Heat shock proteins as biomarkers for stroke and trauma.

Heat shock proteins continue to fascinate scientists from different disciplines even after 40 years since their discovery in fruit flies. Whereas these proteins are expressed at modest levels in cells growing under normal conditions, their expression increases to very high levels after cell injury (1). Hyperthermia, exposure to metals, conditions that lead to glutathione depletion, and ischemic or reperfusion injuries are a few of the many different activators of cellular stress responses that lead to increased heat shock protein expression. The resultant accumulation of heat shock proteins confers added protection to the cell, especially when confronted again with the same insult. This latter phenomenon, referred to as preconditioning, enables tissues, organs, and even organisms to survive insults that would otherwise be lethal (2). First studied in the 1960s and 1970s by cellular and molecular biologists interested in gene expression, heat shock proteins began to attract the attention of scientists studying protein folding. A connection between heat shock proteins and protein folding seemed likely, because many activators of the heat shock response are protein chaotropes; they destabilize the structure and therefore the function of proteins (3). Work over the last 20 years has indeed revealed a role for heat shock proteins in protein folding. Acting as “molecular chaperones,” many heat shock proteins facilitate the early steps in protein maturation (4). For example, although not conveying any direct information about the folding process itself (this information being present within the linear sequence of amino acids within the particular polypeptides), molecular chaperones ensure the fidelity of protein maturation events throughout the cell (5). Newly synthesized proteins that might take a wrong turn during the folding process are helped back on to the right pathway with the help of molecular chaperones. Preexisting proteins, perhaps denatured because of a cellular heat shock event, either are restored to their initial state or, if irreparably damaged, are targeted to a degradative pathway by means of molecular chaperones. Thus, under conditions where protein folding or maturation events might be compromised, cells will increase their levels of heat shock proteins to ensure the continued production and function of their pool of proteins. Immunologists may have determined yet another function of heat shock proteins. Even before knowing its precise identity, immunologists had described “common antigen,” an immunodominant protein antigen shared by most bacterial species that elicited strong humoral responses in animals and humans. Common antigen eventually was shown to be the bacterial form of heat shock protein 60 (hsp60), also known as GroEL. We now know that the mammalian immune response, whether humoral or cellular, is on the lookout for heat shock proteins from different pathogens (6). Like their animal hosts, microbial pathogens contain their own heat shock proteins the expression of which increases upon infection of the host. Hence, over the course of the development of the immune system, heat shock proteins were likely used to help the host identify and respond to infectious pathogens. Such research has led to the hypothesis that heat shock proteins represent primitive danger signals that activate different arms of the immune response (7). As described by Wang et al. in this issue of The Green Journal, heat shock proteins may also play a role in the response of patients to heatstroke or severe trauma (8). Wang et al. examined the serum levels of heat shock protein 70 (hsp70) in persons experiencing heatstroke. Patients were classified as having mild or serious heatstroke, the latter including persons with a fever above 40 C, confusion, delirium, or even coma. Controls for the study involved normal persons who came to the hospital for physical examinations during the summer months, as well as those who had no history of heatstroke and whose blood was collected in the cooler autumn months. Serum hsp70 levels were elevated in the healthy volunteers whenever core temperature reached or exceeded 39 C. In contrast, many of the heatstroke patients failed to show increased serum levels of hsp70. This decreased response was more pronounced in those with serious heatstroke than in those with mild heatstroke. Thus, increased levels of hsp70 appeared to correlate with a better outcome for the patient. Equally interesting was the observation that circulating antibodies to hsp70 occurred in more than half of those patients with serious heatstroke. Moreover, patients older than 60 years exhibited the highest levels of the hsp70 autoantibody. This latter observation is of special interest, because heatstroke occurs mostly in the older population. The higher levels of hsp70 antibody detected in patients with severe heatstroke might have accounted for the lower levels of hsp70 proAm J Med. 2001;111:669 – 670. From the Departments of Surgery, Medicine, and Physiology, University of California, San Francisco, and San Francisco General Hospital, San Francisco, California. Requests for reprints should be addressed to William J. Welch, PhD, San Francisco General Hospital, 1001 Potrero Avenue, Building 1, Room 210, San Francisco, California 94110.