| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
RESEARCH-ARTICLE
Department of Oral Biology, Ohio State University, Columbus, Ohio
Address for reprint requests and other correspondence: N. Quan, Dept. of Oral Biology, Ohio State Univ., 4179 Postle Hall, 305 W. 12th Ave., Columbus, OH 43210 (e-mail: quan.14{at}osu.edu).
Abstract
In 2005, the American Physiological Society (APS) initiated the Living History Project to recognize senior members who have made extraordinary contributions during their career to the advancement of the discipline and profession of physiology. During 2007, the APS Section of Environmental and Exercise Physiology selected Clark M. Blatteis to be profiled in Advances in Physiology Education.
Key words: American Physiological Society history; Living History program
CLARK M. BLATTEIS was born on June 25, 1932, in Berlin, Germany. Much of his childhood was spent during World War II, when his family, as German Jews, escaped Germany and was constantly on the run to avoid the reach of the advancing Germans. After the war, he arrived in the United States in 1948 and received his bachelor's degree at Rutgers University in 1954. Subsequently, he enrolled in the University of Iowa, first for a master's degree and then as a PhD student with Dr. Steven Horvath as his advisor. He earned his PhD in physiology in 1957 with a doctoral dissertation that focused on the effects of hypothermia on renal functions (Fig. 1). Dr. Blatteis' interest in the pathophysiology of fever began when he was a postdoctoral fellow under Dr. Geoffrey Dawes at Oxford University between 1962 and 1963. Dr. Dawes once remarked that a serious problem in the diagnosis of neonatal infections was that neonates did not usually exhibit fever during infectious illness in the first days of postnatal life. Ever since, Dr. Blatteis has been highly intrigued by the puzzle of how fever could be induced by infection. Although he has made many contributions to multiple fields in physiology, his most important contribution is undoubtedly on the mechanisms of fever induction.
|
Research Training and Intervening Years
While Dr. Blatteis was a graduate student with the renowned physiologist Dr. Steven Horvath, they published five articles. These articles were characterized by their broad scope: the wide-ranging subjects included cardiovascular physiology, hemorrhage, renal physiology, respiratory physiology, and hypothermia. Dr. Blatteis' research would later become much more focused. He credits the emergence of his own research style to his postdoctoral training in Oxford (1962–1963, under Dr. Geoffrey S. Dawes), where he learned to conduct research in a rigorously sequential and systematic manner. Dr. Horvath's influence, however, never left him in the sense that although Dr Blatteis' major contributions to physiology are highly focused on fever induction mechanisms, he often steps outside of traditional paradigms in search of clues that are far afield.
The next phase of Dr. Blatteis' career (after graduation and before the development of his own research focus on fever induction mechanisms) was not dictated by the narrow focus of interest that typically afflicts today's young scientists. On the contrary, mandatory military service, personal affairs, and intellectual curiosity conspired to lead him to a broadened and enriched perspective.
Dr. Blatteis served for 3 years at the United States Army Medical Laboratory (USAML) and received assignments concerned with human adaptations to extreme environmental challenges. On one assignment, he conducted research on carbon monoxide poisoning in a camp under ice in the Greenland Icecap. While he reveled in this type of challenge, academic research was not forgotten as he published five articles during this period, the first of which can be found in the Legacy Content of the American Journal of Physiology.
The first independent study he published was the "Afferent initiation of shivering" (1) when he served with the USAML. In this study, he efficiently clarified old confusions and established new concepts. At that time, falling skin, deep body, and brain temperatures, either singly or in combination, were proposed to stimulate shivering. He anesthetized dogs in which shivering was induced by cooling of a partially amputated rear leg, which remained connected to the body by bone, femoral and sciatic-peroneal nerves, and the femoral artery and vein. He demonstrated that the onset of shivering was not dependent on afferent impulses returning from the cooled leg because nerve section before or during cooling did not affect shiver induction. On the other hand, occluding the femoral vessels abolished shivering. This suggested that cooled blood entering the truncal circulation was the trigger of shivering. This study launched the notion of internal body thermoreceptors, which was later further developed by another study (33).
After his military service ended in 1961, Dr. Blatteis spent a year in Peru to study altitude physiology. An unstated motive for this journey to the heights of the Andes was to meet his new parents-in-law in Peru. Again, he was delighted with this adventure-like experience. He was not only pleased by the warm welcome of his in-laws but also enthralled by researching physiological adaptation in another extreme environment. He and his team found that altitude acclimation in neonates was inherent. This is because the fetuses developed in a hypoxic environment and thus become adapted to high altitude. Such studies demonstrated powerful influences of environmental factors on physiology and development. Many of his subsequent studies involved the investigation of the impact and interactions of environmental factors such as hypoxia, cold, and altitude on the physiological state.
Dr. Blatteis went to Oxford in 1962 after his Peruvian excursion for training under Dr. Geoffrey S. Dawes. He often later credited his research style to his Oxford training between 1962 and 1964. However, comparing his brilliant first independent article cited above, which was published before his Oxford training, with his later publications, one cannot detect obvious changes in style. The difference, perhaps, is that in his later works, especially those on fever induction mechanisms, he orchestrates a series of logically compelling studies that gradually reached ever deeper into the heart of the question.
This systematic approach was preceded by individual studies published between 1964 and 1983, during which Dr. Blatteis published 31 original articles.
The topics of these studies were broad, but they gradually focused toward his major interest: mechanisms of fever induction. He discovered the influence of hypoxia on metabolic responses (4) and thermogenic responses (10) to cold, that white adipose tissue changes into brown in the interscapular fat pad under hypoxic conditions (11), that body weight is a critical variable in small animals' febrile responses to endotoxin (5), the influence of catecholamine on thermogenesis and fever (3), and that there are different febrile responses induced by exogenous versus endogenous pyrogens (EPs) (2). He dissected central neural networks controlling body temperature and showed that different sites in the hypothalamus may separately control heat loss and heat production (2). He characterized febrile responses induced by EPs (later identified as inflammatory cytokines) and demonstrated that they would induce fever when given directly to the preoptic area/anterior hypothalamus (PO/AH), a thermoregulatory center controlling fever production (2). It is probably during this period that Dr. Blatteis realized the importance of the febrile response, as he coined the statement "fever is the hallmark of infection" (7), highlighting the near universality of this physiological reaction to infection. His studies in this period showed that fever may be modulated by external conditions as well as by neuroactive substances inside the body and that exogenous pyrogens induce fever by inducing EPs, which somehow affect the critical hypothalamic thermoregulatory centers. These studies set the stage for his most important contribution to physiology, namely, unraveling the pathways by which fever is induced after infection.
The Role of Circumventricular Organs in Fever Induction
Dr. Blatteis' first study on fever induction mechanisms (8) remains his most cited article (to date, it has been cited 150 times according to the ISI Web of Science). In this study, Dr. Blatteis raised the question of how EPs, cytokines produced by the host after infection, negotiate the blood-brain barrier (BBB) to induce fever. This was the right question to ask at the right time. In 1982–1983, the conventional dogma was that the immune system and central nervous system (CNS) were physically separated by the BBB so that large molecules, including cytokines, did not enter the brain via the circulation. Based on the fact that EPs will induce fever when given peripherally and that the most sensitive site in the brain for EPs to induce fever is the PO/AH, Dr. Blatteis deduced that there might be ports of entry that allow circulating EPs to cross the BBB and access the PO/AH. A good candidate was the organum vasculosum laminae terminalis (OVLT). This is one of the circumventricular organs (CVOs) in the brain that possesses a leaky BBB, and it is situated immediately ventral to the PO/AH. This idea was tested by electrolytic lesion of the anteroventral wall of the third ventricle (AV3V), an area that included the OVLT. This lesion abolished fever induced by the peripheral injection of a bacterial endotoxin, lipopolysaccharide (LPS), but did not affect fever induced by the direct injection of EPs into the PO/AH. This study launched a new concept of immune to brain signaling, namely, that CVOs could be critical relays that transmit immune signals to the brain.
This classical study remained a beacon for later studies that sought to identify pathways by which the separation between the immune system and CNS can be bridged, although some of the details of the original postulates needed to be modified based upon newer evidence. For example, the demonstration of a glial limitan surrounding the CVOs (23) made the possibility of direct diffusion of cytokines from the OVLT to PO/AH unlikely, and the demonstration of CVOs themselves as sites of cytokine production after peripheral LPS injection made the conjecture that cytokines in the CVOs need to be derived from circulating cytokines unnecessary (24). Dr. Blatteis expanded on the notion of the CVOs by showing that neurons in the OVLT responded to inflammatory cytokines (32). Therefore, the CVOs need not be ports of entry for cytokines to diffuse into the brain; nonetheless, they may relay peripheral immune signals to the brain via neural projections that originated from neurons inside the CVOs. More than 20 years after the publication of this study, its influence on guiding research in the field of neuroimmune communication is still felt today [see Roth's excellent review for a current perspective (26)]. It is also noteworthy that Dr. Blatteis is critically objective with his own theory. After learning that a small region between the OVLT and PO/AH, the ventromedial preoptic nucleus (VMPO), might play an important role in fever induction (28), he was the first to point out that lesioning of the AV3V might have resulted in the deletion of the VMPO, lending an alternative interpretation to the original study.
Neural Pathways of Fever Induction
Dr. Blatteis' next major contribution involved another paradigm shift. Humoral pathways, namely, pathways by which inflammatory mediators are carried to the CNS via the circulation, had been considered the only ascending pathway by which peripheral inflammation might stimulate the CNS. In 1994, Watkins (36) and Dantzer (12) demonstrated that peripheral inflammation could activate the CNS via the vagus nerve. Dr. Blatteis immediately recognized the importance of this new modality of neuroimmune communication. Furthermore, he observed that during LPS-induced fever, the induction of blood cytokines lags behind the increase in body temperature. He conducted a study to test whether the vagus nerve had an influence on fever induction. The results showed that subdiaphragmatic vagotomy blocked peripheral LPS-induced fever (29) and the associated PGE2 increase in the PO/AH. PGE2 in the PO/AH has long been regarded as the final central mediator for fever induction, although direct demonstration of a correlation between increases of PGE2 in the PO/AH and febrile responses has only been shown recently by his own research (31). These findings led him to postulate that vagal afferents play a critical role in stimulating the release of PGE2 in the PO/AH and the consequent initiation of fever.
The demonstration that vagal afferents contribute to fever induction solved some previously unsettled issues but also raised new questions. Due to the speed of nerve transmission, the appearance of the febrile response ahead of blood cytokine increases may now be explained on the basis that peripheral immune challenges might have stimulated vagal afferents before the induction of circulating cytokines. But this would imply a major break from the dogma that fever is induced by inflammatory cytokines after infection because, according to his new theory, fever can be induced before the induction of inflammatory cytokines. The next breakthrough, therefore, required the discovery of fever-initiating factors that were not inflammatory cytokines.
Induction of Fever by Complement Activation
Dr. Blatteis noted from recent studies that the hepatic branch of the vagus is specifically involved in fever induction (34). In addition, liver Kupffer cells are important in clearing bacterial endotoxin. He deduced that the interaction between bacterial endotoxin and liver Kupffer cells must have generated the unidentified fever inducers, which subsequently induced fever via hepatic vagal afferents. He suspected the involvement of the complement system, which, unlike inflammatory cytokines, can be activated within minutes after microbial stimulation. He tested this idea by depleting complements using cobra venom factor and eliminating Kupffer cells using GdCl3. The results showed that endotoxin-induced fever and the associated increase of PGE2 in the PO/AH were attenuated by either complement depletion or Kupffer cell elimination (30). These studies ushered in the new concept that fever may be initiated by complements, not inflammatory cytokines. Unlike the CVO theory he proposed (which gained immediate popularity because it fulfilled the need at the time to understand the missing link that connected the immune system and CNS across the BBB), his complement theory left him and his associates toiling alone in this uncharted territory for the last 10 years. To date, his laboratory is the only one to investigate the role of complement in fever induction. The majority of published studies in literature still treat inflammatory cytokines as the major, if not the only, initiators of fever induction. Thus, Dr. Blatteis is ahead of his time.
Undaunted, he continued to test his new theory. Using different amounts of cobra venom factor to reduce LPS-induced fever, he showed that the reduction of complement levels was proportional to the reduction of the fever index. Using complement knockout animals, he demonstrated that endotoxin-induced fever was absent in C5 knockout mice and that injection of a C5a antagonist blocked endotoxin-induced fever (17). Using fluorescence-labeled endotoxin, he demonstrated that the onset of fever correlated with the appearance of endotoxin in liver Kupffer cells (19). In addition, he discovered that the interaction between endotoxin and liver Kupffer cells could be restrained by factors generated by the spleen (15) and that these splenic factors could reduce endotoxin uptake by liver Kupffer cells and the concomitant febrile responses induced by endotoxin (16). These results strongly substantiated the thesis that an interaction between bacterial endotoxin and liver Kupffer cells activates the complement system, which then produces C5a to induce fever.
From Complement to PGE2
Dr. Blatteis' next task was to integrate his new theory with the established doctrines of fever induction. One of the most entrenched maxims in fever biology is that fever is mediated by PGE2. It is long known that fever occurs in association with PGE2, and blockade of PGE2 synthesis accounts for the antipyretic effects of well-known drugs such as aspirin (35). Other evidence demonstrated that levels of PGE2 in the hypothalamus correlated with the increase of body temperature during fever (31) and the direct injection of PGE2 into the brain induces fever (21, 27). Furthermore, PGE2 reduces the firing rate of warm-sensitive neurons and increases the firing rate of temperature-insensitive neurons in the hypothalamus (25). These findings suggest that the action of PGE2 in the hypothalamus resets the temperature setpoint, resulting in fever. Contributing to this doctrine, Dr. Blatteis showed that fever is abolished in mice deficient in cyclooxygenase-2, a rate-limiting enzyme in PGE2 synthesis (18). Therefore, a logical corollary from Dr. Blatteis' complement theory is that complement activation in the liver somehow induces the production of PGE2, which then induces fever.
To test the relationship between complement activation and PGE2 production, Dr. Blatteis injected endotoxin into the portal vein and measured the appearance of PGE2 in the blood. LPS caused PGE2 to rise within 5 min. After complement depletion, however, LPS-induced PGE2 rise was delayed by at least 30 min. In addition, the addition of LPS directly to liver Kupffer cells in vitro did not induce PGE2 release until 60 min after LPS stimulation, but the addition of complements or the addition of complements together with LPS to the Kupffer cell culture induced PGE2 release within 10 min (22). These results suggest that LPS-induced complement activation, rather than LPS per se, is responsible for the induction of PGE2 immediately after LPS challenge. However, the complement-induced PGE2 was found in the blood, not in the brain. Dr. Blatteis showed previously that the infusion of PGE2 into the blood does not increase PGE2 levels in the hypothalamus (31). Therefore, the connection between complement activation in the liver and the activation of the brain temperature regulation center is still not complete, although the induction of peripheral PGE2 may add another necessary piece to finish the puzzle. Indeed, Dr. Blatteis demonstrated that depletion of liver Kupffer cells prevented LPS-induced fever and PGE2 rises in the blood and that intravenous administration of antibody against PGE2 attenuated LPS-induced fever (20). Therefore, Kupffer cell-generated PGE2, acting peripherally, constitutes part of the fever induction pathway.
Dr. Blatteis proposes that the bridge between liver-derived PGE2 and the activation of central thermoregulation neurons is the vagus nerve. He envisions that liver PGE2 acts locally on vagal terminals to stimulate neural signaling to the brain. The known neuroanatomic knowledge suggests hepatic vagal afferents project to the nucleus of the solitary tract (NTS) of the caudal medulla. From there, NTS cells may project to noradrenergic cell groups in the ventrolateral medulla, which then send projections to the PO/AH via the ventral noradrenergic bundle. Dr. Blatteis investigated the last part of this putative pathway. To do this, he administered norepinephrine (NE) or specific 
1- or 2-adrenergic receptor (AR) agonists and antagonists into the PO/AH. The results showed that NE in the PO/AH mediates peripheral LPS-induced fever in two steps. First, NE causes an immediate increase of body temperature through an 1-AR-mediated mechanism. Then, NE causes a delayed increase of body temperature through an 2-AR-mediated mechanism (14). Surprisingly, the 1-AR-mediated early phase of fever is not associated with PGE2 in the PO/AH, but the 2-AR-mediated delayed phase of fever is associated with increased levels of PGE2 in the PO/AH. He then showed that the 2-AR-mediated PGE2 increase required cyclooxygenase-2. These results partially confirmed the notion that peripheral LPS-induced vagal activation may indeed stimulate the PGE2 rise in the PO/AH via ascending noradrenergic projections. This mechanism may account for the late phase of the fever response after peripheral LPS injection. The unexpected results regarding 1-AR-mediated effects, however, suggest that the early phase of fever is induced by a mechanism that is independent of PGE2 in the PO/AH. This is heresy according to present literature (6).
Beyond PGE2
Unshackled from the prevailing opinion, Dr. Blatteis felt that there must be factors other than PGE2 in the PO/AH that contribute to fever induction and that these factors might be interactive. To further explore this novel notion, he studied the action of nitric oxide (NO) in the PO/AH. NO is induced by peripheral LPS but exerts antipyretic effects within the PO/AH. NO donor or NO scavenger was microdialyzed into the PO/AH during fever. The NO donor and NO scavenger reduced and enhanced, respectively, the rise of NE, PGE2, and body temperature induced by peripheral LPS (13). Furthermore, Dr. Blatteis showed that NO specifically inhibited the 2-AR-mediated late phase of fever that is associated with the PGE2 rise in the PO/AH. On the other hand, microdialyzation of the antioxidant (+)-catechin into the PO/AH prevented the LPS-induced PGE2 increase but not the increase of body temperature. These results strengthen the new concept that an 2-AR-mediated action in the PO/AH contributes to the late phase of fever. Furthermore, the results demonstrated, once again, that fever can be induced when the increase of PGE2 in PO/AH is absent.
Comments on Style
The series of elegant studies described above highlights the major achievements of Dr. Blatteis' career. Although he has not written the final word in fever induction mechanisms, he has blazed a trail for others to follow. His research demonstrates the quality of a quintessential physiologist: a relentless focus on how a given physiological function (fever) may be induced. He has always pursued answers to important physiological questions rather than following the consensus of the time. This style of research led him to trespass the traditional boundaries of research fields and boldly establish new concepts in uncharted territories. His CVO theory was based on a keen neuroanatomic perspective; his complement theory should have been invented by a perceptive immunologist; and his NE-PGE2 theory was based on sound neuroscience principals. Dr. Blatteis' profundity with his research through broad understanding of multiple disciplines is also reflected in his scholarship (see the Introduction). One exceptional example can be found in his review "Signaling the brain in systemic inflammation: the role of complements" (9). Dr. Blatteis did not study complements until he discovered their role in fever induction in 1997. Yet the description of complements in this review is filled with current and comprehensive knowledge in this field as if it were written by an authority who studied complements for decades.
Formal Recognition
Dr. Blatteis' contribution to physiology has been well recognized throughout the world. He was awarded the Organization of American States fellowship in 1968, when he worked as a Visiting Professor of Physiology at University of San Agustin in Arequipa, Peru. Twice, he was awarded the Senior Fulbright-Hays fellowship in 1975 and then in 1994, when he worked as a Visiting Professor of Physiology at the National University of Trujillo in Trujillo, Peru. He was awarded the Commonwealth Science and Industry Research Organization fellowship for his research in Australia in 1983. He served as the chairman of the International Union of Physiological Sciences Commission on Thermal Physiology between 1988 and 1996 and became the Professor honoris cause of the National University of Trujillo and Peruvian University in 1994. In 1998, he was the Honorary President of the Peruvian Physiological and Pathophysiological Society, and, in 2003, he received the Environmental and Exercise Physiology (EEP) Section Honor Award from the APS. He became the Professor honoris cause of the University of Guanajuato Medical School in Mexico in 2007. Also in 2007, he was nominated by the EEP to be included in the Living History in Physiology project of the APS.
Students and Trainees
Another legacy Dr. Blatteis leaves behind is his students and trainees. Dr. Blatteis has trained many students, postdoctoral fellows, and visiting scholars from all corners of the world. Table 1 shows all his trainees. His enthusiasm, his dedication, his breadth and depth of knowledge, his analytical methods, and, most importantly, his sheer joy of conducting physiological research have made a lasting impact on those who had the opportunity to study under him.
|
Received for publication August 27, 2008. Accepted for publication January 13, 2009.
REFERENCES
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
