Insulin-like growth factor-I: a traffic control device on the road to tissue recovery

STRESSES ASSOCIATED WITH TRAUMA, infection, and burns have a common denominator. There occurs with the onset of these stresses a set of temporally phased and coordinated responses that involve innate assessment of the magnitude of the “event,” redirection of metabolism, coordinated homeostatic rebalancing of the internal milieu, and, finally, if all goes well, recovery. Interestingly, what might appear to be a quite localized site of trauma can force systemic responses that severely affect the prognosis for recovery. Beisel (1) stated that the severity of the host response was largely proportional to the severity of the threat. Similarly, Sir John Hammond (7, 8) was the first to crystallize the theory of metabolic rate-dependant prioritizing of nutrient partitioning between tissues and it is applicable to stress scenarios. Our lab expanded this vision with the superimposition of what we termed the “endocrine-immune gradient” on Hammond’s model, wherein the coordinated push and pull of growth factors and cytokines, driven by the response to stress, served to limit the use of nutrients for growth and to make available those same nutrients for immune defense and tissue stabilizing events. This was especially important when food intake was low because of stressinduced hypophagia and cachexia (5). What is so interesting in all of this is that at the core of these host responses lie perhaps only a few key regulators critical to these physiological mechanisms by having the capacity to “morph” in functionality from one phase into another and insulin-like growth factor-I (IGF-I) appears to be one of these key morphing effectors. Large numbers of investigations have made statistical correlations between some aspect of IGF-I (content or mRNA level) and a given state of pathology for the purpose of implying some cause and effect relationship between IGF-I and the studied condition. However, far fewer investigations have dealt with a structured dissection of biochemical pathways involving IGF-I to explain just how IGF-I plays its regulatory role. Considering IGF-I’s rather ubiquitous distribution among various tissues and cells, as well as differing concentrations throughout a variety of normal and pathological situations, this can be a daunting task. Where this can be delineated, a far greater appreciation and understanding of how a once thought of generalized growth factor can have specific multiple signaling capabilities can be realized. In one instance the key to its participation may be its decreased expression and concentration, whereas in another situation, the effect may reside in the increased expression and additional presence of this “growth factor.” Again, regarding stress and the endocrine-immune gradient, several functions of IGF-I are often observed within the context of making nutrients more or less available to tissues and in turn increasing or decreasing the anabolic character of metabolism. Collectively, IGF-I (along with its binding protein milieu and signal transduction pathway) plays a strong leading role in setting the priority through which tissues are impacted by the onset and recovery from and in particular with degrees of fine tuning existing in the intricate interplay between signal transduction elements. For example,