation. In macrophages under hypoxic stress, CIRP translocates from the nucleus to the cytosol and is released. Recombinant CIRP stimulates the release of tumor necrosis factor-α (TNF-α) and HMGB1 from macrophages and induces inflammatory responses and causes tissue injury when injected in vivo . Hemorrhage-induced TNF-α and HMGB1 release and lethality were reduced in CIRP-deficient mice. Blockade of CIRP using antisera to CIRP attenuated inflammatory cytokine release and mortality after hemorrhage and sepsis. The activity of extracellular CIRP is mediated through the Toll-like receptor 4 (TLR4)–myeloid differentiation factor 2 (MD2) complex. Surface plasmon resonance analysis indicated that CIRP binds to the TLR4-MD2 complex, as well as to TLR4 and MD2 individually. In particular, human CIRP amino acid residues 106–125 bind to MD2 with high affinity. Thus, CIRP is a damage-associated molecular pattern molecule that promotes inflammatory responses in shock and sepsis.

Surgical site infection (SSI) and incisional hernia are common complications after major pancreatectomy. We investigated the effects of negative pressure wound therapy (NPWT) on short-and long-term wound outcomes in patients undergoing pancreatectomy. A randomized controlled trial comparing the effect of NPWT with standard surgical dressing (SSD) on wounds was performed in 265 patients undergoing open gastrointestinal resections from 2012 to 2016. We performed a subset analysis of 73 patients who underwent pancreatectomy. Wound complications in the first 30 days and incisional hernia rates were assessed. There were 33 (45%) female patients in the study and the average BMI was 27.6. The pancreaticoduodectomy rate was 68 per cent, whereas 27 per cent of patients underwent distal or subtotal pancreatectomy, and 4 per cent total pancreatectomy. Incisional hernia rates were 32 per cent and 14 per cent between the SSD and NPWT groups, respectively (P = 0.067). In the SSD (n = 37) and NPWT (n = 36) cohorts, the superficial SSI, deep SSI, seroma, and dehiscence rates were 16 per cent and 14 per cent (P > 0.99), 5 per cent and 8 per cent (P = 0.67), 16 per cent and 11 per cent (P = 0.74), and 5 per cent and 3 per cent (P ≥ 0.99), respectively. After adjusting for pancreatic fistula and delayed gastric emptying, no statistically significant differences in the primary outcomes were observed. These findings were true irrespective of the type of resection performed. Short- and long-term wound complications were not improved with NPWT. We observed a trend toward decreased incisional hernia rates in patients treated with NPWT. Owing to the multifactorial nature of wound complications, it is yet to be determined which cohorts of pancreatectomy patients will benefit from NPWT.