Effects of exogenous ubiquitin in a polytrauma model with blunt chest trauma*

Abstract

Objective To determine whether treatment with the CXC chemokine receptor (CXCR) 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). Design Treatment study. Setting Research Laboratory. Subjects Seventeen Yorkshire pigs. Interventions Intravenous (i.v.) injection of 1.5 mg/kg ubiquitin or albumin (=control) at 60 min after polytrauma. Measurements and Main Results 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 mmHg until t = 420 min. After i.v. ubiquitin, ubiquitin plasma concentrations increased sixteen-fold to 2870 ± 1015 ng/mL at t = 90 min and decreased with t1/2 = 60 min. Endogenous plasma ubiquitin increased two-fold in the albumin group with peak levels of 359 ± 210 ng/mL. Plasma levels of the cognate CXCR4 ligand stromal cell-derived factor (SDF)-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 IL-8, IL-10, TNFα and SDF-1α were reduced in the injured lung and of IL-8 in the contralateral lung, respectively. Conclusions 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 CXCR4 as a drug target after polytrauma.

Chemokine (C-X-C Motif) Receptor 4 and Atypical Chemokine Receptor 3 Regulate Vascular α1-Adrenergic Receptor Function

“…In combination with previously described effects of ubiquitin in various shock models (19)(20)(21)45), these data indicate that selective CXCR4 activation stabilizes blood pressure during the cardiovascular stress response to hemorrhagic shock, providing an extended therapeutic window during which blood pressure can be restored with fluid resuscitation.…”

“…Ubiquitin, a noncognate CXCR4 agonist (1,18), improved hemodynamic stability in large animal models of endotoxic and traumatic-hemorrhagic shock, while blockade of CXCR4 with the selective antagonist AMD3100 (1,1′-[1,4-phenylenebis(methylene)]bis-1,4,8,11-tetraazacyclotetra-decane octahydrochloride, generic name: plerixafor) impaired hemodynamic stability (19)(20)(21). Furthermore, AMD3100 decreased chronic hypoxia-induced pulmonary hypertension and the selective CXCR4 antagonist AMD3465 (N-[(4-[1,4,8,11-tetraazacyclotetradec-1-ylmethyl]phenyl)methyl]-2-pyridinemethanamine hexahydrobromide), which has a several-fold higher affinity for CXCR4 than AMD3100 (22), attenuated mineralocorticoid excess-induced hypertension in mice and rats (23,24).…”

Heteromerization of chemokine (C-X-C motif) receptor 4 with α1A/B-adrenergic receptors controls α1-adrenergic receptor function

“…A similar approach has recently been used to provide structural insight into ligand regulation of the extracellular surface of the β 2 -AR (45). The overlaid 13 To address the possibility that 13 CH 3 probes on α 1a -AR do not report on X4-2-6 binding, we added 10 μM PE to α 1a -AR in the presence of 10 μM X4-2-6 (Fig. 4, Lower Left).…”

“…Several explanations may account for this observation, such as alteration of the receptor heteromerization equilibrium in the plasma membrane or PLA signals resulting from the association of CXCR4 with other receptors that form heteromeric complexes with α 1A -AR, i.e., during receptor clustering (56). 13 C HSQC NMR spectra of reductively methylated membrane preparations of (Upper Left) α 1a -AR (blue) and α 1a -AR treated with 10 μM PE (red); (Upper Right) α 1a -AR (blue) and α 1a -AR treated with 10 μM X4-2-6 (red); (Lower Left) α 1a -AR (blue) and α 1a -AR treated with 10 μM X4-2-6 and 10 μM PE (red); and (Lower Right) CXCR4 (blue) and CXCR4 treated with 10 μM X4-2-6 (red).…”

“…Treatment with the CXCR4 antagonists AMD3100 and AMD3465 reduced blood pressure in experimental models of pulmonary arterial and systemic hypertension (6, 7). We have shown previously that AMD3100 reduces hemodynamic stability and blood pressure during the cardiovascular stress response to traumatic and hemorrhagic shock, whereas selective activation of CXCR4 with the noncognate agonist ubiquitin improves hemodynamic stability and increases systemic blood pressure after traumatic, hemorrhagic, and endotoxic shock (8)(9)(10)(11)(12)(13). Because in vivo pharmacological targeting of CXCR4 did not affect myocardial function, these findings suggested that effects of CXCR4 on hemodynamics and blood pressure are mediated via modulation of vascular function (9).…”