Published By

September-October 2009 l Vol 15 l No 9 -10

Research Articles

The Inverse Association between Cardiorespiratory Fitness and C-Reactive Protein is Mediated by Autonomic Function: A Possible Role of the Cholinergic Antiinflammatory Pathway
Sae Young Jae, Kevin S Heffernan, Eun Sun Yoon, Moon-Kyu Lee, Bo Fernhall, and Won Hah Park
Cardiorespiratory fitness is strongly associated with reducing the risk of developing cardiovascular disease. Fitness is thought to reduce the effects of certain cardiovascular risk factors, such as inflammation, but the mechanism for this connection had not been explored. One clue is the observed inverse relationship between cardiorespiratory fitness and the levels of C-reactive protein (CRP), a major serum marker of inflammation. Jae et al. tested whether the association between high fitness and low CRP levels would be affected by autonomic nervous system function.  The authors found that patients with high fitness exhibited low levels of CRP even after the values were adjusted to account for traditional risk factors and body mass index. However, the relationship between fitness and reduced CRP levels was dependent upon increased parasympathetic tone.  The authors suggest that physical fitness may favorably affect inflammation via the autonomic nervous system.
Page 291| View article: PDF (260 KB) HTML
 
Role of E2F1–Cyclin E1-Cyclin E2 Circuit in Human Coronary Smooth Muscle Cell Proliferation and Therapeutic Potential of Its Downregulation by siRNAs
Barbara Dapas, Rossella Farra, Mario Grassi, Carlo Giansante, Nicola Fiotti, Laura Uxa, Giuseppe Rainaldi, Alberto Mercatanti, Alfonso Colombatti, Paola Spessotto, Valentina Lacovich, Gianfranco Guarnieri, and Gabriele Grassi
Vascular injury caused by coronary bypass surgery or angioplasty can lead to complications including vein graft occlusion, atherosclerosis, and hypertension. These negative side effects of surgical repair can be caused by intimal hyperplasia.  This thickening of the intimal cell layer of blood vessels results from rapid proliferation of coronary vascular smooth muscle cells (CSMCs). Here, Dapas et al. sought to expand the current understanding of control mechanisms governing CSMC proliferation by examining the E2F1–Cyclin E1-Cyclin E2 signaling circuit. They discovered that inhibition of this circuit reduced the phosphorylation of the tumor suppressor retinoblastoma protein and reversibly attenuated CSMC cell proliferation. These results point the way towards new means of addressing the negative consequences of cardiovascular surgery.
Page 297 | View article: PDF (4.4 MB) HTML
Supplementary Data: PDF (1.7 MB)

CD151 Gene Delivery after Myocardial Infarction Promotes Functional Neovascularization and Activates FAK Signaling
Houjuan Zuo, Zhengxiang Liu, Xiaochun Liu, Jun Yang, Tao Liu, Sha Wen, Xin A Zhang, Katherine Cianflone, and Daowen Wang
Following a heart attack (MI), myocardial perfusion is critical for survival. Angiogenesis, a complex process involving endothelial cell proliferation, migration, and remodeling of extracellular matrix, is currently the focus of restoring blood flow after an MI. However, angiogenesis treatments produce vessels that are prone to rupture and may not sufficiently improve regional perfusion. A better approach may be the recruitment of pre-existing arterioles to bypass the causative occlusion. To this end, Zuo et al. examine whether CD151 gene delivery induces arteriogenesis and promotes functional neovascularization in a pig myocardial infarction model. The authors found that overexpression of CD151 enhanced the densities of capillaries and arterioles, increased myocardial perfusion, and reduced myocardial ischemia. They also correlated CD151-dependent neovascularization with MAP kinase signaling. This work could lead to improved methods of treatment in the aftermath of myocardial infarction.
Page 307 | View article: PDF (3 MB) HTML

Severe Burn–Induced Endoplasmic Reticulum Stress and Hepatic Damage in Mice
Juquan Song, Celeste C Finnerty, David N Herndon, Darren Boehning, and Marc G Jeschke
Severe burns can lead to a wide variety of secondary effects, including hyperglycemia and the aberrant degradation of fats and proteins. These negative metabolic changes can result in multi-organ failure, sepsis, and mortality. As a primary center for metabolism, the liver plays a key role in burn patient survival and recovery. Severe burns cause hepatocyte apoptosis in the liver, but the underlying mechanism remains unclear. Song et al. hypothesized that severe burns may cause metabolic dysfunction through the endoplasmic reticulum (ER) stress response, since this pathway is specifically linked with hepatocyte apoptosis. In a mouse model, the authors showed that severe burns lead to both hepatocyte apoptosis and persistent ER stress associated with ER calcium store depletion. This mouse model provides new insight into the mechanism of burn-induced metabolic dysfunction and allows further exploration of the physiologic consequences of thermal injury.
Page 316| View article: PDF (2.9 MB) HTML
 
Intratracheal Delivery of CX3CL1-Expressing Mesenchymal Stem Cells to Multiple Lung Tumors
Hong Xin, Ruowen Sun, Masahiko Kanehira, Takenori Takahata, Jugoh Itoh, Hiroyuki Mizuguchi, and Yasuo Saijo
The highly vascularized nature of the lung makes it a common site for solid tumor metastases. Current chemotherapeutic treatments must be applied systemically, since local treatments lead to lung inflammation. New, less toxic approaches such as transduced mesenchymal stem cells (MSCs) have been used to deliver anti-cancer compounds and proteins - such as Fractalkine (CX3CL1) - to solid tumors. The benefit of these cells is their ability to preferentially migrate to tumors. While these cells are also introduced systemically, the final concentration of MSCs at the tumor site is suboptimal. Xin et al. sought to improve on this stem cell treatment by determining whether intratracheally-applied MSCs could deliver an antitumor agent directly to lung metastases in mice. MSC/CX3CL1 cells injected intratracheally not only suppressed the growth of lung metastases but also prolonged the survival of these mice without causing inflammation. This work increases our understanding of how MSCs can be used in the treatment of solid tumors and provides evidence that anticancer treatments can be increasingly site-specific.
Page 321| View article: PDF (5.9 MB) HTML

Progesterone with Vitamin D Affords Better Neuroprotection against Excitotoxicity in Cultured Cortical Neurons than Progesterone Alone
Fahim Atif, Iqbal Sayeed, Tauheed Ishrat, and Donald G Stein
The inherent complexity and systemic effects of acute-stage traumatic brain injury (TBI) make this disposition very difficult to treat. Indeed, most late phase clinical trials of single drugs have failed and a combined drug approach is seen as more promising. With this concept in mind, Atif et al. wanted to determine whether the neuroprotective effects of progesterone (PROG) and 1,25-dihydroxyvitamin D3 hormone (VDH) were greater in an exitotoxic assay for neuronal cell death than PROG alone. They found that pretreatment of primary rat neurons with either compound alone significantly increased neuroprotection, while the combination of VDH and PROG provided a synergistic effect. This technique allows rapid testing of experimental compounds and may allow faster development of drug candidates for TBI treatment.
Page 328 | View article: PDF (1.3 MB) HTML

Review Articles

The Hepatic Response to Thermal Injury: Is the Liver Important for Postburn Outcomes?
Marc G Jeschke
Thermal injury accounts for an estimated 330,000 deaths per year worldwide – approximately 1,100 of those being U.S. children. One of the most severe forms of trauma, it produces a profound hypermetabolic and hypercatabolic stress response characterized by increased endogenous glucose production via gluconeogenesis and glycogenolysis, lipolysis, and proteolysis – all of which occur through the liver. Over the last 20 years, there have been advances in burn research, in areas such as hypermetabolism, resuscitation, wound healing, pulmonary support, and infection; however, while these successes improved post-burn outcomes – severe burn is still responsible for significant morbidity and mortality.  Dr. Jeschke discusses recent studies and the liver’s role in postburn response.
Page 337| View article: PDF (2.9 MB) HTML

Regulatory NK-Cell Functions in Inflammation and Autoimmunity
Anna Lünemann, Jan D Lünemann, and Christian Münz
Natural Killer (NK) cells are multicompetent lymphocytes with the ability to regulate innate and adaptive immune responses through their interactions with antigen-presenting cells as well as T and B cells. In this review, Lunemann et al. provide insight into the regulation of NK cell-mediated innate and adaptive immune responses as these pertain to autoimmunity and inflammation. The authors highlight the ability of NK cells to limit adaptive immune responses. They also discuss a significant role for these cells in the development and regulation of autoimmune states in both experimental models and patients. Future studies focused on the regulatory role of NK cells may provide promising prospects for NK cell-directed therapies.
Page 352 | View article: PDF (680 KB) HTML

Retraction        PDF            HTML