Molecular medicine
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In the terrorist radiation exposure scenario, radiation victims are likely to suffer from additional injuries such as sepsis. Our previous studies have shown that ghrelin is protective in sepsis. However, it remains unknown whether ghrelin ameliorates sepsis-induced organ injury and mortality after radiation exposure. ⋯ However, vagotomy prevented ghrelin's beneficial effects after RCI. In conclusion, human ghrelin is beneficial in a rat model of RCI. The protective effect of human ghrelin appears to be attributed to re-balancing the dysregulated sympathetic/parasympathetic nervous systems.
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Severe burn injury results in liver dysfunction and damage, with subsequent metabolic derangements contributing to patient morbidity and mortality. On a cellular level, significant postburn hepatocyte apoptosis occurs and likely contributes to liver dysfunction. However, the underlying mechanisms of hepatocyte apoptosis are poorly understood. ⋯ Significantly, upregulation of the ER stress markers glucose-related protein 78 (GRP78)/BIP, protein disulfide isomerase (PDI), p-protein kinase R-like endoplasmic reticulum kinase (p-PERK), and inositol-requiring enzyme 1alpha (IRE-1alpha) were found beginning 1 d postburn (P < 0.05) and persisted up to 21 d postburn (P < 0.05). Hepatic ER stress induced by burn injury was associated with compensatory upregulation of the calcium chaperone/storage proteins calnexin and calreticulin (P < 0.05), suggesting that ER calcium store depletion was the primary trigger for induction of the ER stress response. In summary, thermal injury in mice causes long-term adaptive and deleterious hepatic function alterations characterized by significant upregulation of the ER stress response.
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Traumatic injuries frequently lead to infection, organ failure, and death. Health care providers rely on several injury scoring systems to quantify the extent of injury and to help predict clinical outcome. Physiological, anatomical, and clinical laboratory analytic scoring systems (Acute Physiology and Chronic Health Evaluation [APACHE], Injury Severity Score [ISS]) are utilized, with limited success, to predict outcome following injury. ⋯ The association remained significant after adjustment for injury severity as measured by APACHE or ISS. A single score representing changes in gene expression in peripheral blood leukocytes within hours of severe blunt injury is associated with adverse clinical outcomes that develop later in the hospital course. Assessment of genome-wide gene expression provides useful clinical information that is different from that provided by currently utilized anatomic or physiologic scores.
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Activation of the innate immune system results from severe trauma and the resultant systemic inflammatory response is thought to mediate remote organ injury. In animal models, vagal-mediated innate immune responses have been shown to modulate proinflammatory cytokine release in response to trauma or sepsis. In those models, vagal nerve transaction and splenectomy decreased cytokine release and protected against lung injury and mortality. ⋯ Adjusted mortality rates (OR 1.02; 95% CI 0.98-1.05; P = 0.29) and the reported incidence of ARDS were not significantly different between the two groups (2.4% versus 3.6%; P = 0.213). Patients who underwent splenectomy demonstrated better secondary outcomes than patients who were managed nonoperatively or with splenorrhaphy, even when controlling for injury severity and physiologic derangements. It is possible that the improved outcomes seen in the group undergoing splenectomy were due to favorable modulation of the human innate immune inflammatory response after trauma.
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The cholinergic antiinflammatory pathway modulates inflammatory cytokine production through a mechanism dependent on the vagus nerve and the alpha7 subunit of the nicotinic acetylcholine receptor. GTS-21 [3-(2,4-dimethoxybenzylidene) anabaseine], a selective alpha7 agonist, inhibits inflammatory cytokine production in murine and human macrophages and in several models of inflammatory disease in vivo, but to date its antiinflammatory efficacy in human monocytes has not been characterized. We report here our findings that GTS-21 attenuates tumor necrosis factor (TNF) and interleukin 1beta levels in human whole blood activated by exposure to endotoxin. ⋯ Furthermore, GTS-21 attenuated TNF production in monocytes stimulated with peptidoglycan, polyinosinic-polycytidylic acid, CpG, HMGB1 (high-mobility group box 1 protein), and advanced glycation end product-modified albumin. GTS-21 decreased TNF levels in endotoxin-stimulated whole blood obtained from patients with severe sepsis. These findings establish the immunoregulatory effect of GTS-21 on human monocytes, and indicate the potential benefits of further exploration of GTS-21's therapeutic uses in human inflammatory disease.