|Stephen F. Lowry, MD, professor and chair, and Steve E. Calavano, PhD, associate professor, Department of Surgery, UMDNJ-Robert Wood Johnson Medical School
Injury is the most common cause of disability and death among children and younger adults. The economic costs of involuntary injury account for up to 10% of all heathcare expenditures and untold billions of dollars in terms of lost productivity. Despite these alarming statistics, research commitments devoted to injury prevention, care and rehabilitation significantly pale in comparison to the resources devoted to diseases of life-style and chronic illness. As our population ages, insights into the biology of injury across the entire age spectrum will undoubtedly become a national healthcare mandate.
We have been concerned with the problems of injury biology for more than 20 years. This interest arose initially from the study of burn victims whose unique physiology provides a paradigm of the adaptive response to injury. Burns and other significant injuries may result in manifestations of tissue dysfunction and immunologic abnormalities, eventuating in organ failure and severe infection. Depending upon age and co-morbidity conditions, these manifestations of injury carry a mortality rate which can exceed 50%.
Our original research team at Cornell Medical Center developed a comprehensive approach to injury biology and care by bringing together experts in traumatology, cell biology and immunology, as well as endocrinology and nutritional biochemistry. Recognition of these efforts have included two-decades-long funding, including a recent MERIT award from the NIH. These efforts were greatly aided by strong collaborations with colleagues at Rockefeller University as well as other international academic institutions and industry partners.
We hypothesized that several protein mediators (cytokines) of activated immune cells were the proximal signals arising from injured tissues or invasive infection and that much of the injury-induced clinical phenotype evolved from pro-inflammatory cytokine activity. In a series of widely cited investigations in the non-human primate as well as the low dose human endotoxinemia models, we clearly documented the proximal role of TNF as a mediator of infection induced tissue and organ system injury.
We were also the first group to document that neuroendocrine components of the stress response could, at least transiently, attenuate the early inflammatory manifestations of injury. Utilizing both preclinical and clinical models, we confirmed that the adrenal hormones, cortisol and catecholamines, prompted a brief (hours) suppression of pro-inflammatory cytokine signaling, clinical manifestations of a systemic inflammatory response (so-called "SIRS"), and endothelial cell activation which results in a net pro-coagulant state.
Teleologically, the initial anti-inflammatory properties of neuroendocrine hormones are well suited to injuries of limited extent and duration. These influences are not, however, without potential adverse consequences following more severe injury or infection. Indeed, we have documented a late enhancement of immunosuppressive cytokine activity as well as heightened immune cell apoptosis (programmed cell death) as a consequence of excessive neuroendocrine hormone influence.
We have also been interested in the contribution of other clinical interventions and how they might impact upon the injury phenotype and outcome. This includes the role of nutrition during periods of inflammatory related catabolic stress. Our earlier studies documented that feeding exclusively via the parenteral (intravenous) route predisposed to enhanced pro-inflammatory mediator production. This was also associated with increased tendency toward coagulation activation, a mechanism now believed partly responsible for the organ dysfunction syndrome often observed in critically ill patients. In addition, these studies documented that excessive provision of intravenous lipids also predisposed to heightened pro-inflammatory responses and coagulation activation.
There is increasing evidence that infectious risk is, in part, inheritable and our recent efforts have been directed toward identifying the genetic loci which may modulate human infectious risk and clinical responses. Several chromosomal sites are of current interest, including the highly variable HLA region of chromosome 6 which encodes for numerous proteins that interact during inflammatory stress, including several pro-inflammatory cytokines and heat shock proteins. We are also interested in the influence of single nucleotide polymorphisms (SNPs) of cognate receptors for bacterial ligands, such as the Toll-like 2 and 4 receptors, which bind bacterial lipopolysaccharides and lipoproteins. Recent clinical studies have defined two SNPs of the Toll-like 4 receptor as a risk factor for gram-negative bacterial infection in injured patients.
A hallmark of severe inflammatory stress in critically ill patients is a tendency toward loss of heart rate variability. It remains to be determined whether this represents a single system event or a surrogate marker of wider loss of autonomic regulation and system complexity. Our current studies have begun to dissect the relationship of altered heart rate variability to inflammatory stress in our controlled model of endotoxinemia.
In recent years, we have entered into collaborations with investigators around the country via an NIH funded "GLUE" (named for the connective bond of more than 40 researchers brought together to study complications following trauma) grant project entitled "Inflammation and the Host Response to Injury." This has provided the opportunity to enlist internationally renowned experts in microarray technology, proteomics, genotyping, and systems biology to assess the response to controlled inflammation and severe injury. Our laboratory has been a pivotal site for the development of in vivo sampling techniques and the optimized application of limited biologic materials across platforms. We have also begun to apply whole genome transcriptional information to proprietary networking solutions in an effort to define the temporal sequencing of inflammation-induced gene activation. Efforts are now underway to perform these studies in isolated immune cell populations under conditions of controlled endotoxinemia stress as well as during neuroendocrine hormone influence.
An understanding of the complex interrelationships between genetic variation, gene expression, and proteomic responses to be gained by these studies will, without question, lead to new therapeutic targets and strategies for enhanced clinical care. Ultimately, we would hope to modify the injury phenotype at such a time, and in such a manner, so as to affect more optimal restoration of function and faster rehabilitation. There is little doubt that the lessons of injury biology will also translate into wider benefits for populations suffering from non-traumatic inflammatory stress.
Stephen F. Lowry, MD, is professor and chairman of the Department of Surgery at UMDNJ-Robert Wood Johnson Medical School. A medical graduate of the University of Michigan, he has had further fellowship training at the National Cancer Institute and the Memorial Sloan-Kettering Cancer Center. His early research efforts served as a basis for the evolution of biologic response modification therapies for patients with severe infection and shock. These studies have continued during his tenure at RWJMS and have resulted in receipt of an NIH MERIT award that recognizes the continual performance of outstanding research. In 2003, Dr. Lowry was awarded the prestigious Flance-Karl Award from the American Surgical Association in recognition of his substantial contributions to the basic science of surgery. Dr. Lowry's 400 scientific contributions have also earned him recognition by the Institute for Scientific Information as one of the most highly cited authors in the field of immunology.
Steve E. Calvano, PhD, graduated from the University of Connecticut and received his PhD from the University of California. Dr. Calvano pursued a postdoctoral fellowship in immunobiology at the Memorial Sloan-Kettering Cancer Center. Following this fellowship, he was appointed to the faculty in the Department of Surgery at Cornell University Medical College where he collaborated with Drs. Stephen F. Lowry and G. Tom Shires in studying immunological and inflammatory responses to major injury. Dr. Calvano came to UMDNJ-Robert Wood Johnson Medical School in 1997 where he is currently associate professor in the Department of Surgery.§