Translational research productivity of the division has continued along several fronts. Dr. Randy Sprague’s research involves investigating a novel mechanism by which prostacyclin and its analogs produce vasodilation in the lung and will provide new insights into the pathophysiology and treatment of Idiopathic Pulmonary Arterial Hypertension. Our participation in pivotal multicenter clinical trials has focused on the related areas of severe sepsis/septic shock and acute lung injury/acute respiratory distress syndrome (ARDS), in evaluating the efficacies of novel anti-inflammatory and immunoadjuvant therapies to critically ill patients with these disorders. Dr. Daniela Salvemini continued her national and internationally recognized and extramurally funded studies focusing on the pathogenesis of opiate tolerance during chronic pain syndromes vis a vis peroxynitrite-mediated spinal neuroimmune activation, inflammation, and apoptosis. Divisional research in conjunction with Dr. Andrew J. Lechner of the Department of Pharmacological & Physiological Science has addressed experimental lung injury and septic shock caused by intraperitoneal polymicrobial sepsis as occurs in critically ill and injured patients. The focus of these preclinical studies concerns the specific therapeutic potential of adjunctive adenosine A1 receptor antagonism in combination with fluid resuscitation and antibiotic treatment to ameliorate such pathophysiological effects.
Pulmonary Function and Exercise Laboratory
Facilities available for clinical research include a fully-equipped pulmonary function and exercise laboratory for evaluating cardiopulmonary function during exercise. This laboratory has accreditation from the NIH to evaluate all patients participating in the National Emphysema Treatment Trial (NETT). Dr. Soophia Naydenov is the Medical Director. Gregg Ruppel, MEd, RPFT, RRT is the Technical Director.
Clinical Pharmacology Laboratory
(Dr. Randy Sprague)
In spite of all that is known regarding regulation of pulmonary vascular resistance (PVR), important gaps in our understanding of the pathophysiology and treatment of pulmonary hypertension remain. PGI2 and stable PGI2 analogs have been shown to reduce PVR and increase survival in idiopathic pulmonary arterial hypertension (IPAH).
We are currently investigating the hypothesis that PGI2 analogs stimulate receptor-mediated ATP release from erythrocytes of both healthy humans and humans with IPAH. In support of this hypothesis, we reported that; 1) erythrocyte-derived ATP is a determinant of PVR via stimulation of endogenous NO synthesis, 2) the PGI2 analogs, UT-15C and iloprost, stimulate ATP release from healthy human erythrocytes via a signaling pathway (as depicted in the figure) that requires increases in cAMP and 3) erythrocytes of humans with IPAH fail to release ATP when subjected to mechanical deformation in spite of the fact that total ATP content is not reduced. The ability of PGI2 analogs to stimulate receptor-mediated cAMP accumulation and ATP release from erythrocytes of humans with IPAH demands to be investigated and is a major focus of our group.
This translational research will provide important support for a novel mechanism by which prostacyclin and its analogs produce vasodilation in the lung and will provide new insights into the pathophysiology and treatment of IPAH.
Dr. Daniela Salvemini’s Lab
Our research focus is in the pharmacological mechanisms of pain. We employ translational medicine to bridge the gap between basic research and clinical sciences.
Pain Facts & Figures
Incidence of many crhonic conditions, pain affects more Americans than diabetes, heart disease and cancer combined.
* sources: Pain - 76.2 million people, National Cents for Health Statistics
Highlights from the national center Heath Statistics, Report: Health, United States, 2006, Special Feature on Pain 1
Chronic severe pain is a significant global health problem. In the US alone, one third of Americans suffer some form of chronic pain, and in these individuals over 30% of reported pain is resistant to analgesic therapy.
The economic impact of pain is equally large at approximately $100 billion annually. These figures will continue to be on the rise due to an aging population suffering from diabetes, stroke and cancer. Chronic neuroapthic pain is particularly difficult to manage. Opiate analgesics have limited efficacy in chronic neuropathic pain states. In addition, their clinical utility is often hampered by the development of tolerance which necessitates escalating doses to achieve equivalent pain relief thus affording numerous side effects. Considerable evidence implicates nitroxidative stress in the development of pain of several etiologies.
Reactive oxygen and nitrogen species (nitroxide species) in particular superoxide (O2-), nitric oxide (NO) or peroxynitrite (ONOO-) the product of their interaction are potent pro-inflammatory mediators implicated in a variety of disease processes.
Over the years my lab has shown that in addition peroxynitrite plays a key role in the development of pain of several etiologies.
Using a multidisciplinary approach including molecular, bioanalytical, biochemical and pharmacological tools my lab is actively engaged in the following projects:
1. We are interested in the biosynthetic pathways leading to nitroxidative species (in particular but not restricted to nitric oxide, superoxide and peroxynirite) during the development of pain of several etiologies in particular chronic inflammatory pain (arthritis), chronic neuropathic pain (nerve injuries), chemotherapy induced neuropathic pain (induced by commonly used chemotherapeutics such as Taxol or Cisplatin). We are also particularly interested in understanding the role of nitroxidative stress in the development of opiate induced pain and tolerance.
2. Our efforts address the relative contribution of nitroxidative species and their overall significance in nociceptive processing in these settings. To this end we are interested in understanding how reactive nitroxidative species modify mitochondrial function; how they contribute to neuroimmune activation; how they modify through post-translational modifications, the function of key proteins known to play essential roles in nociception and; how they impact neuronal apoptosis.
3. Another key research interest of my lab is to understand the role of the ceramide metabolic pathway in the development of peripheral and central sensitization and to investigate the reciprocal interaction between this pathway and the nitroxidative pathway.
Through our key collaborative efforts with chemistry groups at other academic institutions, we are involved in synthesizing novel chemical tools /probes to study nitroxidative stress and signaling molecules at the molecular, cellular and organism level that help us unravel the therapeutic importance of these pathways in pain thus addressing major unmet medical needs with huge socioeconomic consequences.