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ABSTRACT: We tested the hypothesis that glycogen synthase kinase 3α/β (GSK3α/β) modulates tumor necrosis factor-a (TNF) induced increased lung vascular permeability. Rats were treated with TNF (i.v., ~100ng/ml) or vehicle 0.5h, 4.0h and 24.0h prior to lung isolation. Rats were co-treated with the GSK3α/β inhibitors SB216763 (0.6mg/kg) or TDZD-8 (1.0mg/kg). After TNF, the isolated lung was assessed for hemodynamics, wet-dry/dry weight (W-D/D) and extravascular albumin. Extravascular albumin significantly increased at TNF-24h compared to Control. In the GSK3α/β-inhibited+TNF groups, extravascular albumin was similar to the Control and respective SB216763 and TDZD-8 groups. In separate studies, to assess GSK3α/β-activity, lung lysate was assessed for phospho-GSK3α/β-Ser(21/9), total GSK3α/β, un-phospho-β-catenin-Ser(33/37) and total β-catenin. In the TNF-4.0h group, there was no change in GSK3α/phospho-GSK3α-Ser(21) but there was an increase in GSK3β/GSK3β-Ser(9) compared to Control, indicating GSK3β activation at TNF-4.0h. GSK3β activation was verified because there was a decrease in un-phospho-β-catenin-Ser(33/37)/β-catenin in the TNF-4.0 group, a specific outcome for GSK3β activation. In the SB216763+TNF group, un-phospho-β-catenin-Ser(33/37) was similar to Control, indicating prevention of TNF-induced GSK3β activation. In the TNF-24h group, there were increases in the biomarkers of inflammation phospho-eNOS-Ser (1117) and oxidized protein, which did not occur in the SB216763+TNF-24h and TDZD-8+TNF-24h groups. In the SB216763+TNF-24h and TDZD-8+TNF-24h groups, un-phospho-β-catenin-Ser(33/37) was greater than in the Control, indicating continued inhibition of GSK3β. The data indicates that pharmacologic inhibition of GSK3β inhibits TNF induced increased endothelial permeability associated with lung inflammation.
European journal of pharmacology 02/2011; 657(1-3):159-66. · 2.59 Impact Factor
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ABSTRACT: We tested the hypothesis that food deprivation alters body temperature (T(b)) responses to bacterial LPS by enhancing inflammatory signaling that decreases T(b) (cryogenic signaling) rather than by suppressing inflammatory signaling that increases T(b) (febrigenic signaling). Free-feeding or food-deprived (24 h) rats received LPS at doses (500 and 2,500 microg/kg iv) that are high enough to activate both febrigenic and cryogenic signaling. At these doses, LPS caused fever in rats at an ambient temperature of 30 degrees C, but produced hypothermia at an ambient temperature of 22 degrees C. Whereas food deprivation had little effect on LPS fever, it enhanced LPS hypothermia, an effect that was particularly pronounced in rats injected with the higher LPS dose. Enhancement of hypothermia was not due to thermogenic incapacity, since food-deprived rats were fully capable of raising T(b) in response to the thermogenic drug CL316,243 (1 mg/kg iv). Neither was enhancement of hypothermia associated with altered plasma levels of cytokines (TNF-alpha, IL-1beta, and IL-6) or with reduced levels of an anti-inflammatory hormone (corticosterone). The levels of PGD(2) and PGE(2) during LPS hypothermia were augmented by food deprivation, although the ratio between them remained unchanged. Food deprivation, however, selectively enhanced the responsiveness of rats to the cryogenic action of PGD(2) (100 ng icv) without altering the responsiveness to febrigenic PGE(2) (100 ng icv). These findings support our hypothesis and indicate that cryogenic signaling via PGD(2) underlies enhancement of LPS hypothermia by food deprivation.
AJP Regulatory Integrative and Comparative Physiology 06/2010; 298(6):R1512-21. · 3.34 Impact Factor
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ABSTRACT: Among the diverse animal models proposed for schizophrenia, the neonatal ventral hippocampal lesion (NVHL) is one of the most widely used. However, its construct validity can be questioned because there is no evidence of a lesion present in schizophrenia. Other approaches that have tried to capture environmental influences on development include diverse models of maternal infection.
As the early postnatal days in rodents are equivalent to the third trimester of human pregnancy in terms of brain development, we decided to test whether a neonatal immune challenge with an injection of the bacterial endotoxin lipopolysaccharide (LPS) into the ventral hippocampus caused deficits in interneuron function similar to those reported for the NVHL.
Neonatal LPS injection caused a persistent elevation in cytokines in several brain regions, deficits in prepulse inhibition of the acoustic startle response, and a loss of the periadolescent maturation in the response of prefrontal cortical fast-spiking interneurons to dopamine.
The same phenotypes elicited by a NVHL can be obtained with an intrahippocampal immune challenge, suggesting that perinatal environmental factors can affect adult prefrontal interneuron maturation during adolescence.
Biological psychiatry 11/2009; 67(4):386-92. · 8.93 Impact Factor
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ABSTRACT: It is widely assumed that LPS lowers arterial pressure during sepsis by stimulating release of TNF-alpha and other vasoactive mediators from macrophages. However, recent data from this and other laboratories have shown that LPS hypotension can be prevented by inhibiting afferent impulse flow in the vagus nerve, by blocking neuronal activity in the nucleus of the solitary tract, or by blocking alpha-adrenergic receptors in the preoptic area/anterior hypothalamic area (POA). These findings suggest that the inflammatory signal is conveyed from the periphery to the brain via the vagus nerve, and that endotoxic shock is mediated through a central mechanism that requires activation of POA neurons. In the present study, we tested whether central cannabinoid 1 (CB1) receptors participate in the control of arterial pressure during endotoxemia based on evidence that hypothalamic neurons express CB1 receptors and synthesize the endogenous CB anandamide. We found that intracerebroventricular administration of rimonabant, a CB1 receptor antagonist, inhibited the fall in arterial pressure evoked by LPS significantly in both conscious and anesthetized rats. Rimonabant attenuated both the immediate fall in arterial pressure evoked by LPS and the second, delayed hypotensive phase that leads to tissue ischemia and death. Rimonabant also prevented the associated LPS-induced rise in extracellular fluid norepinephrine concentrations in the POA. Furthermore, rimonabant attenuated the associated increase in plasma TNF-alpha concentrations characteristic of the late phase of endotoxic hypotension. These data indicate that central CB1 receptors may play an important role in the initiation of endotoxic hypotension.
Shock (Augusta, Ga.) 04/2009; 32(6):614-20. · 2.87 Impact Factor
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ABSTRACT: We recently reported that the preoptic anterior hypothalamic area (POA) mediates the hypotensive response evoked by lipopolysaccharide (LPS). In this study, we investigated how the inflammatory signal induced by LPS reaches the POA. Subdiaphragmatic vagotomy and abdominal perivagal lidocaine administration, or lidocaine injection into the nucleus tractus solitarius (NTS) prevented LPS hypotension. Microinjection of the alpha-adrenergic receptor antagonist phentolamine into the POA, blocked initiation of the hypotensive response and prevented the late decompensatory phase. These data suggest that LPS hypotension is mediated by the vagus nerve which conveys the signal to the NTS and, in turn, stimulates norepinephrine release within the POA.
Journal of Neuroimmunology 10/2008; 203(1):39-49. · 2.96 Impact Factor
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ABSTRACT: The mechanism responsible for the initiation of endotoxic hypotension is not fully understood, although it is often attributed to a direct effect of LPS and other vasoactive mediators on the vasculature. Alternatively, recent evidence raises the possibility that endotoxic hypotension may be initiated through a central mechanism. Previous studies have shown that LPS initiates fever, sickness behavior, and other aspects of the inflammatory response through a neural pathway that sends peripheral inflammatory signals to the preoptic anterior hypothalamic area (POA). It is also well known that the POA plays a role in the regulation of cardiovascular function, but its involvement in LPS-induced hypotension has not been examined previously. Therefore, the aim of the present paper was to investigate whether the initial abrupt fall in arterial pressure evoked by LPS in septic shock is mediated by the POA. LPS (1 mg/kg, i.v.) administration to halothane-anesthetized or conscious rats lowered arterial blood pressure by 24.8+/-2.9 and 25.1+/-5.8 mmHg, respectively. Bilateral lidocaine (2%; 1 microL) injection into the POA, but not the lateral hypothalamus, prevented the hypotension evoked by LPS entirely in both anesthetized and conscious animals. Remarkably, this blockade significantly inhibited the second, delayed fall in arterial pressure induced by LPS, and simultaneously decreased TNF-alpha plasma levels. Together, these data indicate that the initial phase of endotoxic hypotension is mediated by the POA and suggest that the initiation of the hypotensive response induced by LPS can be essential for the development of the late fall in blood pressure.
Shock 03/2008; 29(2):232-7. · 2.85 Impact Factor
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ABSTRACT: Stressor presence during the last weeks of gestation has been associated with behavioral disorders in later life. In this study we support further research on the long term effects of prenatal stress on Swiss mice descendant's behavior. Prenatal stress procedure consisted on restraining the dams under bright light for 45 min, three times per day from the 15th day of pregnancy, until birth. After weaning, offspring's motor performance and spontaneous exploratory behavior were measured by the tight-rope and T-maze tests, respectively. We also evaluated anxiety behavior using elevated plus maze test. We found that maternal stress improves the performance of the animals in the tight rope test and that this effect was sex and age dependent: prenatal stressed males obtained the best scores during the first month of life, while in females the same was achieved at the second month. Spontaneous exploratory behavior analysis revealed that it was elevated in prenatal stressed males and that this effect persisted on time. However, we did not find significant differences on this behavioral response among both females groups. Finally, differences on anxiety behavior were found only in females: prenatally stressed animals showed a higher proportion of entries into the open arms of a plus maze (reduced anxiety) compared to the control group. Our results show that prenatal stress modifies the normal behavior of the progeny: prenatal stressed animals have a better performance in the carried out test. These notably results suggest the existence of an adaptive response to prenatal stress.
Physiology & Behavior 01/2008; 92(5):951-6. · 2.87 Impact Factor
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ABSTRACT: Lipopolysaccharide (LPS) administration induces hypothalamic nitric oxide (NO); NO is antipyretic in the preoptic area (POA), but its mechanism of action is uncertain. LPS also stimulates the release of preoptic norepinephrine (NE), which mediates fever onset. Because NE upregulates NO synthases and NO induces cyclooxygenase (COX)-2-dependent PGE(2), we investigated whether NO mediates the production of this central fever mediator. Conscious guinea pigs with intra-POA microdialysis probes received LPS intravenously (2 mug/kg) and, thereafter, an NO donor (SIN-1) or scavenger (carboxy-PTIO) intra-POA (20 mug/mul each, 2 mul/min, 6 h). Core temperature (T(c)) was monitored constantly; dialysate NE and PGE(2) were analyzed in 30-min collections. To verify the reported involvement of alpha(2)-adrenoceptors (AR) in PGE(2) production, clonidine (alpha(2)-AR agonist, 2 mug/mul) was microdialyzed with and without SIN-1 or carboxy-PTIO. To assess the possible involvement of oxidative NE and/or NO products in the demonstrated initially COX-2-independent POA PGE(2) increase, (+)-catechin (an antioxidant, 3 mug/mul) was microdialyzed, and POA PGE(2), and T(c) were determined. SIN-1 and carboxy-PTIO reduced and enhanced, respectively, the rises in NE, PGE(2), and T(c) produced by intravenous LPS. Similarly, they prevented and increased, respectively, the delayed elevations of PGE(2) and T(c) induced by intra-POA clonidine. (+)-Catechin prevented the LPS-induced elevation of PGE(2), but not of T(c). We conclude that the antipyretic activity of NO derives from its inhibitory modulation of the LPS-induced release of POA NE. These data also implicate free radicals in POA PGE(2) production and raise questions about its role as a central LPS fever mediator.
AJP Regulatory Integrative and Comparative Physiology 10/2007; 293(3):R1144-51. · 3.34 Impact Factor
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ABSTRACT: Norepinephrine (NE) microdialyzed in the preoptic area (POA) raises core temperature (T(c)) via 1) alpha(1)-adrenoceptors (AR), quickly and independently of POA PGE(2), and 2) alpha(2)-AR, after a delay and PGE(2) dependently. Since systemic lipopolysaccharide (LPS) activates the central noradrenergic system, we investigated whether preoptic NE mediates LPS fever. We injected LPS (2 microg/kg iv) in guinea pigs prepared with intra-POA microdialysis probes and determined POA cerebrospinal (CSF) NE levels. We similarly microdialyzed prazosin (alpha(1) blocker, 1 microg/microl), yohimbine (alpha(2) blocker, 1 microg/microl), SC-560 [cyclooxygenase (COX)-1 blocker, 5 microg/microl], acetaminophen (presumptive COX-1v blocker, 5 microg/microl), or MK-0663 (COX-2 blocker, 0.5 microg/microl) in other animals before intravenous LPS and measured CSF PGE(2). All of the agents were perfused at 2 microg/min for 6 h. T(c) was monitored constantly. POA NE peaked within 30 min after LPS and then returned to baseline over the next 90 min. T(c) increased within 12 min to a first peak at approximately 60 min and to a second at approximately 150 min and then declined over the following 2.5 h. POA PGE(2) followed a concurrent course. Prazosin pretreatment eliminated the first T(c) rise but not the second; PGE(2) rose normally. Yohimbine pretreatment did not affect the first T(c) rise, which continued unchanged for 6 h; the second rise, however, was absent, and PGE(2) levels did not increase. SC-560 and acetaminophen did not alter the LPS-induced PGE(2) and T(c) rises; MK-0663 prevented both the late PGE(2) and T(c) rises. These results confirm that POA NE is pivotal in the development of LPS fever.
AJP Regulatory Integrative and Comparative Physiology 10/2007; 293(3):R1135-43. · 3.34 Impact Factor
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ABSTRACT: The mechanism responsible for the initiation of endotoxic hypotension is not fully understood, although it is often attributed to a direct effect of LPS and other vasoactive mediators on the vasculature. Alternatively, recent evidence raises the possibility that endotoxic hypotension may be initiated through a central mechanism. Previous studies have shown that LPS initiates fever, sickness behavior, and other aspects of the inflammatory response through a neural pathway that sends peripheral inflammatory signals to the preoptic anterior hypothalamic area (POA). It is also well known that the POA plays a role in the regulation of cardiovascular function, but its involvement in LPS-induced hypotension has not been examined previously. Therefore, the aim of the present paper was to investigate whether the initial abrupt fall in arterial pressure evoked by LPS in septic shock is mediated by the POA. LPS (1 mg/kg, i.v.) administration to halothane-anesthetized or conscious rats lowered arterial blood pressure by 24.8 +/- 2.9 and 25.1 +/- 5.8 mmHg, respectively. Bilateral lidocaine (2%; 1 muL) injection into the POA, but not the lateral hypothalamus, prevented the hypotension evoked by LPS entirely in both anesthetized and conscious animals. Remarkably, this blockade significantly inhibited the second, delayed fall in arterial pressure induced by LPS, and simultaneously decreased TNF-alpha plasma levels. Together, these data indicate that the initial phase of endotoxic hypotension is mediated by the POA and suggest that the initiation of the hypotensive response induced by LPS can be essential for the development of the late fall in blood pressure.
Shock 08/2007; Publish Ahead of Print. · 2.85 Impact Factor
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ABSTRACT: Because the onset of fever induced by intravenously (i.v.) injected bacterial endotoxic lipopolysaccharides (LPS) precedes the appearance in the bloodstream of pyrogenic cytokines, the presumptive peripheral triggers of the febrile response, we have postulated previously that, in their stead, PGE2 could be the peripheral fever trigger because it appears in blood coincidentally with the initial body core temperature (Tc) rise. To test this hypothesis, we injected Salmonella enteritidis LPS (2 microg/kg body wt i.v.) into conscious guinea pigs and measured their plasma levels of LPS, PGE2, TNF-alpha, IL-1beta, and IL-6 before and 15, 30, 60, 90, and 120 min after LPS administration; Tc was monitored continuously. The animals were untreated or Kupffer cell (KC) depleted; the essential involvement of KCs in LPS fever was shown previously. LPS very promptly (<10 min) induced a rise of Tc that was temporally correlated with the elevation of plasma PGE2. KC depletion prevented the Tc and plasma PGE2 rises and slowed the clearance of LPS from the blood. TNF-alpha was not detectable in plasma until 30 min and in IL-1beta and IL-6 until 60 min after LPS injection. KC depletion did not alter the times of appearance or magnitudes of rises of these cytokines, except TNF-alpha, the maximal level of which was increased approximately twofold in the KC-depleted animals. In a follow-up experiment, PGE2 antiserum administered i.v. 10 min before LPS significantly attenuated the febrile response to LPS. Together, these results support the view that, in guinea pigs, PGE2 rather than pyrogenic cytokines is generated by KCs in immediate response to i.v. LPS and triggers the febrile response.
AJP Regulatory Integrative and Comparative Physiology 06/2006; 290(5):R1262-70. · 3.34 Impact Factor
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ABSTRACT: We reported previously that the onset of LPS-induced fever, irrespective of its route of administration, is temporally correlated with the appearance of LPS in the liver and that splenectomy significantly increases both the febrile response to LPS and the uptake of LPS by Kupffer cells (KC). To further evaluate the role of the spleen in LPS fever production, we ligated the splenic vein and, 7 and 30 days later, monitored the core temperature changes over 6 h after intraperitoneal (ip) injection of LPS (2 microg/kg). Both the febrile response and the uptake of LPS by KC were significantly augmented. Like splenectomy, splenic vein ligation (SVL) increased the febrile response and LPS uptake by KC until the collateral circulation developed, suggesting that the spleen may normally contribute an inhibitory factor that limits KC uptake of LPS and thus affects the febrile response. Subsequently, to verify the presence of this factor, we prepared splenic extracts from guinea pigs pretreated with LPS (8 microg/kg ip) or pyrogen-free saline, homogenized and ultrafiltered them, and injected them intravenously into splenectomized (Splex) guinea pigs pretreated with LPS (8 microg/kg ip). The results confirmed our presumption that the splenic extract from LPS-treated guinea pigs inhibits the exaggerated febrile response and the LPS uptake by the liver of Splex guinea pigs, indicating the presence of a putative splenic inhibitory factor, confirming the participation of the spleen in LPS-induced fever, and suggesting the existence of a novel antihyperpyretic mechanism. Preliminary data indicate that this factor is a lipid.
AJP Regulatory Integrative and Comparative Physiology 10/2005; 289(3):R680-7. · 3.34 Impact Factor
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ABSTRACT: The innate immune system serves as the first line of host defense against the deleterious effects of invading infectious pathogens. Fever is the hallmark among the defense mechanisms evoked by the entry into the body of such pathogens. The conventional view of the steps that lead to fever production is that they begin with the biosynthesis of pyrogenic cytokines by mononuclear phagocytes stimulated by the pathogens, their release into the circulation and transport to the thermoregulatory center in the preoptic area (POA) of the anterior hypothalamus, and their induction there of cyclooxygenase (COX)-2-dependent prostaglandin (PG)E(2), the putative final mediator of the febrile response. But data accumulated over the past 5 years have gradually challenged this classical concept, due mostly to the temporal incompatibility of the newer findings with this concatenation of events. Thus, the former studies generally overlooked that the production of cytokines and the transduction of their pyrogenic signals into fever-mediating PGE(2) proceed at relatively slow rates, significantly slower certainly than the onset latency of fever produced by the i.v. injection of bacterial endotoxic lipopolysaccharides (LPS). Here, we review the conflicts between the earlier and the more recent findings and summarize new data that reconcile many of the contradictions. A unified model based on these data explicating the generation and maintenance of the febrile response is presented. It postulates that the steps in the production of LPS fever occur in the following sequence: the immediate activation by LPS of the complement (C) cascade, the stimulation by the anaphylatoxic C component C5a of Kupffer cells, their consequent, virtually instantaneous release of PGE(2), its excitation of hepatic vagal afferents, their transmission of the induced signals to the POA via the ventral noradrenergic bundle, and the activation by the thus, locally released norepinephrine (NE) of neural alpha(1)- and glial alpha(2)-adrenoceptors. The activation of the first causes an immediate, PGE(2)-independent rise in core temperature (T(c)) [the early phase of fever; an antioxidant-sensitive PGE(2) rise, however, accompanies this first phase], and of the second a delayed, PGE(2)-dependent T(c) rise [the late phase of fever]. Meanwhile-generated pyrogenic cytokines and their consequent upregulation of blood-brain barrier cells COX-2 also contribute to the latter rise. The consecutive steps that initiate the febrile response to LPS would now appear, therefore, to occur in an order different than conceived originally.
Prostaglandins & other lipid mediators 06/2005; 76(1-4):1-18. · 2.70 Impact Factor
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ABSTRACT: To better understand the pathophysiology of the fever often manifested by immunocompromised patients undergoing chemotherapy that become neutropenic and suffer a bacterial infection.
Prospective animal study.
A physiology laboratory in a medical school setting.
We induced leukopenia in guinea pigs with vinblastine (0.7 mg/kg, intravenously, 4 days before) and measured the animals' febrile response to 2 microg of lipopolysaccharide/kg and the uptake of 75 microg of fluorescein isothiocyanate-labeled lipopolysaccharide/kg by Kupffer cells. The leukopenic animals exhibited significantly higher fevers and greater hepatic fluorescein isothiocyanate-lipopolysaccharide uptake than their controls.
Lipopolysaccharide-challenged, vinblastine-induced leukopenic guinea pigs exhibit hyperpyrexia and significantly elevated uptake of lipopolysaccharide by Kupffer cells, the major source of pyrogenic mediators. This could explain "febrile neutropenia."
Critical Care Medicine 11/2004; 32(10):2131-4. · 6.33 Impact Factor
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ABSTRACT: We have shown previously that norepinephrine (NE) microdialyzed into the preoptic area (POA) of conscious guinea pigs stimulates local PGE(2) release. To identify the cyclooxygenase (COX) isozyme that catalyzes the production of this PGE(2) and the adrenoceptor (AR) subtype that mediates this effect, we microdialyzed for 6 h NE, cirazoline (alpha(1)-AR agonist), and clonidine (alpha(2)-AR agonist) into the POA of conscious guinea pigs pretreated intrapreoptically (intra-POA) with SC-560 (COX-1 inhibitor) or nimesulide or MK-0663 (COX-2 inhibitors) and measured the animals' core temperature (T(c)) and intra-POA PGE(2) responses. Cirazoline induced T(c) rises promptly after the onset of its dialysis without altering PGE(2) levels. NE and clonidine caused early falls followed by late rises of T(c); intra-POA PGE(2) levels were closely correlated with this thermal course. COX-1 inhibition attenuated the clonidine-induced T(c) and PGE(2) falls but not the NE-elicited hyperthermia, but COX-2 inhibition suppressed both the clonidine- and NE-induced T(c) and PGE(2) rises. Coinfused cirazoline and clonidine reproduced the late T(c) rise of clonidine but not its early fall and also not the early rise produced by cirazoline; on the other hand, the PGE(2) responses were similar to those to NE. Prazosin (alpha(1)-AR antagonist) and yohimbine (alpha(2)-AR antagonist) blocked the effects of their respective agonists. These results indicate that alpha(1)- and alpha(2)-AR agonists microdialyzed into the POA of conscious guinea pigs evoke distinct T(c) responses: alpha(1)-AR activation produces quick, PGE(2)-independent T(c) rises, and alpha(2)-AR stimulation causes an early T(c) fall and a late, COX-2/PGE(2)-dependent T(c) rise.
AJP Regulatory Integrative and Comparative Physiology 07/2004; 286(6):R1156-66. · 3.34 Impact Factor
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ABSTRACT: The complement (C) cascade is activated in almost immediate reaction to the appearance in the body of pathogenic microorganims and their products, e.g., bacterial endotoxic lipopolysaccharide (LPS), resulting in the generation of a series of potent bioactive fragments that have critical roles in the innate immune response of the afflicted host, including, potentially, the production of the fever that so characteristically marks bacterial infections. For instance, its derivatives C3a, C3b, iC3b, C5a, and C5b-9 independently induce the production by myeloid and non-myeloid cells of the cytokines interleukin (IL)-1(, IL-6 and tumor necrosis factor-(, and of prostaglandin (PG)E2, all putative mediators of fever. Therefore, any one of these C components could be involved, centrally or peripherally, in the induction of the febrile response to LPS. Indeed, we have shown that hypocomplementation by cobra venom factor (CVF) dose-dependently attenuates LPS-induced fever in guinea pigs and wild-type (WT) mice, and that C5 gene-ablated mice are unable to develop fever after LPS. In further studies, we found that a specific antagonist to the C5a receptor, C5aR1a, prevents the LPS-induced febrile rise of WT and C3 null mutant mice, implicating C5a as the responsible factor. Various lines of evidence from our laboratory suggest that the macrophages of the liver (Kupffer cells [Kc]) may be the specific target cells of C5a and that the product they release may be PGE2. PGE2, in turn, may be the substance that binds to vagal afferents in the liver that convey the pyrogenic message to the brain. Other studies by our group (not included in this review) have separately traced the neural pathway by which this message may be transmitted from the liver to the brain and processed there for action. The purpose of this article is to review the studies that have led us to conclude that C5a, Kc and Kc-generated PGE2 may be integrally involved in the pathogenesis of LPS fever. If further verified, these results will be important for better understanding how infectious stimuli may trigger the multivariate acute-phase responses generally, and fever particularly, that promptly spring into action to defend the continued well-being of the afflicted host.
Frontiers in Bioscience 02/2004; 9:915-31. · 3.52 Impact Factor
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ABSTRACT: The febrile responses of splenectomized (Splex) or sham-operated (Sham) guinea pigs challenged intravenously or intraperitoneally with lipopolysaccharide (LPS) 7 and 30 days after surgery were evaluated. FITC-LPS uptake by Kupffer cells (KC) was additionally assessed 15, 30, and 60 min after injection. LPS at 0.05 microg/kg iv did not evoke fever in Sham animals but caused a 1.2 degrees C core temperature (T(c)) rise in the Splex animals. LPS at 2 microg/kg iv induced a 1.8 degrees C greater T(c) rise of the Splex animals than of their controls. LPS at 2 and 8 microg/kg ip 7 days postsurgery induced 1.4 and 1.8 degrees C higher fevers, respectively, in the Splex than Sham animals. LPS at 2 and 8 microg/kg ip 30 days postsurgery also increased the febrile responses of the asplenic animals by 1.6 and 1.8 degrees C, respectively. FITC-LPS at 7 days was detected in the controls within KC 15 min after its administration; the label density was reduced at 30 min and almost 0 at 60 min. In the Splex group, in contrast, the labeling was significantly denser and remained unchanged through all three time points; this effect was still present 30 days after surgery. Similar results were obtained at 60 min after FITC-LPS intraperitoneal injection. Gadolinium chloride pretreatment (-3 days) of the Splex group significantly reduced both their febrile responses to LPS (8 microg/kg ip) and their KC uptake of FITC-LPS 7 days postsurgery. Thus splenectomy increases the magnitude of the febrile response of guinea pigs and the uptake of systemically administered LPS.
AJP Regulatory Integrative and Comparative Physiology 07/2003; 284(6):R1466-76. · 3.34 Impact Factor
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ABSTRACT: The spleen plays a vital role in the host's protection against invading microorganisms. In spite of its fundamental participation and that of fever in the host defenses against infections, the role of the spleen in the febrile response has not yet been systematically investigated. We reported previously that splenectomy significantly increases both the febrile response to lipopolysaccharide (LPS) and the uptake of LPS by Kupffer cells (KC). In support, we also have shown that the ligation of the splenic vein of conscious guinea pigs challenged with LPS intraperitoneally (ip), augmented also both the febrile response and the uptake of LPS by KC until new collateral veins developed. This suggests that the spleen may normally contribute a factor that limits the KC uptake of LPS and thus modulates the febrile response. To verify the presence of a putative splenic antipyretic factor, we injected extract of spleens from guinea pigs pretreated with LPS and ultrafiltrated it, then injected it intravenously (iv) into splenectomized guinea pigs pre-treated with LPS ip. The results confirmed our presumption, viz., the splenic extract from LPS-treated guinea pigs inhibited the exaggerated febrile response observed in the splenectomized guinea pigs, supporting the presence of a putative antipyretic factor. The identity of the splenic factor(s) that may thus be released into the splenic vein, however, is (are) still uncertain, but the fact that the active principle passes through a microporous filter having a nominal molecular weight cutoff of 10,000 Da suggests that this factor could be a prostaglandin or a small peptide. Such factors have been described, e.g., PGD2, PGE2, PGF1α, thromboxane B2, atrial natriuretic peptide and β-endorphins. The identification of this putative splenic antihyperpyretic factor will be crucial for a better understanding of how the febrile response is controlled by the spleen to protect health by mitigating the potentially injurious effects of high fevers of the distressed host during infectious states. The aim of the present review is to focus on the new findings regarding the role that the spleen plays during the febrile response.
Journal of Thermal Biology.
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ABSTRACT: (1) Cobra venom factor (CVF)-induced hypocomplementemia dose-dependently attenuates the febrile responses of guinea pigs and mice to intraperitoneally (ip) but not to intravenously (iv) injected endotoxic bacterial lipopolysaccharide (LPS). (2) Iv but not ip LPS causes fever in complement component 3 (C3) gene-ablated mice, but neither iv nor ip LPS evokes a body core temperature (Tc) rise when WT and these mice's C5a receptors type 1 are blocked. C5 knockout mice also do not develop fever following either iv or ip LPS. C5a thus appears to be a critical mediator of LPS fever. (3) C5 knockouts develop fever in response to intracerebroventricularly (icv) injected LPS or prostaglandin (PG)E2; the site of action of C5a is therefore peripheral rather than central. (4) The initiation of the febrile responses to both iv and ip LPS is temporally correlated with the appearance of LPS in the liver's Kupffer cells (Kc). (5) PGE2 is released by liver in immediate response to the injection of CVF into the portal vein of anesthetized guinea pigs; its level rises quickly to its maximum. LPS injected similarly also evokes a quick release of PGE2 from the liver; it, however, is prevented by prior hypocomplementation. (6) Neither LPS nor IL-1β induces PGE2 release from Kc in vitro within the first hour after treatment, but serum C and C plus LPS or IL-1β very quickly trigger PGE2 increases of similar magnitudes, catalyzed non-differentially by cyclooxygenase (COX)-1 and COX-2. Kc would thus appear to be the principal site of action of C5a, inducing the release of PGE2. (7) PGE2 is detectable in the plasma of conscious guinea pigs in temporal correlation with the onset of the Tc rise following ip LPS; cytokines appear significantly later. (8) Taken together, these results indicate that LPS-activated C, rather than LPS or IL-1β by itself, triggers PGE2 release by Kc. This PGE2 could be the factor that stimulates vagal afferents, thereby providing the signal to the brain that mediates the febrile response.
Journal of Thermal Biology.
