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To determine whether treatment with the CXC chemokine receptor 4 agonist ubiquitin results in beneficial effects in a polytrauma model consisting of bilateral femur fractures plus blunt chest trauma (Injury Severity Score 18–25).Treatment study.Research laboratory.Seventeen Yorkshire pigs.Intravenous injection of 1.5 mg/kg ubiquitin or albumin (control) at 60 mins after polytrauma.Anesthetized, mechanically ventilated pigs underwent polytrauma, followed by a simulated 60-min shock phase. At the end of the shock phase, ubiquitin or albumin were administered and animals were resuscitated to a mean arterial blood pressure of 70 mm Hg until t = 420 mins. After intravenous ubiquitin, ubiquitin plasma concentrations increased 16-fold to 2870 ± 1015 ng/mL at t = 90 mins and decreased with t1/2 = 60 mins. Endogenous plasma ubiquitin increased two-fold in the albumin group with peak levels of 359 ± 210 ng/mL. Plasma levels of the cognate CXC chemokine receptor 4 ligand stromal cell-derived factor-1α were unchanged in both groups. Ubiquitin treatment reduced arterial lactate levels and prevented a continuous decrease in arterial oxygenation, which occurred in the albumin group during resuscitation. Wet weight to dry weight ratios of the lung contralateral from the injury, heart, spleen and jejunum were lower with ubiquitin. With ubiquitin treatment, tissue levels of Interleukin-8, Interleukin-10, Tumor Necrosis Factor α, and stromal cell-derived factor-1α were reduced in the injured lung and of Interleukin-8 in the contralateral lung, respectively.Administration of exogenous ubiquitin modulates the local inflammatory response, improves resuscitation, reduces fluid shifts into tissues, and preserves arterial oxygenation after blunt polytrauma with lung injury. This study further supports the notion that ubiquitin is a promising protein therapeutic and implies CXC chemokine receptor 4 as a drug target after polytrauma.