Intriguingly, in vivo evidence does indeed suggest that in response to various physiological stimuli, HSP can be actively released and subsequently accumulate in the systemic circulation. Several years ago, we demonstrated that the circulating concentration of a specific member of the HSP family, HSP72 - the stress-inducible member of the HSP70 family, was significantly increased following a bout of moderate-intensity exercise (Walsh et al, 2001). Importantly, this increase was observed in the absence of any overt tissue damage and suggested that exercise stress may stimulate the active release of certain HSP from intracellular locales, to the extracellular environment.
While an increase in temperature was the first stimulus identified that promoted the induction of HSP (and hence why they are called heat shock proteins), numerous other stimuli promote the induction of HSP. Interestingly, skeletal muscle contraction is associated with a number of cellular stresses that may induce the heat shock response, e.g. increases in muscle temperature, changes in muscle pH, oxidative stress, mechanical stress and substrate depletion. On this basis, we reasoned that the skeletal muscle may be the source of the increase in the systemic HSP72 concentration. However, determination of the arterial-venous balance over the contracting musculature showed that while the intracellular HSP72 content of the contracting skeletal muscle increased, HSP72 was not released from the contracting skeletal muscle (Febbraio et al, 2002).
It has been shown that exercise induces the expression of numerous HSP, including HSP72, in the liver of exercised rodents (Kregel and Moseley, 1996; Salo et al, 1991). To examine whether liver HSP72 release contributed to the exercise-induced increase in the systemic HSP72 concentration, we (Febbraio et al, 2002) tested the hypothesis that hepatosplanchnic tissues release HSP72 during exercise. The arterial-venous balance of HSP72 was determined via catheterisation of the brachial artery and hepatic vein. The results of this study demonstrate that the hepatosplanchnic tissues release HSP72 during exercise and that this release contributes, in part, to the exercise-induced increase in the systemic HSP72 concentration. Importantly, a full blood analysis revealed no signs of liver damage or dysfunction as a result of the experimental protocol. Therefore, it was concluded that exercise induces the release of HSP72 from liver via a specific exocytotic pathway, as opposed to non-specific processes such as cell lysis.
It is well documented that specific cells within the brain can synthesise HSP72 in response to various cellular stresses, and, importantly, it has been shown that glial cells actively release HSP72 following stimulation (Guzhova et al, 2001). Therefore, we conducted a study to examine whether the human brain was capable of releasing HSP72 in response to exercise. HSP72 release was determined on the basis of the internal jugular venous to arterial balance and we were able to demonstrate that indeed the human brain is capable of releasing HSP72 in response to exercise (Lancaster et al, 2004).
In addition to exercise stress, it has recently been demonstrated that psychological stress results in an increase in the systemic HSP72 concentration. In an interesting study, Fleshner and colleagues exposed Sprague Dawley rats to a cat for 2h. Importantly, no physical contact between the animals occurred. Cat exposure resulted in a marked increase in the extracellular HSP72 concentration and this increase was ameliorated by adrenalectomy, suggesting that adrenal hormones are crucial to the psychological stress-induced increase in extracellular HSP72 (Fleshner et al, 2004).
Collectively, these data demonstrate that both physiological and psychological stress stimulate the release of HSP72 from intracellular locales into the extracellular environment. Importantly, the data strongly argue against cell necrosis being a key mediator of HSP72 release. We did not observe any cell necrosis in our exercise studies and the increase in extracellular HSP72 induced by cat exposure observed by Fleshner and colleagues is highly unlikely to have been mediated by cell necrosis. Thus, it appears that in response to stressful conditions, the cell contains the necessary means to efficiently export specific HSP. In the subsequent section we will discuss some of the recent studies that have examined the mechanistic basis by which cells are able to release HSP in response to stressful cellular conditions.
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