more than 100 manuscripts have been submitted in response to the special call on “Physiology and Pharmacology of Temperature Regulation,” which required spreading publication of the manuscripts over several issues of the journal. Dr. Andrej Romanovsky serves as the Special Editor for this call and has been extremely successful in gathering a plethora of topics regarding temperature regulation, which have contributed greatly to shaping a cutting-edge overview. Because of the number of manuscripts, it was necessary to publish the greater part of these special call papers over the past year. Among these manuscripts were exciting studies, not only in the human being and more common experimental models, but also in diving seals (8) and the king penguin (1).
With regard to diving seals, contributors to the call investigated why seals can respond to diving by hypothermia to degrees that in other species would elicit vigorous shivering. In air, seals, indeed, exhibit normal shivering responses to cold; however, when they are diving, they allow body temperature to decrease to lower oxygen demand, thus extending diving capacity. In the king penguins, there are also differences in temperature regulation between air and water. As shown in Fahlman et al. (1) body temperature does not change in air; however, in water, there are complex alterations in the fasted penguin. These changes are probably due to a loss in body insulation and modifications of peripheral perfusions.
Fever and LPS actions form the bulk of manuscripts published in 2005 (2, 4, 12, 15–17, 19, 21, 22, 24); fever suppression was investigated (2, 12), indicating that there is a factor in the spleen, which at least in the guinea pig inhibits the exaggerated febrile response, thus limiting fever.
The root of the febrile response of LPS was subject to investigation in multiple manuscripts (15, 17, 21, 22). Conventional LPS preparations often contain highly active lipoprotein contaminants, which are endotoxin proteins. LPS itself and these lipoprotein contaminants use different toll-like receptors (21), the original LPS signal uses the TLR4, whereas endotoxin proteins signals via TLR2. The authors conclude that all the known body temperature responses to LPS preparations are mediated by LPS per se and not by the endotoxin contaminants, which would have used non-TLR4 signaling. LPS characteristically evokes rapid fever, and it was tested by Perlik et al. (15), who found that prostaglandin E2 released by Kupffer cells may mediate this early onset of fever. This hypothesis may seem counterintuitive because LPS cannot stimulate prostaglandin E2 production by Kupffer cells as rapidly as it induces fever. However, complement activated by LPS could be the exciting agent. This was tested using cobra venom factor, which is an immediate activator of the C cascade, and indeed, it is suggested that LPS-activated complement, rather than LPS itself, is responsible for the early release of PGE2 by Kupffer cells. This is a prerequisite for the hypothesis that Kupffer cells release PGE2, which causes the rapid component of fever. Remarkably, when LPS is given subcutaneously (17), it seems that a neural pathway may add to the humoral pathway from the local site of inflammation to the brain and thereby cause the fever response. Moreover in birds, fever seems to rely on the synthesis of both prostaglandins and nitric oxide (4). In human studies (6, 24), thermal regulatory function was investigated using functional magnetic resonance imaging (6), in which the representation of the thermoregulatory behavioral motivation, was localized. An important insight was provided to poststroke central pain syndrome associated with lesions in the dorsal posterior insular cortex. Moreover, the attenuated cutaneous vasoconstriction response to cooling in old-age humans could be linked to a blunted response to norepinephrine in these subjects (24). This is important as norepinephrine is the only functional neurotransmitter mediating vasoconstriction in the aged skin, thus predisposing older humans to excess heat loss in the cold.
In this issue of American Journal of Physiology–Regulatory, Integrative, and Comparative Physiology, it was further shown in humans that active vasodilatation of the skin involves prostanoids, which, however, do not play a role during local thermal hyperaemia (10). Moreover, in the aging human (5), not only the skin responses to cooling are investigated, but the recordings of splenic, renal, and adrenal sympathetic nerve activity are tested. Here, it is shown that age blunts the physiological response to hypothermia of the visceral organs, which may add to the already impaired response of the skin.
Genetically modified organisms are used in three of the articles this month. In mice deficient in microsomal PGE synthase-1 (18, 26), it is shown that synthesis of PGE2 by mPGES-1 is a central factor for fever induction, which is distinct from the mechanisms that mediate circadian temperature regulation in stress-induced hyperthermia. In orexin knockout mice (11), a surprising role for orexin in thermoregulation is found. Orexin knockout mice have a narcolepsy-like phenotype that includes severe sleep-wake fragmentation. It was shown that during the onset of sleep, the orexin knockout mice could not decrease their body temperature as much as the wild types over the entire sleep phase. Body temperature of the orexin knockout mice remained 0.7°C higher than the wild-type mice. Because heat loss is a central aspect of sleep, this observation may provide an explanation for fragmented sleep in narcolepsy and describes a hitherto unknown role of orexin for temperature control.
The spleen is also a focus of investigation in this issue. The effect of hypothermia on the relationship between sympathetic nerve activity and cytokine gene expression by the spleen was investigated by a microarray approach (3). Real-time RT-PCR identified a subset of differentially expressed genes, and hypothermia upregulated the transcripts of several genes, including chemokine ligands and interleukins. Remarkably, the expression was not considerably altered by denervating the spleen, showing that hypothermia-enhanced splenic cytokine gene expression is, in fact, independent of splenic sympathetic nervous innervation. Cold defense and sympathetic pathways were further investigated with regard to brain circuits driving sympathetic outflow (14). Here, it was shown that there exist two independent central pathways driving cutaneous vasoconstrictor and thermogenetic sympathetic pathways in this cold defense model. Pathways mediating thermoregulation and fever are also subject to investigation with regard to the role of medullary raphe in fever response (23) and other important areas for hypothalamic neuronal thermosensitivity (25). Moreover, for peripheral input from vagal pulmonary sensory neurons, a role of temperature-sensitive transient receptor potential vanilloid receptors are important in hypothermia. It seems that hypothermia within the normal physiological range stimulates pulmonary sensory neurons via this receptor type (13).
With regard to heat shock transcription factors (20), the role of heat shock factor 3, which is restricted to undifferentiated avian cells and embryonic tissue, is investigated and compared to heat shock protein 1. Finally, two studies (7, 9) shed light onto the role of thermoregulation in the exercising muscle. It could be shown that ANG AT1 receptors are important for heat dissipation in exercise and that the blockade of these receptors will decrease running performance because of a rapid exercise-induced increase in body temperature. After exercise, hypertension is often observed, which, in humans (7), and is paralleled by the magnitude in recovery time of postexercise, esophageal, and active muscle temperatures.
Taken together, this special call provides a framework for understanding thermoregulation and fever from the molecular to the human level. The studies enhance our knowledge of neural pathways and various factors that are important for thermoregulation; moreover, the specific solutions generated by evolutionary pressures are highlighted by comparative studies in various bird models and seals. This special call, which will conclude in January 2007, has been so popular that we look forward to even more publications on this topic.
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