July-August 2009 l Vol 15 l No 7- 8

Research Articles

The Selective α7 Agonist GTS-21 Attenuates Cytokine Production in Human Whole Blood and Human Monocytes Activated by Ligands for TLR2, TLR3, TLR4, TLR9, and RAGE
Mauricio Rosas-Ballina, Richard S Goldstein, Margot Gallowitsch-Puerta, Lihong Yang, Sergio Iván Valdés-Ferrer, Nirav B Patel, Sangeeta Chavan, Yousef Al-Abed, Huan Yang, and Kevin J Tracey
Inflammation is linked with disease forms as varied as atherosclerosis, Alzheimer’s disease, cancer, and sepsis. Stimulation of the vagus nerve activates the cholinergic antiinflammatory pathway, by downregulating proinflammatory cytokines such as tumor necrosis factor (TNF), and has therapeutic benefit in mouse models of sepsis. Rosas-Ballina and colleagues argue in this current work that cholinergic agonists selective to the alpha-7 subunit of the nicotinic acetylcholine receptor could reduce the levels of TNF ex vivo in endotoxin treated whole blood. They show that one such agonist, GTS-21, effectively reduced TNF production in stimulated human monocytes, demonstrating that this compound targets inflammation. GTS-21 also reduced TNF levels in whole blood collected from severe septic patients. Their findings could lead to better solutions for the wide range of patients that suffer from inflammation-associated pathologies.
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Coordinate Control of Expression of Nrf2-Modulated Genes in the Human Small Airway Epithelium Is Highly Responsive to Cigarette Smoking
Ralf-Harto Hübner, Jamie D Schwartz, Bishnu P De, Barbara Ferris, Larsson Omberg, Jason G Mezey, Neil R Hackett, and Ronald G Crystal
Tobacco smoke exposure leads to significantly increased likelihood for the development of cancer, cardiopulmonary diseases, and other morbidities. The small airway epithelium is one of the first lines of defense against the oxidative stress associated with cigarette smoke. Several antioxidant mechanisms, including those in the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor pathway, work to eliminate these toxins. Hubner et al. examined the effects of cigarette smoke on the expression of Nrf2 and Nrf2-linked genes in the airway epithelium of humans and mice. The authors found that Nrf2 is upregulated in human small airway epithelium and that expression can be localized to the nucleus, highlighting its role as a transcription factor responsive to specific oxidative stress. This study not only provides further understanding of the pathways leading to cigarette smoke-induced damage in humans but also underscores similarities between human and murine responses to oxidative stress.
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Supplementary Data: PDF (212 KB)
 
A Genomic Score Prognostic of Outcome in Trauma Patients
H Shaw Warren, Constance M Elson, Douglas L Hayden, David A Schoenfeld, J Perren Cobb, Ronald V Maier, Lyle L Moldawer, Ernest E Moore, Brian G Harbrecht, Kimberly Pelak, Joseph Cuschieri, David N Herndon, Marc G Jeschke, Celeste C Finnerty, Bernard H Brownstein, Laura Hennessy, Philip H Mason, Ronald G Tompkins, and The Inflammation and the Host Response to Injury Large Scale Collaborative Research Program
The Acute Physiology and Chronic Health Evaluation (APACHE) scoring system (in conjunction with Injury Severity Score or ISS) is used to assess patient treatment options and determine prognosis in trauma cases. Infections and other complications such as sepsis and multiple organ dysfunction syndrome (MODS), which lead to longer lengths of stay and more intensive care, drive up the cost of treating trauma cases. Warren et al. took advantage of widely available genomic screening methodologies to assess global mRNA expression from peripheral blood leukocytes drawn from trauma patients. They developed a scoring method that assigns a single value based on these genome wide expression patterns, termed the difference from reference score or DFR, which could then be correlated with patient outcome. The authors found that DFR scoring was useful for predicting outcomes in trauma patients in a manner that both recapitulated and exceeded the existing methodologies. High throughput approaches such as DFR scoring could improve the quality and efficacy of trauma patient care.
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Short-Term Overeating Induces Insulin Resistance in Fat Cells in Lean Human Subjects
Anna Danielsson, Siri Fagerholm, Anita Öst, Niclas Franck, Preben Kjolhede, Fredrik H Nystrom, and Peter Strålfors
With increasing waist sizes and body mass indices come associated health concerns that have garnered significant attention in recent years. Of these concerns, insulin resistance and type 2 or adult-onset diabetes (T2D) are both strongly associated with obesity. However, the short-term effects of a fast food diet on insulin signalling had not been explored. Adipocytes from lean, healthy volunteers were examined after diet-induced increases in body weight and fat for changes in insulin dependent markers such as receptor expression and specific phosphorylation patterns. Danielsson et al. found that, in as little as 4 weeks, signalling and expression of insulin pathway components in these subjects mirrored events found in T2D. This study advances a human model for how diabetes may develop in otherwise healthy individuals and provides further evidence that a high-calorie, high-fat diet is a significant risk factor for T2D.
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Nonerythropoietic Tissue Protective Compounds Are Highly Effective Facilitators of Wound Healing
Zübeyde Erbayraktar, Serhat Erbayraktar, Osman Yilmaz, Anthony Cerami, Thomas Coleman, and Michael Brines
Erythropoietin (EPO) is integral to red blood cell production, and recent efforts have demonstrated that this molecule is important in the regulation of inflammation and wound healing. To accommodate these dual roles of EPO, the body possesses specific receptors that drive either erythrocyte production or healing. In this work, Erbayraktar et al. test compounds that may specifically trigger the effects of healing-specific EPO receptors without engaging systemic erythropoiesis. They found that the non-erythropoietic tissue protective compounds (TPCs) carbamyl-EPO and ARA 290 were able to significantly increase wound healing in several models of injury. Clinical application of their efforts may lessen patient suffering through faster healing times for a variety of wounds and injuries.
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The Immunohistochemical Expression of Growth Hormone–Releasing Hormone Receptor Splice Variant 1 Is a Favorable Prognostic Marker in Colorectal Cancer
Elena Theophanous, Constantina Petraki, Andreas Scorilas, Vassilios Komborozos, George Veloudis, Jozsef L Varga, Marta Zarandi, Andrew V Schally, and Michael Koutsilieris
Colorectal cancer is the third most common cancer in adults worldwide and the fourth leading cause of cancer-related deaths. Since cancer is the direct result of uncontrolled growth, it is not surprising that growth hormones play a role. Although growth-hormone releasing hormone receptor (GHRH-R) expression is canonically localized to the pituitary gland, Theophanous et al. report that a splice variant of GHRH-H, termed SV-1, is found in tumor biopsy samples from colon. Through immunohistochemistry, the authors analysed samples from 70 patients with colorectal cancer (CRC), localized SV-1 to tumor tissue, and found that its presence was correlated with increased patient survival time. Further, the authors demonstrate that SV-1 expression is negatively correlated with the pathological stage of the disease, suggesting that SV-1 is a favorable prognostic factor for CRC. This work furthers our understanding of CRC risk factors and SV-1’s role in the biological pathways leading to metastasis.
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Cadmium Concentrations in Blood and Seminal Plasma: Correlations with Sperm Number and Motility in Three Male Populations (Infertility Patients, Artificial Insemination Donors, and Unselected Volunteers)
Susan Benoff, Russ Hauser, Joel L Marmar, Ian R Hurley, Barbara Napolitano, and Grace M Centola
Humans are readily exposed to cadmium through active or passive cigarette smoke, food, drinking water, and other sources. Since this metal preferentially accumulates in reproductive tissue such as testes, Benoff et al. hypothesized that cadmium exposures contribute to worldwide reports of declining sperm counts and decreased male fecundability. The authors demonstrate that there is increased cadmium in seminal plasma of patients presenting with infertility as contrasted with two healthy populations, that sperm motility and numbers are lower with increased cadmium concentration, and that these endpoints did not correlate with confounders. Experiments in rats recapitulated the human observations, showing that cadmium exposures alone were sufficient, and indicating that animal model systems can serve as a platform for the further study of cadmium toxicity. These findings illuminate a connection between environmental exposures and observed decreases in fertility.
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Does Splenectomy Protect Against Immune-Mediated Complications in Blunt Trauma Patients?
Marie Crandall, Michael B Shapiro, and Michael A West
Millions of nonfatal injuries resulting from blunt trauma occur in the United States each year. Forty percent of traumas include intraabdominal injuries. When the spleen is injured, uncontrolled bleeding may require operative interventions, including splenectomy. In patients that are hemodynamically stable, however, it is not clear whether splenectomy would lead to improved outcome. Using metrics from the National Trauma Data Bank, Crandall et al. found that splenectomy resulted in shorter hospital and ICU lengths of stay than patients managed nonoperatively or with splenorrhaphy, and postulate that this improvement could be due to beneficial modulation of acute inflammatory responses coordinated through the spleen. These results have implications for how emergency departments approach surgical options for blunt trauma patients.
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Genome-Wide Association for Smoking Cessation Success: Participants in a Trial with Adjunctive Denicotinized Cigarettes
Tomas Drgon, Catherine Johnson, Donna Walther, Anthony P Albino, Jed E Rose, and George R Uhl
Smokers and nonsmokers alike can appreciate that some individuals have an easier time quitting than others. Indeed, through twin studies, it is clear that there is a heritability component to this difference. To examine these apparent genetic differences, Drgon et al. have recently employed genome-wide association (GWA) studies to show that genetics can determine success rates in individuals who used nicotine replacement, bupropion or community support quitting methods. The current study expands on this work by demonstrating that many of the genetic patterns found in prior studies also underlie a patient’s ability to quit when using de-nicontinized cigarettes. Not only do these findings support their prior observations, but they also suggest a new method of smoking cessation that mitigates potential side effects of nicotine or similar compounds. These studies also identify specific genes associated with addiction and could help inform future efforts to curb or prevent substance dependence.
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Supplementary Data: PDF (176 KB)
 
Spermine Protects Mice Against Lethal Sepsis Partly by Attenuating Surrogate Inflammatory Markers
Shu Zhu, Mala Ashok, Jianhua Li, Wei Li, Huan Yang, Ping Wang, Kevin J Tracey, Andrew E Sama, and Haichao Wang
The normal response to infection generally involves inflammation, but this response can become dangerous and lead to systemic inflammation and sepsis. As part of the response to infection, macrophages recognize pathogen- or damage-associated molecular patterns, or PAMPs and DAMPs, respectively, leading to the release of cytokines and inflammation. If this mechanism becomes dysregulated, systemic inflammation, sepsis and ultimately death can occur. Based on prior understanding of compounds that can attenuate these responses, Wang et al. examined the effect of spermine on lethal sepsis and found that this antiinflammatory agent can protect mice from lethal sepsis. This work contributes to our understanding of how this systemic inflammatory response system is regulated, and therefore how it may be attenuated in a clinical setting to treat or prevent sepsis.
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Review Article
 
Molecularly Targeted Therapies for Dysimmune Neuropathies
Andreas A Argyriou
The collection of conventional treatment options for diseases of the Peripheral Nervous System (PNS), especially for dysimmune neuropathies, include the administration of corticosteroids, plasmapheresis, long term intermittent intravenous immunoglogulin (IVIG) infusion, and immunosuppressive agents. However, the efficacy of these treatment approaches is usually short-lasting or associated with adverse events, mainly because of the clinical heterogeneity and the huge variability of treatment responses. Recent advances in the understanding of the immunological pathogenesis of dysimmune neuropathies, or nerve root syndromes, have led to an uprise of new molecularly-targeted treatment options, especially for disorders that are resistant to conventional treatment options. Dr. Argyriou highlights recent and possible future developments in molecularly-targeted therapies for dysimmune neuropathies.
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