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Andrej A Romanovsky

Publications and source records attributed to Andrej A Romanovsky.

34 records · Page 2Linked to original sources
PubMed2004

Prostaglandin E2 as a mediator of fever: synthesis and catabolism.

Prostaglandin (PG) E2 is a principal downstream mediator of fever. It is synthesized in three steps catalyzed by phospholipase (PL) A2, cyclooxygenase (COX), and terminal PGE synthase (PGES), where each catalytic activity is represented by multiple enzymes and/or isoenzymes. Inactivation of PGE2 occurs primarily in the lungs and liver via carrier-mediated cellular uptake and enzymatic oxidation. The two principal carriers are PG transporter (PGT) and multispecific organic anion transporter (MOAT); the two principal PGE2-inactivating enzymes are 15-hydroxy-PG dehydrogenase (15-PGDH) and carbonyl reductase (CR). Our data [Ivanov A. I. et al. Am J Physiol Regul Integr Comp Physiol 283, R1104-R1117 (2002); ibid. 284, R698-R706 (2003)] are used to analyze the relationship between transcriptional regulation of PLA2, COX, PGES, PGT, MOAT, 15-PHDH, and CR, on one hand, and the triphasic febrile response of rats to lipopolysaccharide (LPS), on the other. It is concluded that LPS fever is accompanied by up-regulation of four PGE2-synthesizing enzymes [secretory (s) PLA2-IIA, cytosolic (c) PLA2-alpha, COX-2, and microsomal (m) PGES-1] and down-regulation of all PGE2 carriers and dehydrogenases studied (PGT, MOAT, 15PGDH, and CR). It is further concluded that different febrile phases employ different mechanisms to mount an increase in the PGE2 level. Phase 1 involves transcriptional up-regulation of the couple COX-2 -->mPGES-1 in the liver and lungs. Phase 2 entails robust up-regulation of the major inflammatory triad sPLA2-IIA -->COX-2 -->mPGES-1 throughout the body. Phase 3 involves induction of cPLA2-alpha in the hypothalamus and further up-regulation of sPLA2-IIA and mPGES throughout the body. Importantly, Phase 3 occurs despite a drastic decrease in the expression of COX-1 and -2 in both the brain and periphery, thus suggesting that transcriptional up-regulation of COX-2 is not an obligatory mechanism of PGE2-dependent inflammatory responses at later stages. Of importance is also that LPS fever is accompanied by transcriptional down-regulation of PGE2 transporters and dehydrogenases: 15-PGDH in the lungs at Phase 1; 15-PGDH and CR in the lungs at Phase 2; and PGT, MOAT, 15-PGDH, and CR in the liver and lungs at Phase 3. The transcriptional down-regulation of proteins involved in PGE2 inactivation is a largely unrecognized mechanism of systemic inflammation. By increasing the blood-brain gradient of PGE2, this mechanism likely facilitates penetration of PGE2 into the brain. The high magnitude of up-regulation of mPGES and sPLA2-IIA (1,260 and 130 fold, respectively) and that of down-regulation of 15-PGES (30 fold) during LPS fever makes these enzymes attractive targets for anti-inflammatory therapy.

Animals↗
PubMed2004

Febrigenic signaling to the brain does not involve nitric oxide.

1. The involvement of peripheral nitric oxide (NO) in febrigenic signaling to the brain has been proposed because peripherally administered NO synthase (NOS) inhibitors attenuate lipopolysaccharide (LPS)-induced fever in rodents. However, how the unstable molecule of NO can reach the brain to trigger fever is unclear. It is also unclear whether NOS inhibitors attenuate fever by blocking febrigenic signaling or, alternatively, by suppressing thermogenesis in brown fat. 2. Male Wistar rats were chronically implanted with jugular catheters; their colonic and tail skin temperatures (T(c) and T(sk)) were monitored. 3. Study 1 was designed to determine whether the relatively stable, physiologically relevant forms of NO, that is, S-nitrosoalbumin (SNA) and S-nitrosoglutathione (SNG), are pyrogenic and whether they enhance LPS fever. At a neutral ambient temperature (T(a)) of 31 degrees C, afebrile or LPS (1 microg kg(-1), i.v.)-treated rats were infused i.v. with SNA (0.34 or 4.1 micromol kg(-1); the controls received NaNO(2) and albumin) or SNG (10 or 60 micromol kg(-1); the controls received glutathione). T(c) of SNA- or SNG-treated rats never exceeded that of the controls. 4. In Study 2, we tested whether the known fever-attenuating effect of the NOS inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) at a subneutral T(a) (when fever is brought about by thermogenesis) also occurs at a neutral T(a) (when fever is brought about by skin vasoconstriction). At a subneutral T(a) of 24 degrees C, L-NAME (2.5 mg kg(-1), i.v.) attenuated LPS (10 microg kg(-1), i.v.) fever, presumably by inhibiting thermogenesis. At 31 degrees C, L-NAME enhanced LPS fever by augmenting skin vasoconstriction (T(sk) fall). 5. In summary, both SNA and SNG had no pyrogenic effect of their own and failed to enhance LPS fever; peripheral L-NAME attenuated only fever brought about by increased thermogenesis. It is concluded that NO is uninvolved in febrigenic signaling to the brain.

Animals↗
PubMed2004

Cholecystokinin: possible mediator of fever and hypothermia.

Thermoregulatory effects of cholecystokinin (CCK) peptides are reviewed with special emphasis on two types of responses, that is hyperthermia (fever) and hypothermia. Central microinjection of CCK in rats induces a thermogenic response that can be attenuated by CCK-B receptor antagonists, but some authors observed a hypothermia. By contrast to its central fever-inducing effect, in rodents exposed to cold CCK-8 elicits a dose-dependent hypothermia on peripheral injection probably acting on CCK-A receptors. It is suggested that neuronal CCK may have a specific role in the development of hyperthermia, and endogenous CCK-ergic mechanisms could contribute to the mediation of fever. The possible role of CCK-ergic mediation in endotoxin (LPS) fever has revealed that while CCK-B receptors seem to be involved in the development of fever, the role of CCK-A receptors could be more complex. In particular, while rats lacking functional CCK-A receptors show an exaggerated fever response, this phenomenon may be associated with a trait different from the absence of this receptor set. The relationship between the putative CCK-ergic febrile mechanism and the established central PGE mediation needs further study.

Animals↗
PubMed2004

Signaling the brain in the early sickness syndrome: are sensory nerves involved?

Nonspecific manifestations (sickness symptoms) of inflammation and infection occur as two sequential syndromes, the early and late. This review deals with the early sickness syndrome, which occurs at the onset of the inflammatory process and manifests itself with a high deep body temperature, hyperalgesia/allodynia, arousal, motor agitation, and arterial hypertension. Two rat models of intravenous lipopolysaccharide (LPS)-induced fever are used to study the early syndrome: 1) a monophasic response to low, just suprathreshold doses of LPS and 2) the first rise in body temperature (Phase I) of the polyphasic response to higher doses. Experiments in the first model reveal a blockade of monophasic fever by total subdiaphragmatic or selective hepatic vagotomy, thus suggesting mediation of this response by the hepatic vagal fibers, presumably afferent. Experiments in the second model show that Phase I of polyphasic fever is insensitive to surgical vagotomy but does not occur in animals desensitized with low intraperitoneal doses of capsaicin (an agonist of the vanilloid receptor VR1). These findings suggest that Phase I is mediated by intra-abdominal, VR1-receptor-bearing afferents, either splanchnic or possibly splanchnic and vagal. The involvement of the splanchnic nerve and VR1 receptor in Phase I of LPS fever is currently under investigation in our laboratory. Based on studies completed so far, neural signaling mechanisms are involved in both monophasic fever and Phase I of polyphasic fever. We speculate that these mechanisms are triggered by peripherally originated, blood-borne prostaglandin E2.

Animals↗
PubMed2003

Bilateral splanchnicotomy does not affect lipopolysaccharide-induced fever in rats.

Intraperitoneal capsaicin desensitizes sensory fibers traveling within both the vagus and splanchnic nerves. Because capsaicin desensitization blocks the first phase of lipopolysaccharide (LPS) fever, whereas surgical vagotomy does not, splanchnic mediation of the first phase was proposed. However, all phases of the febrile response of splanchnicotomized rats to intravenous LPS (10 microg/kg) were similar to those of sham-operated controls. Hence, the splanchnic nerve is likely uninvolved in LPS fever.

Animals↗
PubMed2003

Platelet-activating factor: a previously unrecognized mediator of fever.

Lipopolysaccharide (LPS)-induced systemic inflammation is accompanied by either hypothermia (prevails when the ambient temperature (Ta) is subneutral) or fever (prevails when Ta is neutral or higher). Because platelet-activating factor (PAF) is a proximal mediator of LPS inflammation, it should mediate both thermoregulatory responses to LPS. That PAF possesses hypothermic activity and mediates LPS-induced hypothermia is known. We asked whether PAF possesses pyrogenic activity (Expt 1) and mediates LPS fever (Expt 2). The study was conducted in Long-Evans rats implanted with jugular catheters. A complex with bovine serum albumin (BSA) was infused as a physiologically relevant form of PAF; free (aggregated) PAF was used as a control. In Expt 1, either form of PAF caused hypothermia when infused (83 pmol kg-1 min-1, 60 min, i.v.) at a subneutral Ta of 20 degrees C, but the response to the PAF-BSA complex (-4.5 +/- 0.5 degrees C, nadir) was ~4 times larger than that to free PAF. At a neutral Ta of 30 degrees C, both forms caused fever preceded by tail skin vasoconstriction, but the febrile response to PAF-BSA (1.0 +/- 0.1 degrees C, peak) was > 2 times higher than that to free PAF. Both the hypothermic (at 20 degrees C) and febrile (at 30 degrees C) responses to PAF-BSA started when the total amount of PAF infused was extremely small, < 830 pmol kg-1. In Expt 2 (conducted at 30 degrees C), the PAF receptor antagonist BN 52021 (29 micromol kg-1, i.v.) had no thermal effect of itself. However, it strongly (~2 times) attenuated the febrile response to PAF (5 nmol kg-1, i.v.), implying that this response involves the PAF receptor and is not due to a detergent-like effect of PAF on cell membranes. BN 52021 (but not its vehicle) was similarly effective in attenuating LPS (10 microg kg-1, i.v.) fever. It is concluded that PAF is a highly potent endogenous pyrogenic substance and a mediator of LPS fever.

Animals↗
PubMed2003

The organum vasculosum laminae terminalis in immune-to-brain febrigenic signaling: a reappraisal of lesion experiments.

The organum vasculosum laminae terminalis (OVLT) has been proposed to serve as the interface for blood-to-brain febrigenic signaling, because ablation of this structure affects the febrile response. However, lesioning the OVLT causes many "side effects" not fully accounted for in the fever literature. By placing OVLT-lesioned rats on intensive rehydration therapy, we attempted to prevent these side effects and to evaluate the febrile response in their absence. After the OVLT of Sprague-Dawley rats was lesioned electrolytically, the rats were given access to 5% sucrose for 1 wk to stimulate drinking. Sucrose consumption and body mass were monitored. The animals were examined twice a day for signs of dehydration and treated with isotonic saline (50 ml/kg sc) when indicated. This protocol eliminated mortality but not several acute and chronic side effects stemming from the lesion. The acute effects included adipsia and gross (14% of body weight) emaciation; chronic effects included hypernatremia, hyperosmolality, a suppressed drinking response to hypertonic saline, and previously unrecognized marked (by approximately 2 degrees C) and long-lasting (>3 wk) hyperthermia. Because the hyperthermia was not accompanied by tail skin vasoconstriction, it likely reflected increased thermogenesis. After the rats recovered from the acute (but not chronic) side effects, their febrile response to IL-1beta (500 ng/kg iv) was tested. The sham-operated rats developed typical monophasic fevers ( approximately 0.5 degrees C), the lesioned rats did not. However, the absence of the febrile response in the OVLT-lesioned rats likely resulted from the untreatable side effects. For example, hyperthermia at the time of pyrogen injection was high enough (39-40 degrees C) to solely prevent fever from developing. Hence, the changed febrile responsiveness of OVLT-lesioned animals is given an alternative interpretation, unrelated to febrigenic signaling to the brain.

Animals↗
PubMed2003

Role for the cholecystokinin-A receptor in fever: a study of a mutant rat strain and a pharmacological analysis.

The involvement of the cholecystokinin (CCK)-A receptor in fever was studied. The polyphasic febrile responses to lipopolysaccharide (LPS; 10 microg kg-1, I.V.) were compared between wild-type Long-Evans (LE) rats and the CCK-A-receptor-deficient Otsuka LE Tokushima Fatty (OLETF) rats. The response of the wild-type rats was biphasic, which is typical for LE rats. Phases 1 and 2 of the response of the OLETF rats were similar to those of the LE rats, but the OLETF rats also developed a robust phase 3. This late enhancement of the febrile response could reflect either the absence of the A receptor per se or a secondary trait of the mutant strain. To distinguish between these possibilities, we conducted a pharmacological analysis. We studied whether the normally low phase 3 of LE rats can be enhanced by a CCK-A-receptor antagonist, sodium lorglumide (4.3 microg kg-1 min-1, 120 min, I.V.), and whether the normally high phase 3 of Wistar rats can be attenuated by a CCK-A receptor agonist, sulphated CCK-8 (up to 0.17 microg kg-1 min-1, 120 min, I.V.). The dose of sodium lorglumide used was sufficient to increase food intake (to block satiety), but it did not affect the fever response. In both febrile and afebrile rats, CCK-8 induced dose-dependent skin vasodilatation and decreased body temperature, but it failed to produce any effects specific for phase 3. We conclude that the exaggeration of phase 3 in OLETF rats reflects a secondary trait of this strain and not the lack of the CCK-A receptor per se. None of the three known phases of the febrile response of rats to LPS requires the CCK-A receptor.

Animals↗
PubMed2002

Expression of genes controlling transport and catabolism of prostaglandin E2 in lipopolysaccharide fever.

Prostaglandin (PG) E(2) is a principal downstream mediator of fever and other symptoms of systemic inflammation. Its inactivation occurs in peripheral tissues, primarily the lungs and liver, via carrier-mediated cellular uptake and enzymatic oxidation. We hypothesized that inactivation of PGE(2) is suppressed during LPS fever and that transcriptional downregulation of PGE(2) carriers and catabolizing enzymes contributes to this suppression. Fever was induced in inbred Wistar-Kyoto rats by intravenous LPS (50 microg/kg); the controls received saline. Samples of the liver, lungs, and hypothalamus were harvested 0, 0.5, 1.5, and 5 h postinjection. The expression of the two principal transmembrane PGE(2) carriers (PG transporter and multispecific organic anion transporter) and the two key PGE(2)-inactivating enzymes [15-hydroxy-PG dehydrogenase (15-PGDH) and carbonyl reductase] was quantified by RT-PCR. All four genes of interest were downregulated in peripheral tissues (but not the brain) during fever. Most remarkably, the expression of hepatic 15-PGDH was decreased 26-fold 5 h post-LPS, whereas expression of pulmonary 15-PGDH was downregulated (as much as 18-fold) throughout the entire febrile course. The transcriptional downregulation of several proteins involved in PGE(2) inactivation, first reported here, is an unrecognized mechanism of systemic inflammation. By increasing the blood-brain gradient of PGE(2), this mechanism likely facilitates penetration of PGE(2) into the brain and prevents its elimination from the brain.

Alcohol Oxidoreductases↗
PubMed2002

Prostaglandin E(2)-synthesizing enzymes in fever: differential transcriptional regulation.

The febrile response to lipopolysaccharide (LPS) consists of three phases (phases I-III), all requiring de novo synthesis of prostaglandin (PG) E(2). The major mechanism for activation of PGE(2)-synthesizing enzymes is transcriptional upregulation. The triphasic febrile response of Wistar-Kyoto rats to intravenous LPS (50 microg/kg) was studied. Using real-time RT-PCR, the expression of seven PGE(2)-synthesizing enzymes in the LPS-processing organs (liver and lungs) and the brain "febrigenic center" (hypothalamus) was quantified. Phase I involved transcriptional upregulation of the functionally coupled cyclooxygenase (COX)-2 and microsomal (m) PGE synthase (PGES) in the liver and lungs. Phase II entailed robust upregulation of all enzymes of the major inflammatory pathway, i.e., secretory (s) phospholipase (PL) A(2)-IIA --> COX-2 --> mPGES, in both the periphery and brain. Phase III was accompanied by the induction of cytosolic (c) PLA(2)-alpha in the hypothalamus, further upregulation of sPLA(2)-IIA and mPGES in the hypothalamus and liver, and a decrease in the expression of COX-1 and COX-2 in all tissues studied. Neither sPLA(2)-V nor cPGES was induced by LPS. The high magnitude of upregulation of mPGES and sPLA(2)-IIA (1,257-fold and 133-fold, respectively) makes these enzymes attractive targets for anti-inflammatory therapy.

Animals↗
PubMed2002

Fever responses of Zucker rats with and without fatty mutation of the leptin receptor.

Leptin is thought to be involved in febrigenic signaling from the periphery to the brain. Zucker obese rats have a so-called fatty mutation in the leptin receptor gene and express a dysfunctional protein. Studies comparing the fever responses of fatty (fa/fa) rats and of their lean (Fa/Fa and Fa/fa) counterparts yield contradictory results. To resolve these contradictions, we evaluated the effect of fatty mutation on infectious and stress-associated fevers at thermoneutrality (29 degrees C) and in a cool environment (20 degrees C). Zucker fa/fa and Fa/? rats were infused with Escherichia coli lipopolysaccharide (LPS; 10 microg/kg) through a jugular catheter (infectious fever) or with saline through the catheter (control) or received a painful intramuscular injection of saline (stress fever). At thermoneutrality, the colonic temperature (T(c)) responses of fatty rats to all stimuli tested were no different from the responses of lean rats. In a cool environment, T(c) responses of fatty rats to all stimuli were ~0.5 degrees C lower than those of lean rats. The observed attenuation of LPS-induced and stress-associated fevers in Zucker fatty rats in the cold agrees with the literature data showing that brown adipose tissue (the major heat production effector) is morphologically and functionally defective in these rats. The normal febrile responses of fatty Zucker rats to pyrogenic stimuli at thermoneutrality indicate that fatty mutation does not interrupt febrigenic signaling from the periphery to the brain.

Animals↗
PubMed2002

Selected contribution: ambient temperature for experiments in rats: a new method for determining the zone of thermal neutrality.

There is a misbelief that the same animal has the same thermoneutral zone (TNZ) in different experimental setups. In reality, TNZ strongly depends on the physical environment and varies widely across setups. Current methods for determining TNZ require elaborate equipment and can be applied only to a limited set of experimental conditions. A new, broadly applicable approach that rapidly determines whether given conditions are neutral for a given animal is needed. Consistent with the definition of TNZ [the range of ambient temperature (T(a)) at which body core temperature (T(c)) regulation is achieved only by control of sensible heat loss], we propose three criteria of thermoneutrality: 1) the presence of high-magnitude fluctuations in skin temperature (T(sk)) of body parts serving as specialized heat exchangers with the environment (e.g., rat tail), 2) the closeness of T(sk) to the median of its operational range, and 3) a strong negative correlation between T(sk) and T(c). Thermocouple thermometry and liquid crystal thermography were performed in five rat strains at 13 T(a). Under the conditions tested (no bedding or filter tops, no group thermoregulation), the T(a) range of 29.5-30.5 degrees C satisfied all three TNZ criteria in Wistar, BDIX, Long-Evans, and Zucker lean rats; Zucker fatty rats had a slightly lower TNZ (28.0-29.0 degrees C). Skin thermometry or thermography is a definition-based, simple, and inexpensive technique to determine whether experimental or housing conditions are neutral, subneutral, or supraneutral for a given animal.

Animals↗