Summary of observations in rats submitted to bilateral carotid neurotomy (BCN) or simulated surgery (SHAM) prior to the i.p. administration of 15 mg/kg LPS (LPS) or vehicle (saline). The data were assessed 90-min after LPS or vehicle administration. Table prepared from part of the data presented in Reyes et al., 2012 (In press. Adv Exp Med Biol)
1. Introduction
“Healthy organs behave as ‘biological oscillators’, which couple to one another, and this orderly coupling is maintained through a communication network, including neural, humoral, and cytokine components” (Godin & Buchman, 1996). The nervous system –acting through the autonomic nervous system (ANS)– coordinates the fine-tuning of cardiorespiratory interplay, to maintain an appropriate oxygen delivery to the tissues (Abboud & Thames, 1983; Eyzaguirre et al., 1983). Autonomic (sympathetic-parasympathetic) balance is maintained by several reflex arcs, like arterial baroreflexes (Kirchheim, 1976), central chemoreflexes, peripheral arterial chemoreflexes, and pulmonary stretch reflexes (Liljestrand, 1958). These reflexes represent the major components of blood pressure and breathing regulation. Therefore, the interactions among these reflexes are of special clinical interest, since the overactivity of a single reflex, occurring pathophysiologically in several disorders, can lead to the suppression of opposite reflex responses (Schmidt et al., 2001).
Sepsis syndromes (SS), which include systemic inflammatory response syndrome (SIRS) and its consequences, severe sepsis and septic shock, involve many pathological processes like systemic inflammation, coagulopathies, hemodynamic abnormalities, and multiple organ dysfunction syndrome (MODS) (Riedemann et al., 2003). The progression of MODS associated to systemic inflammation is mainly due to an uncontrolled release of pro-inflammatory mediators, which damage parenchymatous organs. Additionally, sepsis activates and/or depress numerous other systems within the body, including neural, hormonal, and metabolic pathways (Carre & Singer, 2008; Singer et al.,2004). Thus, systemic inflammation would initiates disruption of communication and uncoupling, and subsequent MODS would reflects the progressive uncoupling of ‘biological oscillators’ that can become irremediable.
Increasing evidences here summarized shown that a particular neural reflection, the carotid body chemoreflexes, not only serves as a chemoreceptor for respiratory reflex responses, as traditionally accepted, but also as a sensor for the immune status, as modulator of autonomic balance tending to coordinate cardiorespiratory interplay, devoted to maintain oxygen homeostasis in different pathologies, and as a protective factor during sepsis and MODS.
2. Sepsis syndromes prevalence and current therapies
Significant demographic variation exists in the risk of developing sepsis. For example, from the standpoint of gender, the incidence of sepsis is higher in men, and the mean age at which men develop sepsis is younger. Case fatality rates also increase with age (Martin et al., 2006). The overall burden of severe sepsis is also increasing, in terms of both the number of patients who develop the syndrome and the extent and intensity of care that they require (Angus et al., 2001). Sepsis also poses a significant burden of disease in pediatric patients, where the incidence is highest in infants, mainly in children younger than one year of age (Watson & Carcillo, 2005). Maternal sepsis and neonatal sepsis are of particular concern. Maternal sepsis is responsible for at least 75,000 deaths annually, disproportionately affecting low-income countries (van Dillen et al., 2010). In the United States, studies of neonatal sepsis have documented rates as high as 170 cases per 1000 live births (Thaver & Zaidi, 2009). The average costs per case are US$22,100. Costs are higher in infants, non-survivors, intensive care unit patients, surgical patients, and patients with more organ failure. The incidence was projected to increase by 1.5% per annum (Angus et al., 2001). The international costs associated with sepsis and its management are reviewed in Chalupka & Talmor (2012).
Instead of many efforts and significant advances in maintaining therapies, SS and MODS, are the main cause of death between critical care patients (Martin et al., 2003). Increased morbi-mortality associated to SS is due to the absence of a really effective therapy (Riedemann et al., 2003). Thus, the knowledge of molecular mechanisms and pathophysiology of sepsis help us to improve current therapies (for a Review see Barochia et al., 2010) and to identify new pharmacological therapeutic targets.
Treatments of sepsis and septic shock involves antibiotic administration, intravenous fluids (crystalloids or colloids), vasopressors and/or inotropes (adrenergic agents), packed red blood cells (PRBC) transfusions, and corticosteroids (Barochia et al., 2010). Sepsis care bundles increase patients’ survival. Numerous studies have demonstrated improved outcomes in life-threatening infections with early administration of appropriate antibiotics. Hemodynamic support with fluids and vasopressors is as important as antibiotic in reducing mortality (Natanson et al., 1990), but there are great differences among different patient populations. A considerable variation in the ranges of central venous pressure and mean arterial pressure prompted physicians to suggest that “
Administration of PRBC decreases inotropes use (Nguyen et al., 2007), but the efficacy of administration in patients with sepsis is unclear. The usage of low-dose corticosteroids is variable between patient populations. However, as questions persist regarding the risk and benefits of these therapies for sepsis, they continue to undergo investigation (Misset et al., 2010). Although the use of these agents may be beneficial for some septic patients, the Surviving Sepsis Campaign guidelines (Dellinger et al., 2004) gave a weak recommendation for use these therapies, even the inclusion of some patients, until the knowledge of individual components that could modify the expected results. It is clear that the course of sepsis and therapies outcomes depend largely from host predisposition factors and response.
The serial evaluation of the SOFA score helps to predict outcome in critically ill patients. SOFA score can help assess organ dysfunction or failure over time and are useful to evaluate morbidity and mortality, by evaluating respiratory, coagulation, liver, cardiovascular, central nervous system (CNS), and renal variables (Peres et al., 2002). However, in spite of SOFA score assessment, “
3. Pathophysiology of sepsis and multiple organ dysfunction syndrome
As it was mentioned, the progression of MODS is due to an uncontrolled release of pro-inflammatory mediators, which damage parenchymatous organs. However, it is still unknown why sepsis progresses to MODS in only certain individuals or what the exact pathway is that leads to this. But, it is clear that if the inflammatory process becomes self-sustained and progressive, MOD results. In addition, because of marked hypotension and tissue hypoperfusion, oxygen delivery fails to meet tissue oxygen demands, which results in a compensatory increase in oxygen extraction. If the imbalance between oxygen delivery and consumption is not corrected, tissue ‘dysoxia’ progress to an anaerobic metabolism and lactate production (Nguyen et al., 2004). Persistent serum lactate elevation is an important marker of decreased tissue perfusion –even in the absence of arterial hypotension (Howell et al., 2007)–, and is strongly associated with mortality rate in critically ill patients (Meregalli et al., 2004). Thus, during sepsis an extraordinarily complex and intricate cascade of inflammatory mediators, extra- and intra-cellular signaling pathways are activated, resulting in microvascular dysregulation and/or mitochondrial dysfunction (‘cytopathic hypoxia’) (Crouser, 2004), which culminate in MODS and death.
To avoid tissue dysoxia, early in the course of sepsis, cardiac output (CO) rises to maintain blood pressure and organ perfusion in the face of reduced peripheral vascular resistance (‘hyperdynamic sepsis’). As sepsis progresses, CO is frequently reduced (‘hypodynamic sepsis’), which has a poor prognosis. Cardiac dysfunction
Contradictory evidences from animal studies suggest that such hypoperfusion does not invariably lead to heart dysfunction and death. But, our preliminary results (unpublished data) reveal many other ECG and vectorcardiographic changes in rats injected intraperitoneally (i.p.) with 15 mg/kg lipopolysaccharide (LPS), which are strongly associated with cardiac dysfunction and, almost certainly, left vetricular hypoperfusion and ischemia. Briefly, LPS administration decreases RR interval (RRI) and R amplitude. Also, sepsis increases QTc interval and ST height. Strikingly, when both carotid/sinus nerves are sectioned (bilateral carotid neurotomy (BCN) prior to LPS administration, the changes in the parameters mentioned above are greater than control condition (with intact carotid chemo- and baro-sensory innervations). In addition, BCN decreases QRS duration, increases JT interval and T amplitude. On the other hand, the cardiac vector is significantly decreased (from
As it was mentioned, the major task toil of autonomic nervous system (ANS) is the fine-tuning of the cardiorespiratory interplay, in order to maintain an appropriate oxygen delivery to the tissues. However, the neural regulation of cardiorespiratory function and the role-played by peripheral reflexes during sepsis, in which organ communications networks are disrupted, is poorly understood. In addition to plasma or urinary levels of neurotransmitters or their metabolites, there are three methods to evaluate autonomic function: a) analysis of heart rate variability (HRV); b) baroreflex sensitivity (BRS); and c) cardiac chemoreflex sensitivity (CCRS).
The analysis of HRV gives a clear idea about the neural (autonomic) control of cardiorespiratory function and interaction. Decreased HRV is consistent with the pathogenesis of MODS, which involves the physiological uncoupling of vital organ systems. In fact, HRV decreases in response to human endotoxemia (Godin et al., 1996; Rassias et al., 2005), and is a good index of cardiac mortality (Schmidt et al., 2001). Moreover, patients with sepsis (Barnaby et al., 2002) and MODS (Korach et al., 2001; Schmidt et al., 2005) have an impaired sympatho-vagal balance. In fact, some evidences describe a sustained sympatho-excitation during sepsis, which accompanies the fall in blood pressure. Baroreceptors and chemoreceptors denervation accelerated the fall in mean blood pressure and increases sympathetic tone (Vayssettes-Courchay et al., 2005). Thus, under altered baro- and chemo-reflexes pathways, the sympathetic output from the
Vayssettes-Courchay et al. (2005) shown that baro- and chemo-reflexes are not inhibited during sepsis, and they give them a minor importance in the sympathetic activation and in the blood pressure modifications. Nevertheless, recently we described the first functional evidence of chemoreceptors inflammation and dysfunction during sepsis. In cats, local or systemic administration of LPS induces a significant reduction in chemoreceptor activity, ventilatory chemoreflexes, and ventilator chemosensory drive (Fernandez et al., 2008). In fact, LPS-induced tachypnea is prevented by prior bilateral carotid neurotomy.
Our results (unpublished data) shown that the i.p. administration of 15 mg/kg LPS to rats, decreases HRV and increases sympathetic tone, assessed by HRV frequency bands and low frequency/high frequency (LF/HF) quotient. Bilateral carotid neurotomy previous to LPS administration evokes a greater decrease in HRV and increase in LF/HF ratio than animals with intact carotid/sinus nerves. As it was mentioned, both decreased HRV and increased sympathetic tone are good markers of morbi-mortality. In fact, BCN prior to LPS administration increases the relative risk of death (Table 1). In addition, rats submitted to peripheral chemodenervation prior to the intravenous (i.v.) administration of high doses of LPS, show a smaller survival time (Tang et al., 1998).
SHAM | BCN | |||
saline | LPS | saline | LPS | |
Relative Risk (RR) (IC 95%) | 1 (n=8) | 1.2 (0.9 – 1.6) (n=12) | 1.3 (0.9 – 1.8) (n=9) | 2.6 (1.5 – 4.5)a (n=21) |
Plasma Cortisol (ng/mL) (Mean SD) | 536.5 383.3 (n=7) | 1552.0 940.5b (n=7) | 637.5 397.0 (n=6) | 321.5 153.2c (n=6) |
Baroreflex sensitivity describes ANS capacity to increase vagal activity and to decrease sympathetic activity after a sudden increase in blood pressure. Baroreflex activation counteract sympathetic activation (Somers et al., 1991). BRS is altered in rats treated with a lethal dose of LPS (Shen et al., 2004). Rougaush
In summary, there is consensus that uncoupling of the autonomic, respiratory and cardiovascular systems occurs over both short- and long-range time scales during sepsis and MODS. However, the origin from these altered reflex arcs is not well described.
4. Inflammatory mediators during sepsis
The development of sequential organ failure in critically ill patients with sepsis is strongly predictive of mortality. However, the mechanisms involved in the dynamic interaction between different organ systems are dictated by the intricate interplay of homodynamic, oxygen transport, and metabolic disturbances. Genetic predisposition is almost certainly relevant in upregulating the expression of inflammatory mediators [
Mammals are continuously exposed to different pathogens, like Gram-negative bacteria and/or its components, such as LPS (endotoxin). LPS exerts many different biological effects. While low-doses could be beneficial, by inducing immunostimulation and by increasing resistance to infection (Schletter et al., 1995), larger-doses of LPS in plasma evoke many pathophysiological reactions, like fever, leucopenia, tachycardia, tachypnea, hypotension, disseminated intravascular coagulation, MODS, and death (Patel et al., 2003; Hotchkiss & Karl, 2003; Pinsky, 2004). The systemic inflammatory response induced by LPS is due to host cells stimulation (monocytes/macrophages, endothelial, and polymorphonuclear cells) to produce and release endogenous mediators like reactive oxygen species (ROS) and pro-inflammatory cytokines (Schletter et al., 1995). Inflammatory mediators and ROS are believed to disrupt communication pathways between organs, which precedes organ failure. Indeed, endothelial dysfunction has been proposed as a common pathway for organ dysfunction in sepsis (Simon & Fernandez, 2009). During systemic inflammation, many physiological functions of endothelial cells are disrupted, contributing to multiple organ failure (Volk & Kox, 2000).
During the last decade, there has been a rapid progress in understanding innate immune response to pathogens or their component. The early concept supposed a nonspecific recognition. But, the discovery of Toll-like receptors (TLRs) showed that recognition by the innate immune system is specific (Akira et al., 2001). TLR-4 is identified as the long-sought receptor that respond to bacterial LPS (Akira et al., 2006). TLR4 forms a complex with MD-2 on the cell surface. Additional proteins such as the soluble plasma protein LPS-binding protein (LBP) and either soluble or membrane-anchored CD14 are also involved in LPS binding (Akashi-Takamura & Miyake, 2008). LPS transfer to the LPS-binding receptor (TLR-4/MD-2) (da Silva
Tumor necrosis factor- has been implicated as an important mediator of the lethal effect of endotoxin. Several publications have shown that by reducing the activity or the expression of TNF- significantly decrease the endotoxin-induced damages. The amount of TNF- in serum can be associated with the degree of tissue damage because of the stagnant blood capillary (Yang et al., 2007). TNF- is a well-known cytotoxic cytokine for certain tissue cells. In fact, plasma levels of several biophysical damage indicators are increased during sepsis, like liver alanine aminotransferase, aspartate aminotransferase, and bilirrubin; heart and other possible organ (such as muscle) lactic dehydrogenase and creatine phosphokinase; ureic nitrogen (BUN, renal function); and pancreatic alkaline phosphatase and amylase.
5. Reflex control of inflammation: Part I – Brain-to-immune communication
Inflammation is a localized protective response to infection or injury. It evokes many different effects upon the organisms tending to solve the inflammatory focus, like humoral factors which increase the blood flow or attract specific immune cells (Libert, 2003). As it was mentioned above, TNF-α, plays a pivotal role during systemic inflammation. Excessive inflammation and TNF-α synthesis increase morbi-mortality in SS. In consequence, highly conserved endogenous mechanisms normally regulate the magnitude of innate immune response and prevent excessive inflammation (Wang et al., 2003).
The CNS regulates systemic inflammatory responses to endotoxin through neural and humoral mechanisms. Evidence accumulated over the last 30 years suggests that norepinephrine (NE), the main neurotransmitter of the sympathetic nervous system, fulfills the criteria for neurotransmitter/neuromodulator in lymphoid organs: i) primary and secondary lymphoid organs receive extensive sympathetic/noradrenergic innervation; ii) under stimulation, NE is released from the sympathetic nerve terminals in these organs; and iii) the target immune cells, including lymphocytes and macrophages, express adrenergic receptors (AR). Adrenoceptors are G-protein coupled receptors that can be divided into two subgroups: the - and -AR, which can be further subdivided into different subtypes. Neutrophils, mononuclear, and natural killer cells, also T- and B-lymphocytes express - and -AR. The most important adrenoceptor –in terms of the immune system– is the 2-AR. Activation of 2-AR results in an increase in cAMP concentrations, which can modulate cytokine expression,
A growing body of literature is aimed at studying -blockade as a treatment of sepsis. Their effects on metabolism and glucose homeostasis, cytokine expression, and myocardial function may be beneficial in the setting of sepsis. Sepsis induces an overall catabolic state, mainly due to excessive adrenergic stimulation (Bergmann et al., 1999). -Blockade has been proposed as a strategy to counteract the devastating consequences of this hyperadrenergic state. But treating a potentially hypotensive condition with a drug with antihypertensive properties may initially seem detrimental (Novotny et al., 2009). Peripheral (i.p.) 1-AR blockade prior to endotoxemia increases survival time, reduces hepatic expression of pro-inflammatory cytokines, decreases protein expression of cardiac dysfunction markers, and preserves arterial blood pressure and left ventricular contractility (Ackland et al., 2010). Surprisingly, few studies report overall mortality in the published -blocker trials in sepsis. Interestingly, of those investigators that do report mortality in sepsis models, one out of four show increased mortality in -blockade groups.
Vasopressor and inotropic therapies for sepsis employ adrenergic support. In fact, a recent publication about the “
It should be noted that different cathecholamines used to treat patients with septic shock, have relative - and -AR effects (depending on the dose). Thus, in addition to individual differences, it is necessary to consider the fine-tuning of both, immune system and cardiovascular effects of adrenergic drugs used for sepsis treatment.
The CNS can also rapidly inhibit the release of macrophage TNF-α, and attenuate systemic inflammatory responses acting through the vagus (parasympathetic) nerve. This physiological mechanism, termed the ‘cholinergic anti-inflammatory pathway (Borovikova et al., 2000)’ has major implications in immunology and in therapeutics (Rosas-Ballina & Tracey, 2009). The main vagal neurotransmitter, acetylcholine (ACh), inhibits LPS-induced TNF-α, IL-1 and IL-6 release, but not anti-inflammatory cytokine IL-10, in LPS stimulated
Recent work on the anatomical basis of the cholinergic anti-inflammatory pathway indicates that the spleen is required for vagus nerve control of inflammation (Huston et al., 2006). The spleen is the major source of serum TNF- during endotoxemia (Mignini et al., 2003). In splenectomized rats injected with endotoxin, serum TNF- is reduced by 70%, and vagus nerve stimulation fails to further suppress TNF-. The celiac branches of the vagus terminate in the celiac-superior mesenteric plexus and not in the spleen (Berthoud & Powley, 1996). The spleen is innervated by the splenic nerve, which originates in celiac-superior mesenteric plexus. The splenic nerve is composed mainly by catecholaminergic fibers, which terminate in close apposition to immune cells (Felten et al., 1987). Thus, attenuation of TNF- production by spleen macrophages induced by vagus nerve stimulation is mediated by norepinephrine released from splenic nerve endings. These data confirms the importance of the adrenergic transmitters in the regulation of immune response. It must be noted that immune cells have all the essential components of a non-neuronal cholinergic system and that ACh synthesized and released from lymphocytes acts as an immunomodulator via both muscarinic (mAChR) and nicotinic ACh receptors (nAChR) (Kawashima & Fujii, 2000; Kawashima & Fujii, 2003). Most evidences points towards a crucial role for the 7 nAChR in the cholinergic regulation of macrophage activity (Wang et al., 2003). Nicotine exerts anti-inflammatory effects through 7 nAChR (Ulloa, 2005). Acetylcholine (and nicotine), also has cardiorespiratory effects (Fernandez et al., 2002; Zapata et al., 2002). Acting through the peripheral arterial chemoreceptors, ACh, nicotine, and epibatidine (a selective agonist for neuronal nAChRs) increases tidal volume and blood pressure in anesthetized cats (Zapata et al., 2003; Reyes et al., 2007), which support the idea that cholinergic nicotinic treatment can also improve cardiorespiratory performance during sepsis, and prevent tissue dysoxia, lactic acidosis and MODS. In addition, nicotine inhibit cardiac apoptosis induced by LPS in rats (Suzuki et al., 2003).
Finally, both endotoxin and cytokines, stimulates HPA anti-inflammatory responses, either by adrenal glucocorticoids (Turnbull & Rivier, 1999) or by inhibiting prolactin secretion, a potent regulator of humoral and cellular immune response during physiological and pathological states (Freeman et al., 2000). Thus, it is clear that the nervous system reflexively regulates the inflammatory response in real time, just as it controls heart rate and other vital functions.
6. Reflex control of inflammation: Part II – Immune-to-brain communication
Much less is known about the effect of the immune system on the CNS. Immune system-derived signals act on the CNS through four different pathways: i) by saturable transport across the blood–brain barrier (BBB) (Banks & Kastin, 1987); ii) by brain circumventricular organs (CVOs) (Stitt, 1990); iii) by cytokine binding to brain endothelial cells, which evokes paracrine mediators release (Fabry et al., 1993; Cao et al., 1998); and iv) by the activation of peripheral sensory nerves (i.e., vagus nerve) (Goehler et al., 1997).
The role of peripheral sensory nerves in immunomodulation is controversial. It is believed that chemosensory transduction begins in immune cells, which release inflammatory mediators to activate neural elements, including vagal paraganglia (Goehler et al., 1997; Goehler et al., 1999) and primary afferent neurons located in sensory ganglia, which evokes host defense reflexes. Two cell types compose vagal paraganglia: type I (glomus) cells and type II (sustentacular) cells (Berthoud et al., 1995). Vagal glomus cells (GC) are innervated by vagal afferent neurons, whose cell bodies are located in the nodose ganglion, and their central projection end primarily within the dorsal vagal complex (DVC) of the
In spite of the interleukin-1 (IL-1) receptor expression in vagal GC (Goehler et al., 1997), IL-1 (and TNF-), had no significant effect on the frequency of action potentials recorded from single fibers from isolated superfused rat GC obtained from vagal nerve paraganglia (Mac Grory et al., 2010). In addition, in rodents exposed to i.p. LPS or IL-1β, bilateral subdiaphragmatic vagotomy prevents sickness manifestations and activation of
The DVC consists of the NTS, the dorsal motor nucleus of the vagus (DMN), and the
In response to plasma levels of TNF-α, vagal immunosensory activity increases (Emch et al., 2000) or decreases (Emch et al., 2002) vagal motor activity. Transection of abdominal vagal trunks suppresses fever and hyperalgesia caused by i.p. LPS but has little effect on the febrile response to i.v. or intramuscular LPS. To elucidate the importance of visceral afferent innervation on the response to LPS, Wan
The number of neurons within the DVC that expressed c-Fos activation after peripheral administration of LPS is correlated with plasma levels of TNF-. Thus, the activation of DVC neurons did not require intact vagal pathways, suggesting that TNF- generated peripherally could acts directly on these neurons, because DVC exhibits the characteristics of CVOs (
Seen from an anatomical standpoint, the carotid body (CB) is the largest paraganglia in the body (Mascorro & Yates, 1980), and like other paraganglia, it receives sensory innervation, and has specialized glomus cells with abundant synapses with the sensory nervous fibers (Verna, 1997).
7. The arterial chemoreceptors in neuroimmunomodulation
The CB is the main peripheral chemoreceptor responsible for the detection of blood oxygen levels. The CB consists of groups of glomus (type I) cells arranged around capillaries, ensheathed by sustentacular (type II) cells, and surrounded by connective tissue. It receives profuse sensory innervation from the carotid (sinus) nerve (CSN), a branch of the glossopharyngeal nerve, whose sensory nerve endings are in close contact with glomus cells (GC) (Hess & Zapata, 1972). CB innervation is essentially by sensory neurons residing mainly in the petrosal ganglion (Kalia & Davies, 1978; Berger, 1980). Interestingly, the first synapsis at the CNS for afferent CSN fibers occurs in the NTS (Donoghue et al., 1984; Finley & Katz, 1992). Thus, inflammation-derived sensory input originated from arterial chemoreceptors (Zapata et al., 2011) can be differentially processed in the peripheral chemoreceptor
Many reports allow us to propose that peripheral arterial chemoreceptors play a pivotal role in afferent signaling during sepsis. Recently, we demonstrated that i.v. administration of LPS to pentobarbitone-anesthetized cats evokes similar symptoms to those observed in patients with severe sepsis and septic shock, with tachycardia, tachypnea and hypotension, and that the increased respiratory frequency is prevented by bilateral section of the carotid and aortic nerves (Fernandez et al., 2008). In addition, LPS enhances tonic CB chemosensory activity (measured by recording the frequency of chemosensory discharges) but reduces its responsiveness to transient excitatory (hypoxia and nicotine) or depressant (pure oxygen) stimuli. Diminished ventilatory responses to moderate and severe hypoxia in cats reproduces the diminished ventilatory responses to hypoxia observed in unanesthetized newborn piglets subjected to
Lipopolysaccharide administration increases cytokine plasma levels in many species, including rats (Waage, 1987), bovines (Ohtsuka et al., 1997) and cats (Otto & Rawlings, 1995). Thus, by using
Apart from the presence of TNF-α and TNF-R1, it is known that GC from rat CB express IL-1 receptor type I (Wang et al., 2002) and IL-6 receptor α (Wang et al., 2006), and that GC respond to IL-1β application with depolarization and a transient rise in intracellular calcium (Shu et al., 2007). On the other hand, i.p. administration of IL-1 evokes IL-1 receptor type I and tyrosine hydroxylase (TH) up-regulation in the rat CB (Zhang et al., 2007). The fact that pro-inflammatory cytokines and their receptors are functionally expressed in the CB type I cells, suggests that inflammatory mediators may have different functional roles in the activation of neurons in the NPJgc, even in the absence of sepsis syndromes –
In view of data mentioned above, we tested whether LPS-induced systemic inflammation exerts a direct effect upon CB chemoreceptors. We determined that the rat CB and NPJgc constitutively express the mRNAs for TLR4, MyD88, TNF- and its receptors (TNF-R1 and TNF-R2). Intraperitoneal administration of 15 mg/kg LPS evokes IKB degradation, and subsequent NF-B p65 translocation into the nucleus from GC and NPJgc chemosensory neurons. LPS also evokes p38 MAPK and ERK phosphorylation. Consistently, LPS treatment increases both mRNA and protein levels of TNF-, TNF-R2, and TH. Double-labeling studies show that TLR4, TNF-α, and TNF-R1 are localized in TH-containing GC and neurons from CB and NPJgc, respectively, suggesting that the expression was confined to the chemoafferent neural pathway. TNF-R2 is also present surrounding GC clusters within the CB and in chemosensitive neurons. TNF-α, and TNF-R2 expression are increased in the carotid chemoreceptors from endotoxemic rats (Fernandez et al., 2011). Thus –in addition to systemic LPS effect– our results suggest that LPS acting directly through TLR-4 modifies TNF- and its receptors expression on chemosensory cells of the carotid chemoreceptors neural pathway. These results show a novel afferent pathway to the CNS during physiological conditions and endotoxemia, and could be relevant in understanding sepsis pathophysiology and therapy.
Thus, it is very interesting to highlight that during sepsis syndromes, LPS acting directly upon carotid chemoreceptors, modify TNF- expression. In addition systemic or local inflammatory mediators could change arterial chemoreceptors function and afferent signaling through TNF- receptors, whose expression is also modified during sepsis (our results), or through IL-1 and/or IL-6 receptors (Figure 1). Interestingly, TNF- stimulates c-Fos activation of neurons in the NTS (Hermann et al., 2001). Results here obtained would imply that arterial chemoreflexes, not only serves as a chemoreceptor for respiratory reflex responses, as traditionally accepted, but also as a sensor for the immune status, as modulator of autonomic balance tending to coordinate cardiorespiratory interplay devoted to maintain oxygen homeostasis in different pathologies, and as a protective factor during sepsis and MODS.
The disruption of continuous detection of the ‘inflammatory status’ of the body exerted by carotid chemoreceptors could be responsible for modifying the activity of the ANS, thus altering the control exerted by the nervous system on the immune system, and evoking an uncontrolled cytokine production. This excessive and uncontrolled systemic inflammatory response and dysautonomy could be responsible for subsequent neural uncoupling of the vital organs and MODS.
8. Conclusion
Sepsis syndromes are the main cause of death between critical care patients. They result from neural, cardiovascular, respiratory, and immune systems uncoupling. Multiple organ dysfunction syndrome (MODS) is due to an uncontrolled release of pro-inflammatory mediators, which damage parenchymatous organs. However, it is still unknown why sepsis progresses to MODS in only certain individuals.
The effects of sepsis therapies are controversial and strongly dependent of individual components, like individual response and genetic predisposition. Thus, the course of sepsis and therapies outcomes depends largely from host factors.
Increasing evidences shown that peripheral carotid chemoreceptors act as sensor for the immune status, as modulator of autonomic balance tending to coordinate cardiorespiratory interplay devoted to maintain oxygen homeostasis in different pathologies, and as a protective factor during sepsis and MODS.
As result of the autonomic and immune imbalance originated from carotid chemoreceptors, neural and cytokine communication networks between healthy organs are disrupted. So, the impaired autonomic function would decrease cardiorespiratory function, oxygen delivery to the tissues, and the reflex control of inflammation. The heterostasis induced by systemic inflammation worsens the uncoupling of biological oscillators, what would lead to MODS and death.
Acknowledgement
Ricardo Fernandez is supported by FONDECYT 1120976 and UNAB DI-40-11/R.
Claudio Acuña-Castillo is supported by FONDECYT 1110734.
References
- 1.
Abboud FM & Thames MD. Interaction of cardiovascular reflexes in circulatory control. Sheperd, J. T, Abboud, F. M, Geiger, S. R, and Bethesda, M. D. [3],675 752 1983 American Physiological Society. Handbook of Physiology. - 2.
Ackland G. L. Yao S. T. Rudiger A. Dyson A. Stidwill R. Poputnikov D. Singer M. Gourine A. V. 2010 Cardioprotection, attenuated systemic inflammation, and survival benefit of beta1-adrenoceptor blockade in severe sepsis in rats. Crit Care Med38 388 394 - 3.
Akashi-Takamura S. Miyake K. 2008 TLR accessory molecules. Curr Opin Immunol20 420 425 - 4.
Akira S. Takeda K. Kaisho T. 2001 Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol2 675 680 - 5.
Akira S. Uematsu S. Takeuchi O. 2006 Pathogen recognition and innate immunity. Cell124 783 801 - 6.
Alanis J. Defillo B. Gordon S. 1968 Changes in the efferent discharges of sympathetic and parasympathetic cardiac nerves provoked by activation of carotid chemoreceptors. Arch Int Physiol Biochim76 214 235 - 7.
Angus D. C. Linde-Zwirble W. T. Lidicker J. Clermont G. Carcillo J. Pinsky M. R. 2001 Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med29 1303 1310 - 8.
Banks WA & Kastin AJ 1987 Saturable transport of peptides across the blood-brain barrier. Life Sci41 1319 1338 - 9.
Barnaby D. Ferrick K. Kaplan D. T. Shah S. Bijur P. Gallagher E. J. 2002 Heart rate variability in emergency department patients with sepsis. Acad Emerg Med9 661 670 - 10.
Barochia A. V. Cui X. Vitberg D. Suffredini A. F. O’Grady N. P. Banks S. M. Minneci P. Kern S. J. Danner R. L. Natanson C. Eichacker P. Q. 2010 Bundled care for septic shock: an analysis of clinical trials. Crit Care Med38 668 678 - 11.
Berger AJ 1980 The distribution of the cat’s carotid sinus nerve afferent and efferent cell bodies using the horseradish peroxidase technique. Brain Res190 309 320 - 12.
Bergmann M. Gornikiewicz A. Sautner T. Waldmann E. Weber T. Mittlbock M. Roth E. Fugger R. 1999 Attenuation of catecholamine-induced immunosuppression in whole blood from patients with sepsis. Shock12 421 427 - 13.
Berthoud H. R. Kressel M. Neuhuber W. L. 1995 Vagal afferent innervation of rat abdominal paraganglia as revealed by anterograde DiI-tracing and confocal microscopy. Acta Anat (Basel)152 127 132 - 14.
Berthoud HR & Neuhuber WL 2000 Functional and chemical anatomy of the afferent vagal system. Auton Neurosci85 1 17 - 15.
Berthoud HR & Powley TL 1996 Interaction between parasympathetic and sympathetic nerves in prevertebral ganglia: morphological evidence for vagal efferent innervation of ganglion cells in the rat. Microsc Res Tech35 80 86 - 16.
Bluthe R. M. Walter V. Parnet P. Laye S. Lestage J. Verrier D. Poole S. Stenning B. E. Kelley K. W. Dantzer R. 1994 Lipopolysaccharide induces sickness behaviour in rats by a vagal mediated mechanism. C R Acad Sci III317 499 503 - 17.
Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, & Sibbald WJ 1992 Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest101 1644 1655 - 18.
Borovikova L. V. Ivanova S. Zhang M. Yang H. Botchkina G. I. Watkins L. R. Wang H. Abumrad N. Eaton J. W. Tracey K. J. 2000 Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature405 458 462 - 19.
Borsody MK & Weiss JM 2005 The subdiaphragmatic vagus nerves mediate activation of locus coeruleus neurons by peripherally administered microbial substances. Neuroscience131 235 245 - 20.
Bret-Dibat J. L. Bluthe R. M. Kent S. Kelley K. W. Dantzer R. 1995 Lipopolysaccharide and interleukin-1 depress food-motivated behavior in mice by a vagal-mediated mechanism. Brain Behav Immun9 242 246 - 21.
Cao C. Matsumura K. Yamagata K. Watanabe Y. 1998 Cyclooxygenase-2 is induced in brain blood vessels during fever evoked by peripheral or central administration of tumor necrosis factor. Brain Res Mol Brain Res56 45 56 - 22.
Carre J. E. Singer M. 2008 Cellular energetic metabolism in sepsis: the need for a systems approach. Biochim Biophys Acta1777 763 771 - 23.
Chalupka A. N. Talmor D. 2012 The economics of sepsis. Crit Care Clin28 57 76 vi. - 24.
Chen WL, Chen JH, Huang CC, Kuo CD, Huang CI, & Lee LS 2008 Heart rate variability measures as predictors of in-hospital mortality in ED patients with sepsis. Am J Emerg Med26 395 401 - 25.
Crouser ED 2004 Mitochondrial dysfunction in septic shock and multiple organ dysfunction syndrome. Mitochondrion4 729 741 - 26.
da Silva. C. J. Soldau K. Christen U. Tobias P. S. Ulevitch R. J. 2001 Lipopolysaccharide is in close proximity to each of the proteins in its membrane receptor complex. transfer from CD14 to TLR4 and MD-2. J Biol Chem276 21129 21135 - 27.
De Backer D. Aldecoa C. Njimi H. Vincent J. L. 2012 Dopamine versus norepinephrine in the treatment of septic shock: a meta-analysis*. Crit Care Med40 725 730 - 28.
Dellinger R. P. Carlet J. M. Masur H. Gerlach H. Calandra T. Cohen J. Gea-Banacloche J. Keh D. Marshall J. C. MM Parker Ramsay. G. Zimmerman J. L. Vincent J. L. MM Levy 2004 Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med32 858 873 - 29.
Donoghue S. Felder R. B. Jordan D. Spyer K. M. 1984 The central projections of carotid baroreceptors and chemoreceptors in the cat: a neurophysiological study. J Physiol347 397 409 - 30.
Donoso V. Gomez C. R. MA Orriantia Perez. V. Torres C. Coddou C. Nelson P. Maisey K. Morales B. Fernandez R. Imarai M. Huidobro-Toro J. P. Sierra F. Acuna-Castillo C. 2008 The release of sympathetic neurotransmitters is impaired in aged rats after an inflammatory stimulus: a possible link between cytokine production and sympathetic transmission. Mech Ageing Dev129 728 734 - 31.
Dvorakova M. Hohler B. Vollerthun R. Fischbach T. Kummer W. 2000 Macrophages: a major source of cytochrome b558 in the rat carotid body. Brain Res852 349 354 - 32.
Elenkov IJ & Chrousos GP 1999 Stress Hormones, Th1/Th2 patterns, Pro/Anti-inflammatory Cytokines and Susceptibility to Disease. Trends Endocrinol Metab10 359 368 - 33.
Elenkov IJ, Wilder RL, Chrousos GP, & Vizi ES 2000 The sympathetic nerve--an integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev52 595 638 - 34.
Emch GS, Hermann GE, & Rogers RC 2002 Tumor necrosis factor-alpha inhibits physiologically identified dorsal motor nucleus neurons in vivo. Brain Res951 311 315 - 35.
Emch GS, Hermann GE, & Rogers RC 2000 TNF-alpha activates solitary nucleus neurons responsive to gastric distension. Am J Physiol Gastrointest Liver Physiol 279, G582 G586. - 36.
Eyzaguirre C. Fitzgerald R. S. Lahiri S. Arterial Chemoreceptors. Sheperd J. T. Abboud F. M. Geiger S. R. Bethesda M. D. [3] 557 66 .1983 American Physiological Society. Handbook of Physiology. Ref Type: Serial (Book,Monograph) - 37.
Fabry Z. Fitzsimmons K. M. Herlein J. A. Moninger T. O. Dobbs M. B. Hart M. N. 1993 Production of the cytokines interleukin 1 and 6 by murine brain microvessel endothelium and smooth muscle pericytes. J Neuroimmunol47 23 34 - 38.
Felten DL, Ackerman KD, Wiegand SJ, & Felten SY 1987 Noradrenergic sympathetic innervation of the spleen: I. Nerve fibers associate with lymphocytes and macrophages in specific compartments of the splenic white pulp. J Neurosci Res18 28 21 - 39.
Fernandez R. Gonzalez S. Rey S. Cortes P. P. Maisey K. R. Reyes E. P. Larrain C. Zapata P. 2008 Lipopolysaccharide-induced carotid body inflammation in cats: functional manifestations, histopathology and involvement of tumour necrosis factor-alpha. Exp Physiol93 892 907 - 40.
Fernandez R. Larrain C. Zapata P. 2002 Acute ventilatory and circulatory reactions evoked by nicotine: are they excitatory or depressant? Respir Physiol Neurobiol133 173 182 - 41.
Fernandez R. Nardocci G. Simon F. Martin A. Becerra A. Rodriguez-Tirado C. Maisey K. R. cuna-Castillo C. Cortes P. P. 2011 Lipopolysaccharide signaling in the carotid chemoreceptor pathway of rats with sepsis syndrome. Respir Physiol Neurobiol175 336 348 - 42.
Finley JC & Katz DM 1992 The central organization of carotid body afferent projections to the brainstem of the rat. Brain Res572 108 116 - 43.
ME Freeman Kanyicska. B. Lerant A. Nagy G. 2000 Prolactin: structure, function, and regulation of secretion. Physiol Rev80 1523 1631 - 44.
Gaykema R. P. Dijkstra I. Tilders F. J. 1995 Subdiaphragmatic vagotomy suppresses endotoxin-induced activation of hypothalamic corticotropin-releasing hormone neurons and ACTH secretion. Endocrinology136 4717 4720 - 45.
Godin PJ & Buchman TG 1996 Uncoupling of biological oscillators: a complementary hypothesis concerning the pathogenesis of multiple organ dysfunction syndrome. Crit Care Med24 1107 1116 - 46.
Godin P. J. Fleisher L. A. Eidsath A. Vandivier R. W. Preas H. L. Banks S. M. Buchman T. G. Suffredini A. F. 1996 Experimental human endotoxemia increases cardiac regularity: results from a prospective, randomized, crossover trial. Crit Care Med24 1117 1124 - 47.
Goehler LE, Gaykema RP, Nguyen KT, Lee JE, Tilders FJ, Maier SF, & Watkins LR 1999 Interleukin-1beta in immune cells of the abdominal vagus nerve: a link between the immune and nervous systems? J Neurosci19 2799 2806 - 48.
Goehler L. E. Relton J. K. Dripps D. Kiechle R. Tartaglia N. Maier S. F. Watkins L. R. 1997 Vagal paraganglia bind biotinylated interleukin-1 receptor antagonist: a possible mechanism for immune-to-brain communication. Brain Res Bull43 357 364 - 49.
Hansen MK & Krueger JM 1997 Subdiaphragmatic vagotomy blocks the sleep- and fever-promoting effects of interleukin-1beta. Am J Physiol 273, R1246 R1253. - 50.
Hermann GE, Emch GS, Tovar CA, & Rogers RC 2001 c-Fos generation in the dorsal vagal complex after systemic endotoxin is not dependent on the vagus nerve. Am J Physiol Regul Integr Comp Physiol 280, R289 R299. - 51.
Hess A. Zapata P. 1972 Innervation of the cat carotid body: normal and experimental studies. Fed Proc31 1365 1382 - 52.
Hotchkiss RS & Karl IE 2003 The pathophysiology and treatment of sepsis. N Engl J Med348 138 150 - 53.
MD Howell Donnino. M. Clardy P. Talmor D. Shapiro N. I. 2007 Occult hypoperfusion and mortality in patients with suspected infection. Intensive Care Med33 1892 1899 - 54.
Huston J. M. Ochani M. Rosas-Ballina M. Liao H. Ochani K. Pavlov V. A. Gallowitsch-Puerta M. Ashok M. Czura C. J. Foxwell B. Tracey K. J. Ulloa L. 2006 Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis. J Exp Med203 1623 1628 - 55.
Kalia M. Davies R. O. 1978 A neuroanatomical search for glossopharyngeal efferents to the carotid body using the retrograde transport of horseradish peroxidase. Brain Res149 477 481 - 56.
Kawashima K. Fujii T. 2000 Extraneuronal cholinergic system in lymphocytes. Pharmacol Ther86 29 48 - 57.
Kawashima K. Fujii T. 2003 The lymphocytic cholinergic system and its biological function. Life Sci72 2101 2109 - 58.
Kirchheim HR 1976 Systemic arterial baroreceptor reflexes. Physiol Rev56 100 177 - 59.
Korach M. Sharshar T. Jarrin I. Fouillot J. P. Raphael J. C. Gajdos P. Annane D. 2001 Cardiac variability in critically ill adults: influence of sepsis. Crit Care Med29 1380 1385 - 60.
Ladino J. Bancalari E. Suguihara C. 2007 Ventilatory response to hypoxia during endotoxemia in young rats: role of nitric oxide. Pediatr Res62 134 138 - 61.
Lam SY, Tipoe GL, Liong EC, & Fung ML 2008 Chronic hypoxia upregulates the expression and function of proinflammatory cytokines in the rat carotid body. Histochem Cell Biol130 549 559 - 62.
MJ Lenczowski Van Dam. A. M. Poole S. Larrick J. W. Tilders F. J. 1997 Role of circulating endotoxin and interleukin-6 in the ACTH and corticosterone response to intraperitoneal LPS. Am J Physiol 273, R1870 R1877. - 63.
Libert C. 2003 Inflammation: A nervous connection. Nature421 328 329 - 64.
Liljestrand A. 1958 Neural control of respiration. Physiol Rev38 691 708 - 65.
Liu X. He L. Stensaas L. Dinger B. Fidone S. 2009 Adaptation to chronic hypoxia involves immune cell invasion and increased expression of inflammatory cytokines in rat carotid body. Am J Physiol Lung Cell Mol Physiol 296, L158 L166. - 66.
Mac Grory. B. O’Connor E. T. O’Halloran K. D. Jones J. F. 2010 The effect of pro-inflammatory cytokines on the discharge rate of vagal nerve paraganglia in the rat. Respir Physiol Neurobiol171 122 127 - 67.
Martin G. S. Mannino D. M. Eaton S. Moss M. 2003 The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med348 1546 1554 - 68.
Martin G. S. Mannino D. M. Moss M. 2006 The effect of age on the development and outcome of adult sepsis. Crit Care Med34 15 21 - 69.
JD Martinez Babu. R. V. Sharma G. 2009 Escherichia coli septic shock masquerading as ST-segment elevation myocardial infarction. Postgrad Med121 102 105 - 70.
Mascorro JA & Yates RD 1980 Paraneurons and paraganglia: histological and ultrastructural comparisons between intraganglionic paraneurons and extra-adrenal paraganglion cells. Adv Biochem Psychopharmacol25 201 213 - 71.
Mc Deigan G. E. Ladino J. Hehre D. Devia C. Bancalari E. Suguihara C. 2003 The effect of Escherichia coli endotoxin infusion on the ventilatory response to hypoxia in unanesthetized newborn piglets. Pediatr Res53 950 955 - 72.
Medvedev AE, Kopydlowski KM, & Vogel SN 2000 Inhibition of lipopolysaccharide-induced signal transduction in endotoxin-tolerized mouse macrophages: dysregulation of cytokine, chemokine, and toll-like receptor 2 and 4 gene expression. J Immunol164 5564 5574 - 73.
Meregalli A. Oliveira R. P. Friedman G. 2004 Occult hypoperfusion is associated with increased mortality in hemodynamically stable, high-risk, surgical patients. Crit Care 8, R60 R65. - 74.
Mignini F. Streccioni V. Amenta F. 2003 Autonomic innervation of immune organs and neuroimmune modulation. Auton Autacoid Pharmacol23 1 25 - 75.
Miksa M. Das P. Zhou M. Wu R. Dong W. Ji Y. Goyert S. M. Ravikumar T. S. Wang P. 2009 Pivotal role of the alpha(2A)-adrenoceptor in producing inflammation and organ injury in a rat model of sepsis. PLoS One 4, e5504. - 76.
Misset D. Martin C. Cariou A. Carlet J. Brun-Buisson C. Annane D. Activated Protein. C. Corticosteroids for. Human Septic. Shock . A. P. R. O. C. C. H. S. 2010 Ref Type: Internet Communication - 77.
Montarolo P. G. Passatore M. Raschi F. 1976 Carotid chemoreceptor influence on the cardiac sympathetic nerve discharge. Experientia32 480 481 - 78.
Natanson C. Danner R. L. Reilly J. M. Doerfler M. L. Hoffman W. D. Akin G. L. Hosseini J. M. Banks S. M. Elin R. J. Mac Vittie. T. J. . 1990 Antibiotics versus cardiovascular support in a canine model of human septic shock. Am J Physiol 259, H1440 H1447. - 79.
Nguyen H. B. Corbett S. W. Steele R. Banta J. Clark R. T. Hayes S. R. Edwards J. Cho T. W. Wittlake W. A. 2007 Implementation of a bundle of quality indicators for the early management of severe sepsis and septic shock is associated with decreased mortality. Crit Care Med35 1105 1112 - 80.
Nguyen H. B. Rivers E. P. Knoblich B. P. Jacobsen G. Muzzin A. Ressler J. A. Tomlanovich M. C. 2004 Early lactate clearance is associated with improved outcome in severe sepsis and septic shock. Crit Care Med32 1637 1642 - 81.
Novotny N. M. Lahm T. Markel T. A. Crisostomo P. R. Wang M. Wang Y. Ray R. Tan J. Al-Azzawi D. Meldrum D. R. 2009 beta-Blockers in sepsis: reexamining the evidence. Shock31 113 119 - 82.
Ohtsuka H. Ohki K. Tanaka T. Tajima M. Yoshino T. Takahashi K. 1997 Circulating tumor necrosis factor and interleukin-1 after administration of LPS in adult cows. J Vet Med Sci59 927 929 - 83.
Otto CM & Rawlings CA 1995 Tumor necrosis factor production in cats in response to lipopolysaccharide: an in vivo and in vitro study. Vet Immunol Immunopathol49 183 188 - 84.
Patel G. P. Grahe J. S. Sperry M. Singla S. Elpern E. Lateef O. Balk R. A. 2010 Efficacy and safety of dopamine versus norepinephrine in the management of septic shock. Shock33 375 380 - 85.
Patel GP, Gurka DP, & Balk RA 2003 New treatment strategies for severe sepsis and septic shock. Curr Opin Crit Care9 390 396 - 86.
Pavlov V. A. Wang H. Czura C. J. Friedman S. G. Tracey K. J. 2003 The cholinergic anti-inflammatory pathway: a missing link in neuroimmunomodulation. Mol Med9 125 134 - 87.
Perel A. 2008 Bench-to-bedside review: the initial hemodynamic resuscitation of the septic patient according to Surviving Sepsis Campaign guidelines--does one size fit all? Crit Care 12, 223. - 88.
BD Peres Melot. C. Lopes F. F. Nguyen B. V. Vincent J. L. 2002 The Multiple Organ Dysfunction Score (MODS) versus the Sequential Organ Failure Assessment (SOFA) score in outcome prediction. Intensive Care Med28 1619 1624 - 89.
Pinsky MR 2004 Dysregulation of the immune response in severe sepsis. Am J Med Sci328 220 229 - 90.
Povoa P. Carneiro A. H. 2010 Adrenergic support in septic shock: a critical review. Hosp Pract (Minneap )38 62 73 - 91.
Rassias AJ, Holzberger PT, Givan AL, Fahrner SL, & Yeager MP 2005 Decreased physiologic variability as a generalized response to human endotoxemia. Crit Care Med33 512 519 - 92.
Reyes E. P. Abarzua S. Martin A. Rodriguez J. Cortes P. P. Fernandez R. 2012 LPS-induced c-Fos activation in NTS neurons and plasmatic cortisol increases in septic rats are suppressed by bilateral carotid chemodenervation. Adv Exp Med Biol. In Press. - 93.
Reyes E. P. Fernandez R. Larrain C. Zapata P. 2007 Carotid body chemosensory activity and ventilatory chemoreflexes in cats persist after combined cholinergic-purinergic block. Respir Physiol Neurobiol156 23 32 - 94.
Riedemann NC, Guo RF, & Ward PA 2003 The enigma of sepsis. J Clin Invest112 460 467 - 95.
Rogausch H. Vo N. T. Del R. A. Besedovsky H. O. 2000 Increased sensitivity of the baroreceptor reflex after bacterial endotoxin. Ann N Y Acad Sci917 165 168 - 96.
Romanovsky AA, Ivanov AI, Berthoud HR, & Kulchitsky VA 2000 Are vagal efferents involved in the fever response to intraperitoneal lipopolysaccharide? J Therm Biol25 65 70 - 97.
Rosas-Ballina M. Tracey K. J. 2009 Cholinergic control of inflammation. J Intern Med265 663 679 - 98.
Sanlioglu S. Williams C. M. Samavati L. Butler N. S. Wang G. Mc Cray P. B. Jr Ritchie T. C. Hunninghake G. W. Zandi E. Engelhardt J. F. 2001 Lipopolysaccharide induces Rac1-dependent reactive oxygen species formation and coordinates tumor necrosis factor-alpha secretion through IKK regulation of NF-kappa B. J Biol Chem276 30188 30198 - 99.
Schletter J. Heine H. Ulmer A. J. Rietschel E. T. 1995 Molecular mechanisms of endotoxin activity. Arch Microbiol164 383 389 - 100.
Schmidt H. Muller-Werdan U. Hoffmann T. Francis D. P. Piepoli M. F. Rauchhaus M. Prondzinsky R. Loppnow H. Buerke M. Hoyer D. Werdan K. 2005 Autonomic dysfunction predicts mortality in patients with multiple organ dysfunction syndrome of different age groups. Crit Care Med33 1994 2002 - 101.
Schmidt H. Muller-Werdan U. Nuding S. Hoffmann T. Francis D. P. Hoyer D. Rauchhaus M. Werdan K. 2004 Impaired chemoreflex sensitivity in adult patients with multiple organ dysfunction syndrome--the potential role of disease severity. Intensive Care Med30 665 672 - 102.
Schmidt H. B. Heinroth K. Werdan K. 1999 Autonomic dysfunction in critically ill patients. In Yearbokk of Intensive Care and Energency Medicine, ed. Vincent JL,519 536 Springer, New York. - 103.
Schmidt H. B. Werdan K. Muller-Werdan U. 2001 Autonomic dysfunction in the ICU patient. Curr Opin Crit Care7 314 322 - 104.
Schueller P. O. Steiner S. Hennersdorf M. G. Strauer B. E. 2008 Cardiac chemoreflex sensitivity in critically ill patients. J Physiol Pharmacol 59 Suppl6 623 627 - 105.
Shen FM, Guan YF, Xie HH, & Su DF 2004 Arterial baroreflex function determines the survival time in lipopolysaccharide-induced shock in rats. Shock21 556 560 - 106.
Shu H. F. Wang B. R. Wang S. R. Yao W. Huang H. P. Zhou Z. Wang X. Fan J. Wang T. Ju G. 2007 IL-1beta inhibits IK and increases [Ca2+]i in the carotid body glomus cells and increases carotid sinus nerve firings in the rat. Eur J Neurosci25 3638 3647 - 107.
Simon F. Fernandez R. 2009 Early lipopolysaccharide-induced reactive oxygen species production evokes necrotic cell death in human umbilical vein endothelial cells. J Hypertens27 1202 1216 - 108.
Singer M. De Vitale S. V. D. Jeffcoate W. 2004 Multiorgan failure is an adaptive, endocrine-mediated, metabolic response to overwhelming systemic inflammation. Lancet364 545 548 - 109.
Singh S. Evans T. W. 2006 Organ dysfunction during sepsis. Intensive Care Med32 349 360 - 110.
Somers VK, Mark AL, & Abboud FM 1991 Interaction of baroreceptor and chemoreceptor reflex control of sympathetic nerve activity in normal humans. J Clin Invest87 1953 1957 - 111.
Stitt JT 1990 Passage of immunomodulators across the blood-brain barrier. Yale J Biol Med63 121 131 - 112.
Suzuki J. Bayna E. ME Dalle Lew W. Y. 2003 Nicotine inhibits cardiac apoptosis induced by lipopolysaccharide in rats. J Am Coll Cardiol41 482 488 - 113.
Tang GJ, Kou YR, & Lin YS 1998 Peripheral neural modulation of endotoxin-induced hyperventilation. Crit Care Med26 1558 1563 - 114.
Thaver D. Zaidi A. K. 2009 Burden of neonatal infections in developing countries: a review of evidence from community-based studies. Pediatr Infect Dis J 28, S3 S9. - 115.
Tracey K. J. Beutler B. Lowry S. F. Merryweather J. Wolpe S. Milsark I. W. Hariri R. J. Fahey T. J. I. I. I. Zentella A. JD Albert . 1986 Shock and tissue injury induced by recombinant human cachectin. Science234 470 474 - 116.
Turnbull AV & Rivier CL 1999 Regulation of the hypothalamic-pituitary-adrenal axis by cytokines: actions and mechanisms of action. Physiol Rev79 1 71 - 117.
Ulloa L. 2005 The vagus nerve and the nicotinic anti-inflammatory pathway. Nat Rev Drug Discov4 673 684 - 118.
van Dillen J. Zwart J. chutte J. an R. J. 2010 Maternal sepsis: epidemiology, etiology and outcome. Curr Opin Infect Dis23 249 254 - 119.
Vayssettes-Courchay C. Bouysset F. Verbeuren T. J. 2005 Sympathetic activation and tachycardia in lipopolysaccharide treated rats are temporally correlated and unrelated to the baroreflex. Auton Neurosci120 35 45 - 120.
ver Elst. K. M. Spapen H. D. Nguyen D. N. Garbar C. Huyghens L. P. Gorus F. K. 2000 Cardiac troponins I and T are biological markers of left ventricular dysfunction in septic shock. Clin Chem46 650 657 - 121.
Verna A. 1997 The Mammalian Carotid Body: morphological data. In The Carotid Body Chemoreceptors, ed. González C,1 29 Springer, New York. - 122.
Volk T. Kox W. J. 2000 Endothelium function in sepsis. Inflamm Res49 185 198 - 123.
Waage A. 1987 Production and clearance of tumor necrosis factor in rats exposed to endotoxin and dexamethasone. Clin Immunol Immunopathol45 348 355 - 124.
Wan W. Wetmore L. Sorensen C. M. Greenberg A. H. Nance D. M. 1994 Neural and biochemical mediators of endotoxin and stress-induced c-fos expression in the rat brain. Brain Res Bull34 7 14 - 125.
Wang H. Yu M. Ochani M. CA Amella Tanovic. M. Susarla S. Li J. H. Wang H. Yang H. Ulloa L. Al-Abed Y. Czura C. J. Tracey K. J. 2003 Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature421 384 388 - 126.
Wang X. Wang B. R. Duan X. L. Zhang P. Ding Y. Q. Jia Y. Jiao X. Y. Ju G. 2002 Strong expression of interleukin-1 receptor type I in the rat carotid body. J Histochem Cytochem50 1677 1684 - 127.
Wang X. Zhang X. J. Xu Z. Li X. Li G. L. Ju G. Wang B. R. 2006 Morphological evidence for existence of IL-6 receptor alpha in the glomus cells of rat carotid body. Anat Rec A Discov Mol Cell Evol Biol288 292 296 - 128.
Watkins L. R. Goehler L. E. Relton J. K. Tartaglia N. Silbert L. Martin D. Maier S. F. 1995 Blockade of interleukin-1 induced hyperthermia by subdiaphragmatic vagotomy: evidence for vagal mediation of immune-brain communication. Neurosci Lett183 27 31 - 129.
Watson RS & Carcillo JA 2005 Scope and epidemiology of pediatric sepsis. Pediatr Crit Care Med 6, S3 S5. - 130.
Yang FL, Li CH, Hsu BG, Tsai NM, Lin SZ, Harn HJ, Chen HI, Liao KW, & Lee RP 2007 The reduction of tumor necrosis factor-alpha release and tissue damage by pentobarbital in the experimental endotoxemia model. Shock28 309 316 - 131.
Yucel T. Memis D. Karamanlioglu B. Sut N. Yuksel M. 2008 The prognostic value of atrial and brain natriuretic peptides, troponin I and C-reactive protein in patients with sepsis. Exp Clin Cardiol13 183 188 - 132.
Zapata P. Larrain C. Fernandez R. 2002 Nicotine-evoked ventilatory reflexes in cats: sites of origin and afferents. J Anat 200, 204. - 133.
Zapata P. Larrain C. Fernandez R. Reyes E. P. 2003 Cholinergic actions on carotid chemosensory system. Adv Exp Med Biol536 277 283 - 134.
Zapata P. Larrain C. Reyes P. Fernandez R. 2011 Immunosensory signalling by carotid body chemoreceptors. Respir Physiol Neurobiol178 370 374 - 135.
Zhang X. J. Wang X. Xiong L. Z. Fan J. Duan X. L. Wang B. R. 2007 Up-regulation of IL-1 receptor type I and tyrosine hydroxylase in the rat carotid body following intraperitoneal injection of IL-1beta. Histochem Cell Biol128 533 540