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ObjectiveMaintaining adequate oxygen delivery after major surgery is associated with minimizing organ dysfunction, although the precise molecular mechanisms remain unclear.BackgroundSkin, the largest organ in the body, is vulnerable to reduced oxygen delivery. We hypothesized that the skin proteome, assessed before and after surgery, would reveal molecular differences in patients randomized to receive cardiovascular therapy aimed at maintaining preoperative oxygen delivery (DO2).MethodsAbdominal punch skin biopsies were snap frozen or fixed in paraformaldehyde immediately before and 48h after elective esophageal or liver resection. Immediately after surgery, patients were randomized to standard of care or therapy to maintain preoperative DO2. 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 mass spectrometry were confirmed by immunohistochemistry and immunoblot. In a murine hepatic resection model, confirmation of specific proteomic signatures identified in patients was sought by immunoblotting.ResultsPaired biopsies were analyzed from 35 patients (mean age:68±9y; 31% female). We identified 2096 proteins, of which 157 were differentially expressed after surgery. Similar results for selected proteins were found using immunohistochemistry (n=6 patients), immunoblots (n=12 patients) and 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.values. Failure to maintain preoperative DO2 was associated with upregulation of proteins counteracting oxidative stress and.ConclusionsSerial skin biopsies afford mechanistic insight into end-organ injury by quantifying proteomic changes associated with impaired oxygen delivery during high-risk surgery.Trial registrationISRCTN76894700FundingAcademy of Medical Sciences/Health Foundation Clinician Scientist Award [GLA]; British Oxygen Company research chair grant in Anesthesia [GLA]; Great Ormond Street Hospital Biomedical Research Centre [EB,WH,KM]; British Heart Foundation:PG/17/40/33028 [MC]; UK NIHR [GLA]; Barts Charity [TJ]Mini-AbstractSkin, one of the largest organs in the body, is vulnerable to reduced oxygen delivery. Proteomic analysis of skin biopsies obtained before and after surgery show distinct metabolic and inflammatory changes related to perioperative oxygen delivery. Mirrored by complementary laboratory data in mice, skin proteomics reveal new insights into perioperative organ dysfunction. |
