A variety of laboratory and clinical studies indicate that anesthetic agents may lead to cardioprotective effects against injury (1, 2). The anesthetic agents protect the myocardium through a complex “preconditioning” mechanism, which mediates cardioprotection by activating protecting enzymes in the signaling pathways and changing the structure of the protective proteins in the heart (3, 4). Severe injuries induce immune suppression, predisposing victims to postinjurious complications (5–7). Anesthetic agents possess potential anti-inflammatory effects, which would result in the reduction of cytokine production, the alteration of the expression of nitric oxide, and the inhibition of neutrophil function (8–10). Anesthetic agents might also act as antioxidants (9). Thus, by modulating the stress response mediated by injuries, anesthetic agents might indirectly affect the immune system. This article provides a brief overview of potential use of anesthetic agents to protect both cardiovascular and immune functions against injuries and a discussion of the possible mechanism of cardioprotection and immunity modulation.
CARDIOPROTECTION BY ANESTHETIC AGENTS
Volatile anesthetic agents provide a myocardial protection when they are administered before myocardial ischemia (i.e., anesthetic preconditioning) (3). Isoflurane preconditioning has been shown to attenuate myocardial ischemia and reperfusion injury in patients undergoing coronary artery bypass graft surgery (2). Caveolins are structural proteins found in caveolae that have scaffolding properties to allow organization of signaling (11). Isoflurane-induced preconditioning involves translocation of caveolin 3 and glucose transporter 4 to caveolae, resulting in protection in the myocardium (11). One possible mechanism of anesthetic preconditioning is the activation of the transcription factor hypoxia-inducible factor 1α and its target gene responses (12). That the pharmacologic activation of the hypoxia-inducible factor 1α is organ protective and the upregulation of hypoxia-inducible factor 1α is led by isoflurane would correlate the anesthetic preconditioning of isoflurane (12, 13). Sevoflurane-induced preconditioning is strengthened by multiple preconditioning cycles, and phosphorylation of endothelial nitric oxide synthase is a critical step in mediating sevoflurane-induced preconditioning (3). However, these effects are abolished by aprotinin (3). Sevoflurane-induced preconditioning also reduces infarct size in isolated rat hearts and activates different signaling kinases, indicating the existence of different cardioprotective intracellular signaling cascades (14). 5′-adenosine monophosphate (AMP)–activated protein kinase, a well-known regulator of cellular energy status, is also implicated in ischemic preconditioning leading to cardioprotection (1). Lamberts et al. (1) reported that reactive oxygen species–induced stimulation of 5′-AMP–activated protein kinase mediated sevoflurane-induced cardioprotection. Sevoflurane preconditioning provides cardioprotection against ischemia and reperfusion injury in a rodent model and limits nuclear factor κB activation and the production of proinflammatory cytokines (15). In addition, sevoflurane administered before hypoxia exerts cardioprotective effects against hypoxia-reoxygenation injury in the isolated rat heart (16). Activation of heat shock protein 70 is known to be cardioprotective (17, 18). Sevoflurane preconditioning–induced upregulation of heat shock protein 70 is reported to be protective against myocardial ischemia-reperfusion injury (19). Desflurane-induced preconditioning reduces the myocardial infarct size in a rabbit model of 30-min coronary artery occlusion followed by a 3-h reperfusion, but the pharmacologic activation of adenosine monophosphate–activated protein kinase abolishes cardioprotection elicited by desflurane (20). In addition to protection of the heart against necrosis and contractile dysfunction, isoflurane-induced preconditioning has been reported to decrease arrhythmias and improve regional conduction in isolated hearts (21). Postinfarct remodeling in the heart may affect protective signaling (22). Myocardial preconditioning with isoflurane retains its protection against ischemia and reperfusion injury in postinfarct remodeling rat hearts via similar signaling pathways, as previously reported in healthy hearts (22). The use of desflurane in patients undergoing coronary artery bypass graft surgery provides a pharmacologic preconditioning so as to reduce myocardial necrosis and improve cardiac performance in the postoperative period (23).
Mechanism of anesthetic preconditioning in the heart
From animal and clinical studies, it is known that multiple cycles of anesthetic-induced preconditioning strengthened the cardioprotective effect. Cellular mechanisms involved in anesthetic preconditioning are now better understood.
Calcium ion homeostasis
Because of the overproduction of calcium ion, prolonged ischemia and reperfusion induce severe myocardial injury, resulting in the impairment of energy production and subsequent cellular adenosine triphosphate–sensitive potassium depletion (24). Calcium overload during reperfusion is two and a half times greater in the isolated hypertrophied rat hearts than in the control hearts and shows significant relationships of recovery of left ventricular systolic function with left ventricular end-diastolic pressure (24). The homeostasis of calcium ion contributes directly to myocardial function during both ischemia and anesthetic preconditioning (4). Ischemia and reperfusion injury–induced depression in cardiac performance is associated with a downregulation of the major calcium ion–cycling proteins (25). The pretreatment with inhaled anesthetic agents is documented to protect the heart by reducing calcium ion loading (4). Anesthetic preconditioning with isoflurane prevents ischemia and reperfusion injury–related degradation of the calcium ion release channels and calcium ion–adenosine triphosphatase in the sarcoplasmic reticulum (25). Cellular injury of cardiac myocytes is greatly determined by sarcoplasmic reticulum calcium ion handling (26, 27). When given during the reoxygenation stage of ischemia and reperfusion injury, isoflurane results in the blockade of the release of the calcium ions from sarcoplasmic reticulum and the inhibition of calcium ion efflux (26). Hannon et al. (28) reported that the administration of isoflurane and sevoflurane led to a decrease in intracellular calcium ion and alteration of sensitivity to calcium ions in ventricular myocytes. Consistent with these findings, halothane and isoflurane also decrease the availability of myoplasmic calcium ions and the sensitivity to calcium ions in ferret cardiac muscle (29, 30). Furthermore, isoflurane-induced preconditioning triggers persistent changes in the inactivation of L-type calcium channel, leading to a reduction of calcium ion influx and attenuation of calcium ion overload during ischemia and reperfusion injury (31). The decrease in accumulation of both intracellular and mitochondrial calcium ions during ischemia and reperfusion observed in sevoflurane preconditioning is associated with greater adenosine triphosphate–sensitive potassium recovery and would diminish cell injury in newborn myocardium (32). The blockade of mitochondrial adenosine triphosphate–sensitive potassium channels attenuates the sevoflurane preconditioning during ischemia and reperfusion, suggesting that adenosine triphosphate–sensitive potassium channels are involved in the protective effects of sevoflurane preconditioning in the newborn (32). In addition to volatile anesthetic agents, propofol has been shown to provide cardioprotective effects, likely by affecting sarcoplasmic reticulum calcium ion handling (33, 34).
Adenosine triphosphate–sensitive potassium channels
Adenosine triphosphate–sensitive potassium channels are coupled with energy metabolism and serve as a unique cellular role among signal transduction cascades (4, 35, 36). Adenosine triphosphate–sensitive potassium channels are reported to be end-effectors of preconditioning, and the opening of adenosine triphosphate–sensitive potassium channels may lead to depolarization of the mitochondrial membrane (4). A lot of investigators find that adenosine triphosphate–sensitive potassium channels play an essential role in mediating anesthetic preconditioning with the use of adenosine triphosphate–sensitive potassium-channel blockers in animal models and experimental conditions (4). Sevoflurane preconditioning elicits a potent threshold-dependent protective effect, and blockers of adenosine triphosphate–sensitive potassium channels (glibenclamide and 5-hydroxydecanoic acid) counteract the protection produced by early sevoflurane preconditioning (37). Adenosine-enhanced ischemic preconditioning extends the protection afforded by ischemic preconditioning by both decreasing infarct size and enhancing postischemic functional recovery (38). Two types of adenosine triphosphate–sensitive potassium channels exist in cardiomyocytes, including the mitochondrial adenosine triphosphate–sensitive potassium channels and sarcolemmal adenosine triphosphate–sensitive potassium channels (4). Previous studies have shown that adenosine-enhanced ischemic preconditioning infarct size reduction is modulated by mitochondrial adenosine triphosphate–sensitive potassium channels primarily during ischemia, and functional recovery is modulated by sarcolemmal adenosine triphosphate–sensitive potassium channels during ischemia and reperfusion (38). Isoflurane is found to modulate sarcolemmal adenosine triphosphate–sensitive potassium channels in anesthetic preconditioning (39). The activation of mitochondrial adenosine triphosphate–sensitive potassium channels has been reported to contribute to the anesthetic preconditioning by isoflurane and sevoflurane (40, 41). Opening of mitochondrial adenosine triphosphate–sensitive potassium channels, followed by superoxide signaling, induces postischemic augmentation of manganese superoxide dismutase and preservation of mitochondrial respiratory enzyme activities, leading to an attenuation of cardiac superoxide surge, the restoration of adenosine triphosphate–sensitive potassium production during reperfusion, and the underlying of isoflurane preconditioning-induced cardioprotection (42). Hanouz et al. (43) also suggested that mitochondrial adenosine triphosphate–sensitive potassium channels contributed to desflurane-induced preconditioning effect in isolated human right atria. Toller et al. (44) found that desflurane reduced experimental myocardial infarct size by activating specific sarcolemmal and mitochondrial adenosine triphosphate–sensitive potassium channels in dogs.
With a preconditioning stimulus, the nitric oxide synthase mediates the release of nitric oxide, a unique signaling messenger that would later trigger anesthetic preconditioning (4). The nitric oxide released would then protect against ischemia-reperfusion–induced myocardial dysfunction, cell death, or neurotoxicity (45). Documented study results show that heat shock protein 90 plays a critical role in mediating anesthetic preconditioning through protein-protein interaction, and endothelial cells are important contributors to nitric oxide–mediated signaling during anesthetic preconditioning (46). Desflurane induces a first (0.5–2 h) and a second window of anesthetic preconditioning (24–72 h) in the rabbit model of acute myocardial infarction, and the second window of anesthetic preconditioning is mediated by nitric oxide (47). The second window of anesthetic preconditioning is afforded by multiple signaling pathways (48). Desflurane is reported to govern a second window of anesthetic preconditioning by increasing 15-deoxy-12,14-prostaglandin J (2), subsequently activating peroxisome proliferator–activated receptor γ, resulting in a diminished myocardial infarct size by increasing the downstream of nitric oxide (48). In addition, desflurane-induced anesthetic postconditioning seems to be mediated by nitric oxide in an animal model of coronary artery occlusion (49). Fradorf et al. found that sevoflurane-induced anesthetic preconditioning reduced infarct size in the rat heart and induced nitric oxide synthase phosphorylation (3). The findings suggest that sevoflurane-induced anesthetic preconditioning is strengthened by multiple preconditioning cycles, and phosphorylation of endothelial nitric oxide synthase is a crucial step in mediating sevoflurane-induced anesthetic preconditioning (3). Isoflurane pretreatment improves regional cerebral blood flow and increases the regional oxygen consumption in the focal ischemic area; however, the isoflurane-induced increase in regional cerebral blood flow in the ischemic area becomes insignificant with inhibition of inducible nitric oxide synthase (50). Chen et al. (51) reported that nitric oxide generated immediately after isoflurane exposure triggered downstream activation of nuclear factor κB, resulting in subsequent upregulation of inducible nitric oxide synthase expression and nitric oxide synthesis that mediate anesthetic preconditioning–induced cardioprotection.
Preconditioning results in the activation of multiple kinases that translocation and phosphorylation in the parallel signaling pathways may provide protection against ischemia and reperfusion injury (4). Sevoflurane-induced stimulation of AMP-activated protein kinase protects the heart against ischemia and reperfusion injury and relies on upstream production of reactive oxygen species (1). The protein kinase C family has been implicated as an important upstream of the closely associated mitochondrial adenosine triphosphate–sensitive potassium channels (4). Isoflurane preconditioning induces endothelial protection against in vitro–stimulated ischemia, and the protection may be mediated by conventional protein kinase C and mitochondrial adenosine triphosphate–sensitive potassium channels (52). In addition, isoflurane preconditioning induces delay of opening of mitochondrial permeability transition pore through the opening of protein kinase Cε–mediated mitochondrial permeability transition pore (53). Intramyocyte translocation of protein kinase C is known to be a key mediator in anesthetic preconditioning (54). Sevoflurane preconditioning has been reported to induce the maintenance of translocation of protein kinase C in isolated perfused guinea pig hearts (54). Mitogen-activated protein kinases are other important signaling elements of the signal transduction for anesthetic preconditioning (4). Sevoflurane preconditioning can induce neuroprotection against oxygen and glucose deprivation injury in vitro, and the activation of extracellular signal–regulated protein kinase seems to be involved in the process (55). Consistent with these findings, sevoflurane preconditioning induces rapid tolerance to spinal cord ischemia and reperfusion in rabbits, and the tolerance is likely mediated through the activation of extracellular signal–regulated protein kinase (56). Sevoflurane is reported to be involved in the activation of p38 mitogen–activated protein kinase in Jurkat T cells (57).
Reactive oxygen species
Reactive oxygen species are thought to be essential components of cardiac injury (58). Anesthetic-induced preconditioning with isoflurane stimulates generation of reactive oxygen species and elicits competent protective mechanisms in human embryonic stem cell–derived cardiomyocytes against oxidative stress (59). Scientists frequently use isolated mitochondria for bioenergetic studies, so the regulatory roles of other cellular compartments are neglected to express the thorough function of mitochondria (60). Isoflurane exhibits complex effects on the electron transport chain in intact cardiomyocytes, altering its electron fluxes and thereby enhancing reactive oxygen species production (60). Isoflurane can also enhance the accumulation of reactive oxygen species and induce apoptosis by regulating Bcl-2 family proteins (61). Preconditioning with sevoflurane or desflurane protects isolated rat cardiomyocytes from oxidative stress–induced cell death; however, scavenging of reactive oxygen species abolishes the preconditioning effect of both anesthetic agents and attenuates anesthetic-induced mitochondrial uncoupling, suggesting a crucial role for reactive oxygen species in the anesthetic-induced preconditioning and implying that reactive oxygen species act upstream of mitochondrial uncoupling (62). Sevoflurane and desflurane protect human myocardium against hypoxia through a reactive oxygen species–dependent mechanism (63). Yang et al. (64) reported that sevoflurane preconditioning induced cerebral ischemic tolerance in a dose-response manner through the release of reactive oxygen species and the consequent upregulation of antioxidant enzyme activity before ischemic injury in rats. Yao et al. (65) found that sevoflurane protected isolated rat hearts against ischemia-reperfusion injury via the recruitment of the reactive oxygen species, the extracellular signal–regulated protein kinase, and the mitochondrial permeability transition pore signaling cascade.
Guanine nucleotide-binding proteins
Guanine nucleotide-binding proteins are essential second messengers among various signaling pathway. Preconditioning causes the activation of various receptors and the generations of other free radicals that then transmit signals through guanine nucleotide-binding proteins leading to the formation of inositol triphosphate and production of diacylglycerol and causing the activation of protein kinases, phosphorylation of ADP, and the enhancement of opening of adenosine triphosphate–sensitive potassium channels (4). Isoflurane reduces myocardial infarct size by an inhibitory guanine nucleotide-binding protein-mediated mechanism in vivo (66). Pentyala et al. (67) reported that isoflurane and sevoflurane, at clinically relevant doses, had a direct effect on the conformation and stability of guanine nucleotide-binding proteins.
Taken together, volatile anesthetic agents may induce the activation of protein kinase through interacting with receptors via guanine nucleotide-binding proteins. Protein kinases may activate the opening of adenosine triphosphate–sensitive potassium channels and then modulate the formation of reactive oxygen species (4). Calcium ion homeostasis may mediate the activation of adenosine triphosphate–sensitive potassium channels. A variety of intracellular signaling pathways are involved in anesthetic preconditioning (Fig. 1). A better and more thorough understanding of the multiple signaling steps and the underlying mechanisms may lead to the improvements in cardioprotection.
ANESTHETIC AGENTS AS IMMUNOLOGIC MODULATORS
Natural killer cells
Natural killer (NK) cells are important in the elimination of tumor target cells at the early stage of tumor development. However, NK cells would become activated and harmful during sepsis (68, 69). Documented study results showed that the mice that were depleted of NK cells were resistant to injury caused by cecal ligation and puncture (70). The decrease in cecal ligation and puncture-induced mortality rate observed in NK cell–deficient mice is associated with the decreased metabolic acidosis, less hypothermia, and an attenuated proinflammatory response (68). The anesthetic agents may decrease the cytotoxicity of NK cells (71–73). The preponderance of evidence from both animal and human studies suggests that inhalational agents, e.g., halothane, isoflurane, and sevoflurane, suppress NK cell activity (71–73). Natural killer cell activity is suppressed in rats subjected to a laparotomy during general halothane anesthesia (71). Bar-Yosef et al. (71) also found that NK cell activity is suppressed to a similar extent by surgery and by anesthesia alone. Similar inhibition of NK activity by anesthesia and surgery is again observed in humans (72). Kutza et al. (72) reported a significant decrease in human basal and interferon α–stimulated NK cytotoxicity. The level of NK activity obtained with interferon stimulation after surgery is lower than the level of NK activation achieved preoperatively with interferon, and interferon restores the level of NK activity to the basal level seen before surgery (72). Mice subjected to laparotomy during general anesthesia with sevoflurane alone or combined with spinal block achieved with bupivacaine are also tested to determine whether regional anesthesia improves postoperative NK activity related to the stress response to surgery and general anesthesia (73). The addition of spinal block to sevoflurane general anesthesia accompanying surgery attenuates the suppression of NK activity (73). Further studies may be required to determine the mechanisms of anesthetic agents on NK cell activation and determine how anesthetic agents might attenuate NK cell–induced inflammatory response following injury.
Prostanoids, including prostaglandins (PGs) and thromboxanes, are abundant at the site of inflammation (74, 75). Prostaglandin E2 is especially important in both modulating inflammation and determining the characteristics of the immune reaction (74). Although many immune cells can produce PGE2, macrophages are considered to be one of the most powerful cells in the modulation of inflammation and immune function through their abilities to produce a large amount of PGE2 (74). Prostanoids are produced by cyclooxygenase (COX) and specific prostanoid synthases. The COX enzyme has at least two isoforms; COX-1 is constitutively expressed in most cells, whereas COX-2 expression is undetectable during the resting state and is induced dramatically upon stimulation. Inada et al. (76) found that intravenous anesthetic agents, e.g., propofol, suppress COX activity in murine peritoneal macrophages, leading to a decreased PGE2 production. Most studies of the effects of anesthetic agents on monocyte and macrophage functions are based on the investigations of the functions of alveolar macrophages. Volatile anesthetic agents, e.g., sevoflurane and desflurane, decrease the alveolar macrophage in bronchoalveolar lavage fluid and induce significant apoptosis in the lung tissue in the animal model of ventilator-induced lung injury (77). These findings are accompanied by atelectasis and inflammatory cell infiltration. However, propofol causes only a minor degree of inflammation and preserves cell composition in the bronchoalveolar lavage fluid without triggering apoptosis (77). In an in vitro lipopolysaccharide-stimulated macrophage inflammation model, isoflurane preconditioning attenuates the cell injury and the decrease in cell viability (78). Pretreatment of isoflurane induces heme oxygenase 1 protein expression and causes an induction of heme oxygenase activity. The findings correlate with a decrease in inducible nitric oxide synthase expression, a decrease in the production of nitric oxide, and impaired release of cytokines in lipopolysaccharide-stimulated macrophages (78). Xu et al. (79) also found that isoflurane preconditioning reduced the rat macrophage injury induced by lipopolysaccharide and interferon γ. Pretreatment with 2% isoflurane inhibited lipopolysaccharide plus interferon γ–induced accumulation of nitrite in the rat macrophages and improved cell viability. The protective effects of isoflurane were abolished by chelerythrine, calphostin C, or protein kinase C inhibitors (79). Halothane anesthesia might have beneficial effects on the inflammatory response mediated by peritoneal macrophages (80). The ex vivo peritoneal macrophage respiratory burst and phagocytic activity showed a higher response in anesthetized animals compared with the nonanesthetized animals (80). Inhalational agents are shown to reduce ischemia-reperfusion injury in various organs. Annecke et al. (81) showed that the severity of remote lung injury was not different between sevoflurane and propofol anesthesia in a porcine model of thoracic aortic occlusion and reperfusion. They found that there were no significant differences between sevoflurane and propofol with respect to the oxygenation index, composition in epithelial lining fluid, morphologic lung damage, wet-to-dry weight ratio, and alveolar macrophage burst activity. Lee et al. (82) demonstrated that isoflurane protected against renal ischemia and reperfusion injury by producing anti-inflammatory effects in mice. Mice subjected to renal ischemia and reperfusion injury under isoflurane anesthesia showed a reduction of inflammation, which was evidenced by a reduced influx of macrophages, a reduced intercellular adhesion molecule 1 expression, and a lesser production of proinflammatory mediators (tumor necrosis factor- α and interleukin 1β [IL-1β]) at 24 h after renal ischemia and reperfusion injury. Taken together, macrophage cell modulation may play a significant role in organ protection by anesthetic agents.
Various studies show that the anesthetic agents inhibit the proliferation of lymphocytes and suppress the release of cytokines in peripheral blood mononuclear cells (83, 84). Rodent splenic T cells anesthetized with 1% halothane for 5 h showed a reduced capacity of proliferation (83). Inhalational agents, such as isoflurane and sevoflurane, suppress the release of IL-1β and tumor necrosis factor α from human peripheral blood mononuclear cells (84). In addition, Beilin et al. (85) reported that small doses of ketamine (0.15 mg/kg) given to patients undergoing abdominal surgery before induction of general anesthesia resulted in the attenuation of secretion of the proinflammatory cytokines tumor necrosis factor α and IL-6 from human peripheral blood mononuclear cells. They suggested that small doses of ketamine may be of value in preventing the alteration of immune functions of peripheral blood mononuclear cells in the early postoperative period (85). Schneemilch et al. (86) found that both thiopental and nitrous oxide inhibited the proliferation of human peripheral blood mononuclear cells, and the inhibitory effects of these two agents were compensated by sevoflurane when sevoflurane was added to either of two. These findings suggest that sevoflurane may have a beneficial effect to attenuate the immunosuppressive effects of thiopental and nitrous oxide. It is suggested that the activation and differentiation of helper T cells are required for anti-infection immunity (87). Propofol stimulates the activation and differentiation of helper T cells and increases the CD4+ CD8+ percentage and the ratio of interferon γ to IL-4 in patients undergoing lung surgery (87). Li et al. (88) demonstrated that the in vitro treatment of propofol suppressed endocytosis of human peripheral blood mononuclear cells likely through the regulatory cytokine transforming growth factor β1 pathway, because the effect is abrogated by the transforming growth factor β1 pathway inhibitor SB431542. Yuki et al. (89) showed that isoflurane and sevoflurane bounded and blocked integrin lymphocyte function–associated antigen 1. They suggested that isoflurane and sevoflurane at clinically relevant concentrations inhibited the ligand-binding function of lymphocyte function–associated antigen 1, and the allosteric mode of action exemplified by sevoflurane and isoflurane via lymphocyte function–associated antigen 1 might represent one of the underlying mechanisms of anesthetic-mediated immunomodu lation (89). The inhibitory effects of anesthetic agents on lymphocyte function may reduce the immunocapacity of these cells against microorganisms. However, these inhibitory effects may contribute to anti-inflammatory responses, especially by regulating the secretion of proinflammatory cytokines implicated in the pathophysiology of systemic infection (90).
Apoptosis plays a central role in immune alterations following surgery, and there are increasing evidence suggesting that apoptosis is mainly responsible for the changes commonly seen in the early postoperative period in cells such as lymphocytes (91). Transient immune deficiency syndrome along with lymphocytopenia, commonly seen in the early postoperative period after surgical trauma, may be dependent on the increased lymphocyte commitment to apoptosis (91). Previous studies of patients undergoing open major abdominal surgery showed that the percentage of total peripheral blood lymphocytes counts decreased after general anesthesia, and the progression of programmed cell death was promoted (91). Matsuoka et al. (92) reported that isoflurane and sevoflurane induced apoptosis in human peripheral lymphocytes in a dose-dependent manner. These findings indicate that the induction of apoptosis is accompanied by the elevated caspase 3 activity in lymphocytes (92). Loop et al. (93) reported that sevoflurane and isoflurane induced apoptosis in T lymphocytes via increased mitochondrial membrane permeability and caspase 3 activity. These findings indicated that the apoptotic signaling pathway used by sevoflurane involved in the disruption of the mitochondrial membrane potential and the release of cytochrome C from mitochondria to the cytocol and sevoflurane-induced apoptosis was blocked by general caspase inhibitor Z-VAD.fmk (93). Loop et al. (94) also found that sevoflurane inhibited the activation of the transcription factor activator protein 1 in human T lymphocytes and might thus provide a molecular mechanism for the anti-inflammatory effects associated with the administration of sevoflurane. Sevoflurane inhibits the transcription factor activator protein 1 especially; however, isoflurane and desflurane do not affect activator protein 1 (94). Sevoflurane inhibits activator protein 1–driven reporter gene and the expression of the activator protein 1 target gene IL-3 (94). Suppression of activator protein 1 is associated with phosphorylation of p38 mitogen–activated protein kinases. Roesslein et al. (57) reported that sevoflurane-mediated activation of p38 mitogen–activated stress kinase was independent of apoptosis in T cells. They found that sevoflurane exposure induced p38 phosphorylation and did not affect the mitogen-activated protein kinases ERK and JNK (57). Sevoflurane-induced phosphorylation of p38 is not prevented by pretreatment of T cells with general caspase inhibitor, and sevoflurane-mediated caspase 3 processing and apoptosis cannot be prevented by pretreatment with the specific p38 mitogen–activated protein kinase inhibitor SB203580 (57).
The enhanced secretion of proinflammatory cytokines is an important factor in the initiation and perpetuation of organ injury (95–99). These cytokines recruit other immune cells including neutrophils, thereby increasing leukocyte trafficking and organ injury (100–103). Neutrophils can release mediators, which diffuse across the endothelium and injure parenchymal cells, or alternatively, neutrophils can leave the microcirculation and migrate to and adhere to matrix proteins or other cells (104–106). Intercellular adhesion molecule 1 is known to play a major role in the firm adhesion of neutrophils to the vascular endothelium. Intercellular adhesion molecule 1 is constitutively present on the surface of endothelial cells and is markedly upregulated following trauma-hemorrhagic shock (107–109). In addition to adhesion molecules, members of the CXC chemokine family, such as cytokine-induced neutrophil chemoattractant 1 and cytokine-induced neutrophil chemoattractant 3, are also potent chemotactic factors for neutrophils (110,111). The activation of heme oxygenase 1 is proved to reduce organ injury following injury (112–114). Lv et al. (115) reported that pretreatment with isoflurane could be sufficient to activate heme oxygenase 1 and attenuate the hepatic injuries and inflammatory responses caused by ischemia and reperfusion in rats. Clinical relevant doses of isoflurane attenuate ischemia and reperfusion–induced neutrophil infiltration in the liver by increasing heme oxygenase 1 expression and activity (115). However, Frithiof et al. (116) found that isoflurane anesthesia (minimum alveolar concentration 1.0) with mechanical ventilation aggravated renal dysfunction and enhanced neutrophil activity and accumulation in the kidney during 48 h of endotoxemia in sheep. Kong et al. (117) reported that sevoflurane anesthesia could attenuate renal injury and neutrophil infiltration in the kidney in a rodent model of small-liver transplantation. The findings indicated that sevoflurane anesthesia reduced neutrophil gelatinase-associated lipocalin, an early predicative biomarker of acute kidney injury, and plasma tumor necrosis factor α and IL-6 concentrations (117). Sevoflurane attenuates the pulmonary sequestration of neutrophil and preserves the pulmonary consumption of cytokines (IL-6, IL-8, and tumor necrosis factor α) after cardiopulmonary bypass (118). Preconditioning with sevoflurane also reduces pulmonary neutrophil accumulation after lower body ischemia and reperfusion injury in rats (119).
Propofol is often administered to critically ill patients as a sedative or anesthetic. Patients with peritonitis, infection, or sepsis may sometimes receive propofol for sedation. Propofol is shown to modulate various inflammatory responses. Propofol decreases production of proinflammatory cytokines, alters expression of nitric oxide, and inhibits neutrophil function (9). Administration of propofol in rats with endotoxemia significantly reduced production of the proinflammatory cytokines tumor necrosis factor α, IL-1, and IL-6 (120, 121). Chen et al. (122) demonstrated that either pretreatment or posttreatment with propofol in oleic acid–induced, acute-lung-injured rats significantly reduced the production of proinflammatory cytokines (i.e., tumor necrosis factor α, IL-1β, and IL-6), nitrate/nitrite (as nitric oxide metabolites), and Na, K-ATPase, neutrophil elastase, myeloperoxidase, and malondialdehyde (as a marker for oxidative stress) in the plasma. The administration of propofol also attenuated protein concentration in bronchoalveolar lavage fluid and the expression of inducible nitric oxide synthase in the lung (122). A wide-range improvement of lung functions including epithelial transport with propofol is thus observed in oleic acid–induced acute lung injury (122). Propofol also attenuates production of IL-6 production from lipopolysaccharide-stimulated polymorphonuclear cells (123). In polymorphonuclear neutrophils, phagocytosis and respiratory burst activity are mainly responsible for killing bacteria. Erol et al. (124) showed that propofol anesthesia increased the respiratory burst function of polymorphonuclear neutrophils in bronchoalveolar lavage fluid from patients undergoing tympanoplasty surgery. Propofol is reported to produce a dose-dependent inhibition of phagocytosis and superoxide anion production during the respiratory burst of polymorphonuclear cells in vitro (125). To decrease the intracellular calcium might be the mechanism responsible for the inhibition of neutrophil function by propofol (125). Heine et al. (126) reported that the percentage of polymorphonuclear cells with respiratory burst activity following tumor necrosis factor α/formyl-methionyl-leucyl-phenylalanine stimulation was reduced after 2 and 4 h of anesthesia with propofol. An et al. (127) found that the propofol administered during cardiopulmonary bypass could reduce intrapulmonary polymorphonuclear neutrophil sequestration. Propofol attenuates the severity of pulmonary dysfunction and production of proinflammatory mediator IL-8 and malondialdehyde (127). In addition to attenuating the production of proinflammatory cytokines, propofol may have additional effects to modulate the production of nitric oxide (128). A clinically relevant concentration of propofol can inhibit the production of nitric oxide and the geneexpression of inducible nitric oxide synthase in the lipopolysaccharide-activated macrophage-like cells (8). The suppressive mechanism may occur through sequential downregulation of toll-like receptor 4/mitogen-activated protein kinase/activator protein 1 activation (8). Hsing et al. (129) reported that propofol reduced lipopolysaccharide-induced inducible nitric oxide, nitric oxide, and the proinflammatory cytokines tumor necrosis factor α and IL-6 in murine macrophages. The findings suggest that propofol reduces lipopolysaccharide-induced inflammatory responses in macrophages by inhibiting the interconnected reactive oxygen species/Akt/nuclear factor κB signaling pathways (129). Propofol may attenuate nitric oxide–induced renal tubular cell apoptosis by downregulating the expression of inducible nitric oxide synthase in an animal model of unilateral ureteral obstruction (130). Propofol treatment for 10 min induces a concentration-dependent increase in the phosphorylation of endothelial nitric oxide synthase at Ser(1177) and the production of nitric oxide; however, protein kinase C inhibitors block propofol-induced endothelial nitric oxide synthase and the production of nitric oxide in human umbilical vein endothelial cells (131). These findings suggest that propofol may induce the Ser(1177) phosphorylation-dependent endothelial nitric oxide synthase activation through the translocation of protein kinase C isoforms to distinct sites (131). In addition, Wang et al. (132) found that propofol reduced hydrogen superoxide–induced damage and apoptosis in human umbilical vein endothelial cells, by suppressing caspase 3 activity and by increasing endothelial nitric oxide synthase expression via an Akt-independent mechanism. Propofol also possesses antioxidant property. The use of propofol to induce and maintain anesthesia prevents intestinal ischemia and reperfusion–induced lung injury in experimental animals (133). Propofol demonstrates beneficial effects on systemic antioxidant protection, improvement of intestinal injury, and inhibition of the inflammatory response and preserved the alveolar-capillary permeability in a rodent model of intestinal ischemia and reperfusion injury (133). Ischemia and reperfusion–induced renal injury in rats is reduced in the presence of propofol possibly due to its antioxidant properties (134). Tumor necrosis factor α exacerbates myocardial injury by inducing endothelial apoptosis, and L-arginine exacerbates tumor necrosis factor α–induced endothelial apoptosis by enhancing peroxynitrite-mediated nitrative stress (135). Propofol attenuates the L-arginine–mediated enhancement of nitrative stress and tumor necrosis factor cellular toxicity in human endothelial cells (135). In addition, propofol protects against hydrogen superoxide–induced oxidative stress and cell dysfunction in human umbilical vein endothelial cells (136). Hydrogen superoxide increased the adhesion of monocyte, a marker of endothelial cell dysfunction, to human umbilical vein endothelial cells, and propofol pretreatment reduces the adhesion in a fashion similar to SB203580 (136). By inhibiting p38 mitogen–activated protein kinase activity and decreasing nitric oxide synthase expression and nitric oxide production, propofol can protect human endothelial cells that are exposed to oxidative stress and becoming dysfunctional (136). Treatment of propofol has been found to protect cardiac H9c2 cells from hydrogen peroxide–induced injury by triggering the activation of Akt and a parallel upregulation of Bcl2 (137). Taken together, propofol has anti-inflammatory and antioxidant properties (Fig. 2). Therefore, it may be useful to modulate the immune system following injury, such as sepsis and reperfusion injuries. Additional studies are required to validate the potential role of propofol in critical care and to determine the effect of propofol on clinical end points.
There is increasing evidence that anesthetic agents may maintain organ function following injury. Studies show that there exists strong evidence that anesthetic agents, especially inhalational anesthetics, exert cardioprotective mechanisms. Volatile anesthetic agents can protect ischemic myocardium, and several clinical studies show that volatile anesthetic agents can prevent myocardial damage during operations (4). Volatile anesthetic agents might be choices to be recommended to the patients with heart diseases who were scheduled for operation. In addition, anesthetic agents may also act as immunologic modulators following injury. Recent studies indicate that the phenomenon of anesthetic-induced maintenance of organ function can be transferred, at least in part, to clinical situation. Further progress in elucidating the underlying mechanisms of anesthetic-induced beneficial effects may provide the new insight of using different anesthetic agents for improvement of organ function following injury. However, this complex network needs additional elucidation in future experimental studies and clinical trials.
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