Spinal Cord Injury: Are Interleukins a Molecular Link between Neuronal Damage and Ensuing Pathobiology?

SPINAL CORD INJURY: ARE INTERLEUKINS A MOLECULAR LINK BETWEEN NEURONAL DAMAGE AND ENSUING PATHOBIOLOGY? JACK L. SEGAL* There is at bottom only one genuinely scientific treatmentfor all diseases, and that is to stimulate the phagocytes. Stimulate the phagocytes. Drugs are a delusion.—G. B. Shaw, The Doctor's Dilemma, Act I (1906). Laying a Foundation Spinal cord injury causes physical disruption of the central nervous system and results in multiorgan dysfunction [I]. The decentralization of the nervous system caused by injury is characterized by changes in physiology that are expressed as a generalized impairment of homeostasis . The magnitude of the impairment is in turn dependent on the extent of decentralization, i.e., the neurologic level and completeness of injury. To a large degree, the extent of the pathophysiology can be predicted in an individual, and victims with cervical spinal cord injury (tetraplegia) experience a greater impairment of homeostasis than do individuals with paraplegia. There appears to exist a disproportionate increase in pathologic manifestations as more of the spinal cord becomes isolated from cerebral influence [2]. Spinal reflex arcs normally modulated by feedback from the brain become deregulated and contribute to the pathobiology of injury. In humans, the molecular mechanisms which mediate the physiologic disarray caused by traumatic spinal cord injury (SCI) are not well underThe author extends a special thanks to the victims of SCI and those able-bodied volunteers who unselfishly subject themselves to the risks and inconvenience ofclinical research. The support of the Department of Veterans Affairs Medical Center, Long Beach, California , is acknowledged. The reviews, comments, and suggestions of Martin Jadus, Sherry Brunnemann, and Sid Helprin are deeply appreciated. *Associate professor of medicine, University of California, Irvine, and Department of Medicine, Veterans Affairs Medical Center, 5901 East Seventh Street, Long Beach, California 90822 (11 IGM correspondence address).© 1993 by The University of Chicago. All rights reserved. 003 1-5982/93/3602-08 1 6$0 1 .00 222 Jack L. Segal ¦ Spinal Cord Injury stood. While our understanding of the pathobiology of SCI has substantially increased in recent years [3-5], knowledge ofcause-effect relationships is sparse or fragmentary. The central autonomic dysfunction that accompanies trauma to the spinal cord [6, 7], however, appears to be pivotal in initiating the myriad changes in physiology that result in lifelong disability and an incapacity to maintain metabolic or physiologic equilibrium. The pathobiology of spinal cord injury is extensive and is expressed through a wide range of changes in physiologic and metabolic processes. A truncated, but representative list of the pathologic manifestations of spinal cord injury in humans might include: impairment of cardioregulatory mechanisms and pulmonary function, anemia, altered hepatic metabolism, immune incompetence, carbohydrate intolerance, changes in drug disposition kinetics, accelerated bone turnover, and impaired thermoregulation [3, 6, 8-17]. Victims of spinal cord trauma are chronically exposed to large numbers of medications during the acute and post-acute phase of injury. Because of my longstanding interest in drug therapy and therapeutic drug monitoring in patients with SCI, the opportunity has been afforded to me to study the clinical pharmacology and physiology of these individuals. I have observed changes in the absorption, distribution, metabolism, and excretion of commonly prescribed medications that can be attributed to the pathophysiology of SCI [3]. I believe these alterations in population-specific pharmacokinetic behavior can be explained by invoking a model that incorporates a single biomolecule or family of bioactive molecules in a final, common pathway. The diverse, seemingly unrelated manifestations of the pathobiology of SCI are probably distinct end points of a spectrum of disease having the same pathogenesis, and postulating a final common effector in their etiology is a tenable, potentially falsifiable hypothesis. As the literature of medicine provides little experimental evidence or support for this theory, I shall attempt to develop a paradigm that supports my hypothesis , a paradigm that is dependent upon arguments that implicate interleukins (cytokines) as the primary mediators of the several metabolic and physiologic sequelae of spinal cord injury most inimical to survival. Interleukins are ubiquitous, naturally occurring soluble cell products (peptides, glycoproteins). They function as protein hormones that modify the behavior and growth of cells, particularly those of the immune system. Moreover, interleukin-1 (IL-I) and...