Proteomic signatures of perioperative oxygen delivery in skin after major surgery.

Background: Maintaining adequate oxygen delivery after cancer surgery is associated with fewer infections, although the precise molecular mechanisms remain unclear. Skin, the largest organ in the body, is vulnerable to reduced oxygen delivery. We hypothesized that the differences in the skin proteome assessed before and after surgery, would reveal key molecular pathways associated with maintaining preoperative oxygen delivery (DO2). Methods. Abdominal punch skin biopsies were obtained from patients immediately before, and 48h after, elective esophageal or liver resection. Immediately postoperatively, patients were randomized to standard care or hemodynamic therapy (fluid and/or dobutamine inotropic support) to maintain DO2 at, or above, preoperative levels. On-line two-dimensional liquid chromatography, followed by ultra-high definition label-free mass spectrometry analysis, and/or immunoblots quantified significant proteomic changes. Selected proteins identified by proteomics were confirmed by immunohistochemistry/immunoblot, and by immunoblotting skin from mice after hepatic resection. Results. Paired biopsies were analyzed from 35 patients (mean age (SD):68 (9)y; 31% female). We identified 2096 proteins, of which 157 were differentially expressed after surgery (n=20 patients). Differentially expressed proteins were confirmed in patient samples by immunohistochemistry (n=6), immunoblots (n=12); these findings translated to murine abdominal skin obtained after liver resection (n=14). After surgery, 14 proteins distinguished esophagectomy patients with normal (n=10) versus low (n=7) DO2. Maintenance of preoperative DO2 upregulated proteins that promote smooth muscle migration and leukocyte activation, while counteracting oxidative stress. Conclusions. Serial skin biopsies afford mechanistic insight into end-organ injury by quantifying proteomic changes associated with impaired oxygen delivery during high-risk surgery.