SEPSIS, LEUKOCYTES, AND NITRIC OXIDE (NO): AN INTRICATE AFFAIR
Fortin, Carl F.*; McDonald, Patrick P.*; Fülöp, Tàmàs†; Lesur, Olivier*‡
*Pulmonary Division and Groupe de Physiopathologie Respiratoire, Université de Sherbrooke; †Biogerontology Laboratory, Research Center on Aging, Sherbrooke Geriatric University Institute; and ‡Medical Intensive Care Unit, CHU Sherbrooke, Université de Sherbrooke, Sherbrooke, Quebec, Canada
Received 13 Apr 2009; first review completed 28 Apr 2009; accepted in final form 23 Jul 2009
Address reprint requests to Olivier Lesur, MD, Pulmonary Division and Groupe de Physiopathologie Respiratoire, and Medical Intensive Care Unit, CHU Sherbrooke, Université de Sherbrooke, 3001, 12e Avenue Nord, Sherbrooke, Quebec, Canada J1H 5N4. E-mail: Olivier.Lesur@USherbrooke.ca.
The author Fortin is a recipient of a Doctoral Award Scholarship from the Canadian Institutes of Health Research.
Sepsis is exceedingly burdensome for hospital intensive care unit caregivers, and its incidence, as well as sepsis-related deaths, is increasing steadily. Sepsis is characterized by a robust increase in NO production throughout the organism that is driven by iNOS. Moreover, NO is an important factor in the development of septic shock and is synthesized by NOS, an enzyme expressed by a variety of cells, including vascular endothelium, macrophages, and neutrophils. However, the effects of NO on leukocyte functions, and the underlying mechanisms, are relatively unknown. Thus, the present review focuses on the effects of NO and its derivatives on cells of the immune system. Experimental evidences discussed herein show that NO induces posttranslational modifications of key proteins in targeted processes with the potential of deterring cellular physiology. Consequently, the manipulation of NO distribution in septic patients, used in conjunction with conventional treatments aimed at restoring normal immune functions, may represent a valuable therapeutic strategy.
An extended survey conducted between 1979 and 2000 in the United States concluded that the incidence of sepsis and the number of sepsis-related deaths rose at a rate of 8.7% per year during this interval, and that the number of hospitalizations for severe sepsis has almost doubled in the 1993 to 2003 period (1, 2). Sepsis is also a major health concern worldwide (3-10). Inasmuch, the acute phase of sepsis is burdensome for hospital caregivers in intensive care units. Septic patients receive extensive treatments during prolonged periods and have their hospital stay extended by 2 to 3 weeks, mainly in the intensive care unit ward, with a mean stay of 15.7 days (11). Moreover, the average individual cost of a septic patient has been estimated at US $22,100 in the United States, which, on an annual basis, amounts to US $16.7 billion for all septic patients (12). Recent estimates in the United States reported 750,000 sepsis cases annually, of which almost 50% received intensive care (12). In addition, the incidence and mortality of sepsis are increasing with patient age (i.e., increased >100-fold with age for the former and increased 4-fold for the latter) (12). Further compounding the problem is that Gram-positive bacteria and fungal organisms have increasingly replaced Gram-negative bacteria as common causes leading to sepsis (1).
DEFINITIONS OF SEPSIS AND RELATED STATES
The avid reader is directed to the final report of the 2001 International Sepsis Definitions Conference for complete definitions of sepsis (13). Briefly, sepsis is the clinical syndrome defined by the presence of both infection and systemic inflammatory response, which is the presence of systemic inflammation occurring in the presence of an infection. However, systemic inflammatory response can also occur in the absence of infection such as in patients with burns, trauma, pancreatitis, and other diseases. The primary sites of infection leading to sepsis are, beginning with the most common, the respiratory tract, intra-abdominal space, and the urinary tract (14-17). Severe sepsis refers to "systemic invasive" sepsis complicated by organ dysfunction(s), potentially leading to multiple organ dysfunction and failure syndrome (MODS). Severe sepsis is, in fact, the clinical representation of an extreme and combined proinflammatory and anti-inflammatory state (18). Septic shock is a state of acute circulatory failure characterized by persistent arterial hypotension unexplained by other causes and requiring vasopressive-supporting drugs.
NO is synthesized by NOS along the pathway leading from l-arginine to l-citrulline and is produced by the vascular endothelium, macrophages, and neutrophils, among others (19). It is now recognized as a major second messenger in cell biology because newly synthesized NO, acting locally, enters nearby cells by diffusion, where it activates cytosolic guanylate cyclase, leading to the formation of cyclic GMP (cGMP) in target cells (19). In vascular smooth muscle, elevated levels of cGMP lead to altered protein phosphorylation, which is associated with smooth muscle and vascular relaxations (20). There are three recognized isoforms of NOS: eNOS; nNOS, and iNOS. Two of these isoforms, eNOS and nNOS, are Ca2+-dependent and constitutively expressed, whereas iNOS is Ca2+-independent, and its expression is induced by cytokines or inflammatory mediators in most cell types. The combination of NO and superoxide anion (O2-), which is derived from NADPH oxidase, results in the production of reactive nitrogen species such as peroxynitrite (ONOO-) (21). Peroxynitrite is a potent oxidizing agent that can contribute to nitrosylation of proteins, including iNOS itself, as well as oxidization of biological molecules such as amino and nucleic acids (21, 22). It is known that peroxynitrite is produced by neutrophils and macrophages after LPS stimulation (23) and contributes to the immunosuppression of leukocytes during sepsis (24-26). It is thought that a large portion of NO-mediated effects are the result of peroxynitrite action on signal transduction molecules (21).
NO IN SEPSIS
NO is a major factor regulating microvascular homeostasis under normal conditions. In the vascular endothelium, the regulation of blood flow is principally mediated by eNOS-produced NO (27). Inflammatory stimuli (LPS, IL-1β, macrophage migration inhibitory factor [MIF], or IL-6) are known to alter microvascular homeostasis owing in part to iNOS-produced NO (28-30). Furthermore, alteration of microvascular homeostasis is thought to lead to heterogeneity in tissue perfusion, a phenomenon observed both in experimental and human sepsis (31-33). Such alterations also deflect blood flow away from needy microvascular units (33), which is a leading factor of tissue hypoxia (34), and, eventually, a contributive one to MODS. On one hand, iNOS-induced NO has also been associated with acute lung injury in the context of cecal ligation and puncture (CLP)-induced sepsis in C57Bl/6 mice (35); on the other hand, septic iNOS-/- mice developed more lung apoptosis (36). Although data were contradictory regarding this point, it was reasoned that the inhibition of NO synthesis in a context of sepsis could improve clinical outcome. At first, the inhibition of iNOS was shown to reverse LPS- or TNF-α-induced hypotension in animal models (37, 38). These results were subsequently replicated in humans (39, 40), and it was further described that NO inhibition led to increases in arterial pressure, systemic and pulmonary vascular resistance, and decreased cardiac output (41). However, despite an observed improvement in vascular tone, the overall clinical condition was not improved, and mortality remained high (41-43). Nevertheless, a recent survey of preclinical and clinical data reveal that experimental NO supplementation is associated with a favorable outcome in various models of animal sepsis (44). Interestingly, administration of exogenous NO before, or after, induction of sepsis has beneficial effects on mortality and tissue injury such as microscopic intestinal lesions (44). Finally, NO production in the early phases of sepsis is likely to contribute, together with respiratory burst, to efficient microbial clearance by phagocytic cells, especially because respiratory burst and NO-derived mediators have well-known antimicrobial activities (45-47). Therefore, such clearance in the early phases of sepsis is likely to explain why a nonspecific inhibitor of iNOS was found to be detrimental in a clinical trial (48). The beneficial and detrimental roles of NO in the pathophysiology of sepsis have been depicted previously (49), and some aspects of this are represented in Figure 1.
In the following sections, the potential alterations caused by NO on leukocyte functions will be further examined because these alterations have often been overlooked in the current model of sepsis pathophysiology. This is of particular interest especially because sepsis is associated with decreased leukocyte functions, and immunosuppression in survivors of sepsis, in experimental models, and in septic patients (50, 51). By illustrating the dual effect of sepsis on the immune system, it is our hope that this review may contribute in sparking new interests in the study of sepsis pathophysiology.
NEUTROPHILS IN SEPSIS
Neutrophils migrate rapidly to the site of infection where they are activated in response to specific structures on microbial pathogen surfaces, as well as by various classes of inflammatory mediators, including cytokines and chemokines. Once on site, the neutrophils attempt to clear the site of pathogens by phagocytosis and the generation of reactive oxygen species such as H2O2 (52). Reactive oxygen species and NO are not only involved in bacterial killing (45) but are also linked to tissue damage, increased vascular permeability, and organ injury (53, 54). Neutrophils have been found to be resistant to constitutive apoptosis in human sepsis (55, 56) and septic rats (57). In both instances, C5a, PI3-K, as well as IFN-γ, IL-2, IL-15, granulocyte-macrophage- and granulocyte-colony stimulating factor were reported to play a major role in the prolongation of neutrophil survival (56, 57). Alterations induced by sepsis on the functions of neutrophils and other leukocytes are shown in Table 1.
EFFECT OF NO ON NEUTROPHIL FUNCTION IN SEPSIS
An exogenous source of NO, sodium nitroprusside, is able to enhance the secretion of TNF-α by neutrophils when used in conjunction with LPS or IFN-γ by mechanisms independent of cGMP or increased mRNA (58), thereby suggesting that NO may act as a secretagogue on neutrophils. In the early phase of sepsis, NO is known to increase neutrophil phagocytosis (59). In contrast, in the latter phase of sepsis, neutrophil adhesion, rolling, migration, oxidative, and microbicidal activities are decreased by NO in various animal (60) and human (61-68) models. Emerging insights have recently arisen in connection with this NO-mediated decrease in neutrophil function. Indeed, the impaired migration of neutrophils observed in sepsis has been shown to result in part from NO-mediated down-regulation of CXCR2, a chemokine receptor (69). Furthermore, peroxynitrite, an NO-derived oxidizing and nitrating compound, is involved in the migratory failure of neutrophils in sepsis by yet undefined mechanisms (25). Recent studies, however, have shed some insight into the processes involved in neutrophil migration failure induced by NO donors such as peroxynitrite and 3-morpholinosydnonimine (70-72). Incubation of neutrophils with NO donors nitrosylates actin, thereby impeding its polymerization, and in turn, cell migration and phagocytosis (70, 72), thus providing a likely explanation for the neutrophil migration failure observed in sepsis. In addition, NO donors have been found to induce the nitration of signaling proteins, thereby reducing total tyrosine phosphorylation after activation of neutrophils by N-formyl-methionine-leucine-phenylalanine (fMLP) or phorbol myristic acid ester (71). Conversely, peroxynitrite has been found to be a potential priming agent for respiratory burst by human neutrophils (73). A low dose of peroxynitrite (300 μM) was shown to enhance superoxide anion production by phorbol myristic acid ester or fMLP, as well as induce expression of cell surface proteins by a mechanism involving tyrosine nitration (73). Alterations induced by NO, or by NO donors, on leukocytes are shown in Table 2.
The previously described observations are in keeping with the fact that neutrophils have both protective and detrimental effects on the outcome of sepsis, as shown in a rat model of CLP-induced sepsis (74). Neutrophil depletion before CLP has been found to result in substantial increases in bacteremia, with no evidence of attenuated liver or renal dysfunction (74). By comparison, neutrophil depletion 12 h after CLP resulted in a dramatic reduction in bacteremia, in liver and renal dysfunction, and in sharp reductions in serum levels of several cytokines (IL-1β, IL-6, IL-1β, TNF-α, and IL-2), as well as in improved survival (74). The increased levels of cytokines in late sepsis may be related to earlier findings describing that exogenous NO augments TNF-α secretion by human neutrophils (58). Moreover, Skidgel et al. (75) observed an increase in NO-mediated macrophage inflammatory protein (MIP) 2 in response to Escherichia coli challenge in mice. Interestingly, in their settings, NO had almost no role in the activation of nuclear factor (NF)-κB (75), akin to the failure of exogenous NO to induce TNF-α mRNA expression in neutrophils (58). These observations suggest that the NO-mediated increase in cytokine levels in sepsis does not involve the activation of transcription factors in leukocytes, thereby evoking potentially new therapeutic targets such as the use of secretion inhibitors. This is in striking contrast with other cell types where, for instance, Sparkman and Boggaram (76) found that NO induced IL-8 gene expression in H441 lung epithelial cells via a cGMP-independent mechanism. Alternatively, acute-phase serum proteins could be responsible for increased cytokine levels in late sepsis because serum amyloid A has been shown to induce the release of TNF-α, IL-1β, and IL-8 in human neutrophils (77). The use of a proteasome inhibitor (thereby impairing NF-κB activation), in combination with antibiotics, was reported to significantly improve the outcome of septic mice (78).
Whatever the case may be, it remains puzzling that neutrophils seem to secrete cytokines in late sepsis (74), whereas other functional responses are decreased by NO under the same condition (60-68). This is further complicated by findings showing a possible secretagogue effect of NO on neutrophils in early sepsis (58, 75). Overall, these results are very intriguing and stress the need for further investigation into the effects of NO on cytokine secretion by neutrophils in early and late sepsis.
MONOCYTES/MACROPHAGES AND SEPSIS
Within the innate immunity, resident macrophages and infiltrating monocytes provide immediate defense against foreign pathogens and coordinate leukocyte infiltration (79, 80). Macrophages collaborate with, and educate, T and B cells to initiate the immune response through cell-cell interactions and various mediators such as cytokines, chemokines, enzymes, arachidonic acid metabolites, and reactive radicals (80). Thus, macrophages play an essential role in triggering, instructing, and terminating the adaptive immune response, depending on the functional phenotypes they acquire as a consequence of tissue-derived signals.
For circulating monocytes, the progression of sepsis severity leads to decreased human leukocyte antigen (HLA)-DR expression (81, 82). Additionally, this decreased expression is linked to poor outcome for septic patients (82). Furthermore, monocytes from septic patients have been shown to have a significantly reduced production of cytokines (TNF-α, IL-1β, and IL-12) and were unable to acquire high levels of CD80 and CD86 molecules or be rescued from apoptosis by CD40L (84). Consequently, CD40L-activated monocytes from septic patients were unable to induce CD4+ lymphocyte proliferation and secretion of IFN-γ (83). Moreover, investigation of the chemokine fractalkine (CXC3CL1) and its receptor (CX3CR1) on monocytes from septic patients have shown that CX3CR1 expression is down-regulated, and that monocytes are unresponsive upon fractalkine challenge (84). Although sepsis induces monocyte apoptosis in humans and rabbits (85, 86), these studies revealed that survivors exhibit increased monocyte apoptosis linked to a lower secretion of serum TNF-α relatively to nonsurvivors (85, 86).
To our knowledge, the effect of macrophage depletion on the course of sepsis has yet to be tested. A recent study, however, showed that sepsis induces a major depletion of immature macrophages in a mouse model of sepsis (87). Furthermore, a prospective study conducted with rat macrophages incubated with serum from septic patients did reveal some alterations in rat macrophage function (66). In particular, secretion of TNF- and IL-1β was increased when rat macrophages were incubated with serum of septic patients but not with serum from healthy volunteers (66). Moreover, rat macrophages displayed a decreased phagocytic capacity upon addition of serum from septic patients into the medium (66). These findings suggest that alterations in macrophage number and function may be of importance in sepsis-induced immune suppression.
EFFECT OF NO ON MONOCYTE/MACROPHAGE FUNCTION IN SEPSIS
Evidences showing altered functions of monocytes/macrophages by NO in sepsis are less abundant than for neutrophils. Nevertheless, NO has been found to inhibit monocyte adhesion to porcine aortic endothelial cell monolayers and chemotaxis stimulated by fMLP, whereas it failed to influence cell surface expression of CD11b/CD18 (62). In addition, an exogenous source of NO, sodium nitroprusside, inhibited fMLP-induced monocyte migration and increased cGMP concentrations (61). Moreover, NO donors have been found to cause a transitory inhibition of cell respiration and a 50% reduction in cellular adenosine triphosphate in T lymphocytes and monocytes, leading to an inhibition of cell proliferation and cytokine (IL-2, IL-4, IL-5, and IFN-γ) secretion (65). The effect of NO donors has been tested on monocyte differentiation into immature dendritic cells, and the results suggest that NO affects DC differentiation and maturation (63). Finally, monocyte-derived dendritic cell functions are impaired by NO as shown by a decrease in CD23-triggered cytokine secretion (MIP1-α and IL-6) in IL-4- or GM-CSF-matured monocytes (67).
On the other hand, there is evidence that NO and peroxynitrite, an NO-derived mediator, play a role in the physiological functions of monocytes and macrophages. In whole blood, peroxynitrite induces IL-8 mRNA expression and stimulates IL-8 release by human leukocytes (64, 68). Peroxynitrite also induces cytokine secretion (TNF-α and IL-6) in human macrophages through a NF-κB-dependent mechanism (88). Furthermore, in monocytes, the LPS-induced expression of tissue factor, which induces intravascular coagulation in sepsis (89, 90), is mediated by previous formation of peroxynitrite (24). These results suggest that because leukocytes produce peroxynitrite after LPS stimulation (23, 64), the high amount of NO observed in sepsis could exert adverse effects on normal autocrine peroxynitrite signaling by promoting NO tolerance. In this regard, it was found that, although NO inhibits NF-κB activation in rat vascular smooth muscle cells, peroxynitrite exposure leads to sustained NF-κB activity (91). This phenomenon is reminiscent of endotoxin tolerance, where sustained endotoxin concentrations lead to desensitization of cells and blunted responsiveness (92). Likewise, it is known that IRAK-M inhibits the TLR/IRAK pathway during endotoxin tolerance (93, 94), and an NO donor was found to induce a sustained IRAK-M mRNA and protein expression in monocytes (95). In addition, insights obtained from other experimental settings helped shed some light into the mechanistic aspects contributing to these alterations. Cell lysates from RAW 264.7 cells incubated with 1 mM peroxynitrite resulted in the nitration of several proteins in the range of 60 to 250 kDa (96). The authors identified one of the nitrated proteins as p85, the regulatory subunit of phosphatidylinositol 3-kinase, a key enzyme involved in the signal transduction cascades initiated by many agonists, including growth factors (96). In addition, in a macrophage cell line, induction of iNOS resulted in tyrosine-nitration of cellular proteins and in the presence of nitrated tyrosine residues in STAT1, leading to a reduction in phospho-STAT1 after IFN-γ stimulation (97). Interestingly, the upper kinase Jak2 had its activity impaired but displayed no nitrated tyrosine residues (97), suggesting that NO and derivatives could negatively impact cellular signaling by other means than nitration. Peroxynitrite also induces the nitration of tyrosine residues on peroxisome proliferators-activated receptor γ in a macrophage cell line; however, the authors did not asses the functional consequences of this nitration (98). Moreover, 3-morpholinosydnonimine-derived peroxynitrite was found to induce apoptosis in monocytes by activation of caspase 3 and caspase 9, bcl-2 depletion, as well as accumulation of proapoptotic proteins (99). This is likely due to the potentially detrimental defects in signaling transduction induced by tyrosine nitration of Rac and Lyn, among others (99). Further studies are clearly needed to fully characterize the physiology of macrophages in a state of NO-induced tolerance in sepsis models.
DENDRITIC CELLS AND SEPSIS
Dendritic cells (DCs) are the most potent antigen-presenting cells known and play a key role in T- and B-cell activation by antigen presentation and production of cytokines and chemokines. Dendritic cells participate in either Th1 or Th2 cell responses depending on factors such as activating stimulus and presentation of pathogen-derived antigens (100, 101).
Dendritic cells are lost by apoptosis from the spleen and lymph nodes (87, 102), late after the onset of sepsis, in mouse models and in septic patients (103-105). This loss of DCs, however, occurs after CD4+ T-cell activation (106). Nonetheless, in a mouse model of CLP-induced sepsis, it was demonstrated that DCs from septic mice were unable to secrete IL-12, even upon stimulation with CpG or LPS and CD40L, but, were capable to release high levels of IL-1β in late sepsis (107). In the same study, the remaining DCs showed a reduced capacity for allogeneic T-cell activation, associated with decreased IL-2 synthesis, in late sepsis (107). Furthermore, DCs from septic mice demonstrated an impaired capacity to release proinflammatory and Th1-promoting cytokines (TNF-α, IFN-γ, and IL-12) in response to bacterial stimuli in late sepsis (108). On the contrary, these DCs secreted higher levels of IL-1β in late sepsis (108), suggesting a potential role for DCs in the immune suppression observed in sepsis. Despite that, CD86 and CD40, costimulatory molecules for T-cell activation, are up-regulated on the surface of DCs in sepsis (107, 108). No experimental evidences have shown that the other costimulatory molecules are increased by sepsis on the surface of DCs. Up-regulation of IL-1β secretion and costimulatory molecule expression on DCs suggest a potential ability to induce T-cell energy in late sepsis. In contrast, DCs seem to function normally in early sepsis because they secrete normal amounts of IL-12 (107). Together, these observations support the notion that DCs contribute to the altered immune response observed in late sepsis in nonhuman models.
EFFECT OF NO ON DENDRITIC CELL FUNCTIONS IN SEPSIS
To the best of our knowledge, NO-mediated effects on DCs in the context of sepsis have not been described to date. Nevertheless, some experimental evidences from in vitro studies suggest that sepsis-induced excess NO could alter DC function in a subset-specific manner. For instance, it was found that NO protects immature DCs from the apoptogenic effects of large amounts of E. coli and LPS through cGMP formation and stimulation of the cGMP-dependent protein kinase (109). Furthermore, addition of an NO donor, S-nitrosoglutathione, to monocyte-derived DCs (whether matured by LPS or soluble CD40 ligand) was shown to lead to a decreased capacity to activate naive allogeneic T cells, owing in part to a reduced expression of CD86 (110). In contrast, S-nitrosoglutathione led to a strong Th1 polarization with an accompanying increase in IFN-γ and TNF-α release, but a decrease in IL-1β secretion (110). Adding further intricacy to the matter, NO favors the polarization of plasmacytoid dendritic cells toward a Th2 phenotype (111). In fact, plasmacytoid dendritic cells secrete less cytokines (IFN-γ, TNF-α, and IL-6) after exposure to NO; however, they up-regulate their CD40L surface expression and, consequently, promote the differentiation of naive CD4+ T cells into a Th2 phenotype upon stimulation with TLR9 ligand (CpG) (111). Experimental evidences regarding possible alterations of DC function in the context of sepsis and NO excess is thus warranted, especially because DCs are key players in both innate and adaptive immunity.
LYMPHOCYTES IN SEPSIS
During sepsis, it is known that lymphocytes exhibit accelerated apoptosis, loss of phagocytic function, and unbalanced cytokine secretion (e.g., decreased secretion of TNF-α and IL-6 but increased secretion of IL-1β) during sepsis (102, 112, 113). Furthermore, in a mouse model of sepsis induced by live E. coli, a large proportion of both CD4+ and CD8+ T cells was found to be activated within 1 day after E. coli infection (114). The role of αβ T cells in the pathophysiology of sepsis has been confirmed by experiments with T-cell-efficient mice (114-116). These studies indicate that mice depleted of αβ T cells were more resistant to mortality in an acutely lethal model of CLP (115) or in sepsis induced by injection of E. coli (114). Authors observed that improved survival of T-cell-deficient mice was associated with decreased proinflammatory cytokines (IL-6 and MIP-2) (114, 115), with less hypothermia, and an improved acid-base balance (115).
In the case of γδ T cells, their depletion in a mice model of CLP-induced sepsis resulted in decreased survival 10 days after the onset of sepsis, as well as in altered plasma cytokine levels (increased IL-6 and IFN-γ but slightly decreased IL-1β), in tissue damage and in bacteremia (117). However, other groups (115, 118) have reported conflicting findings whereby depletion of γδ T cells in a mouse model of sepsis either resulted in a sharp increase in survival 7 days after the onset of sepsis by CLP surgery (118) or had no significant effect on survival (115). The observed discrepancies between these reports may be the result of differences in the severity of sepsis models used. Although all the aforementioned models use CLP-induced sepsis, the survival rates differ widely among the three models, ranging from 45% (117) to 0% (115). Interestingly, it is only when a nonacutely lethal CLP model is used that γδ T cells seem to play a role in sepsis (117, 118). These results strengthen the need for further research to assert the role of γδ T cells in sepsis, and that the severity of sepsis, indicated by survival rate of the CLP model used, may influence the contribution of these cells in this pathophysiology.
Additionally, it was recently found that number of T reg cells and soluble CD25 plasma levels are increased in septic patients (119), although T reg cells did not contribute to mortality in a murine CLP-induced model of sepsis (120). Therefore, it seems that the various lymphocyte subsets contribute differentially to the severity and mortality of sepsis. Furthermore, it was recently found that CD4 knockout mice were more susceptible to CLP-induced sepsis within the first 30 h than CD8 knockout and wild-type mice (116) possibly because of the loss of IL-1β secretion and helper functions of Th2 cells. This increased mortality was, in addition, linked to increased bacteremia and IL-6 concentration in plasma (116).
EFFECT OF NO ON LYMPHOCYTE FUNCTION IN SEPSIS
Although there are, to our knowledge, no studies showing the effect of NO on lymphocyte function in the context of sepsis, there are indications of such effects in other contexts that could thus represent important mechanisms contributing to their decreased function in sepsis. Recently, CD8+ T cells were found to undergo nitration of tyrosines in the TCR-CD8 complex, through reactive oxygen species and peroxynitrite, in the context of cancer-induced tolerance (121). As a result, these cells were unable to bind a specific peptide presented by the major histocompatibility complex but were responsive to nonspecific stimulation (121). Moreover, it is known that NO and peroxynitrite can impair the proliferation of activated T cells (122, 123) by mechanisms involving the inhibition of activation-induced protein phosphorylation by nitration of tyrosines residues and by priming for apoptosis (123). In keeping with this observation, Kong et al. (124) found that tyrosine phosphorylation of a pentadecameric peptide representing a tyrosine phosphorylation site of p34cdc2 (a kinase implicated in cell cycle regulation and normally phosphorylated by Lck) was disrupted because of peroxynitrite-promoted nitration of this tyrosine residue. Moreover, NO-mediated inhibition of T-cell proliferation was associated with the inhibition of caspase activity by reversible S-nitrosylation (125). These results suggest that NO-induced alteration of substrates that are important in lymphocyte physiology could represent a major factor underlying the decrease of their functions in sepsis and the ensuing immunosuppression observed in sepsis survivors.
This review presents documented evidences that elevated NO concentrations observed in sepsis are detrimental for normal leukocyte functions, as summarized in Table 1 and Table 2. Paradoxically, iNOS-derived NO influences the physiological functions of most leukocytes and is implicated in phagocytic, antimicrobial, and tumoricidal activities (122, 126, 127). One of the features of sepsis is endotoxin tolerance (128), and in light of this review, a similar NO-induced tolerance must also be taken into account in the pathophysiology of sepsis. Furthermore, an additional feature of sepsis is that surviving patients (or animals in experimental sepsis models) are temporarily immunodepressed (129), owing, in part, to mechanisms involving epigenetic changes at the nucleosomal level (51, 130). Eventually, these epigenetic changes can lead to decreased HLA-DR mRNA and protein levels as well as surface expression in human monocytes (131, 132). It is therefore possible that these epigenetic changes, which would presumably lead to tolerance, are driven by NO or NO-derived mediators because it is known that peroxynitrite oxidizes nucleic acids and induces DNA repair mechanisms (21). Finally, depletion of lymphocytes and neutrophils can improve survival rates in models of sepsis (albeit with different kinetics), in part by decreasing proinflammatory cytokine concentrations in serum. The experimental evidences discussed herein show that NO is potentially implicated in this phenomenon. Therefore, manipulation of NO distribution in septic patients, used in conjunction with other therapies aimed at restoring normal immune functions, may represent a valuable therapeutic strategy.
1. Martin GS, Mannino DM, Eaton S, Moss M: The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med
2. Dombrovskiy VY, Martin AA, Sunderram J, Paz HL: Rapid increase in hospitalization and mortality rates for severe sepsis in the United States: a trend analysis from 1993 to 2003. Crit Care Med
3. Cheng B, Xie G, Yao S, Wu X, Guo Q, Gu M, Fang Q, Xu Q, Wang D, Jin Y, et al: Epidemiology of severe sepsis in critically ill surgical patients in ten university hospitals in China. Crit Care Med
4. Robson WP Daniel R: The Sepsis Six: helping patients to survive sepsis. Br J Nurs
5. Andreu Ballester JC, Ballester F, Gonzalez Sanchez A, Almela Quilis A, Colomer Rubio E, Penarroja Otero C: Epidemiology of sepsis in the Valencian Community (Spain), 1995-2004. Infect Control Hosp Epidemiol
6. Zielinki A, Czarkowski MP: [Infectious diseases in Poland in 2005]. Przegl Epidemiol
7. Reinhart K, Brunkhorst FM, Bone HG, Gerlach H, Grundling M, Kreymann G, Kujath P, Marggraf G, Mayer K, Meier-Hellmann A, et al: [Diagnosis and therapy of sepsis]. Clin Res Cardiol
8. Inigo J, Sendra JM, Diaz R, Bouza C, Sarria-Santamera A: [Epidemiology and costs of severe sepsis in Madrid. A hospital discharge study]. Med Intensiva
9. Silva E, Pedro Mde A, Sogayar AC, Mohovic T, Silva CL, Janiszewski M, Cal RG, de Sousa EF, Abe TP, de Andrade J, et al: Brazilian Sepsis Epidemiological Study (BASES study). Crit Care
10. Moss M, Martin GS: A global perspective on the epidemiology of sepsis. Intensive Care Med
11. Riedemann NC, Guo RF, Ward PA: The enigma of sepsis. J Clin Invest
12. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR: Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med
13. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G: 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Intensive Care Med
14. Harbarth S, Garbino J, Pugin J, Romand JA, Lew D, Pittet D: Inappropriate initial antimicrobial therapy and its effect on survival in a clinical trial of immunomodulating therapy for severe sepsis. Am J Med
15. Valles J, Rello J, Ochagavia A, Garnacho J, Alcala MA: Community-acquired bloodstream infection in critically ill adult patients: impact of shock and inappropriate antibiotic therapy on survival. Chest
16. Guidet B, Aegerter P, Gauzit R, Meshaka P, Dreyfuss D: Incidence and impact of organ dysfunctions associated with sepsis. Chest
17. Vincent JL, Sakr Y, Sprung CL, Ranieri VM, Reinhart K, Gerlach H, Moreno R, Carlet J, Le Gall JR, Payen D: Sepsis in European intensive care units: results of the SOAP study. Crit Care Med
18. Pinsky MR: Sepsis: a pro- and anti-inflammatory disequilibrium syndrome. Contrib Nephrol
19. Ignarro LJ: Nitric oxide: a novel signal transduction mechanism for transcellular communication. Hypertension
20. Murad F, Waldman S, Molina C, Bennett B, Leitman D: Regulation and role of guanylate cyclase-cyclic GMP in vascular relaxation. Prog Clin Biol Res
21. Pacher P, Beckman JS, Liaudet L: Nitric oxide and peroxynitrite in health and disease. Physiol Rev
22. Hazen SL, Zhang R, Shen Z, Wu W, Podrez EA, MacPherson JC, Schmitt D, Mitra SN, Mukhopadhyay C, Chen Y, et al: Formation of nitric oxide-derived oxidants by myeloperoxidase in monocytes: pathways for monocyte-mediated protein nitration and lipid peroxidation In vivo. Circ Res
23. Gagnon C, Leblond FA, Filep JG: Peroxynitrite production by human neutrophils, monocytes and lymphocytes challenged with lipopolysaccharide. FEBS Lett
24. Gerlach M, Keh D, Bezold G, Spielmann S, Kurer I, Peter RU, Falke KJ, Gerlach H: Nitric oxide inhibits tissue factor synthesis, expression and activity in human monocytes by prior formation of peroxynitrite. Intensive Care Med
25. Torres-Duenas D, Celes MR, Freitas A, Alves-Filho JC, Spiller F, Dal-Secco D, Dalto VF, Rossi MA, Ferreira SH, Cunha FQ: Peroxynitrite mediates the failure of neutrophil migration in severe polymicrobial sepsis in mice. Br J Pharmacol
26. Alves-Filho JC, de Freitas A, Spiller F, Souto FO, Cunha FQ: The role of neutrophils in severe sepsis. Shock
27. Palmer RM, Ferrige AG, Moncada S: Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature
28. Tyml K, Wang X, Lidington D, Ouellette Y: Lipopolysaccharide reduces intercellular coupling in vitro and arteriolar conducted response in vivo. Am J Physiol Heart Circ Physiol
29. Su CF, Yang FL, Chen HI: Inhibition of inducible nitric oxide synthase attenuates acute endotoxin-induced lung injury in rats. Clin Exp Pharmacol Physiol
30. Wu F, Tyml K, Wilson JX: iNOS expression requires NADPH oxidase-dependent redox signaling in microvascular endothelial cells. J Cell Physiol
31. Lam C, Tyml K, Martin C, Sibbald W: Microvascular perfusion is impaired in a rat model of normotensive sepsis. J Clin Invest
32. Farquhar I, Martin CM, Lam C, Potter R, Ellis CG, Sibbald WJ: Decreased capillary density in vivo in bowel mucosa of rats with normotensive sepsis. J Surg Res
33. Trzeciak S, Dellinger RP, Parrillo JE, Guglielmi M, Bajaj J, Abate NL, Arnold RC, Colilla S, Zanotti S, Hollenberg SM: Early microcirculatory perfusion derangements in patients with severe sepsis and septic shock: relationship to hemodynamics, oxygen transport, and survival. Ann Emerg Med
49:88-98; 98.e1-2, 2007.
34. Ellis CG, Bateman RM, Sharpe MD, Sibbald WJ, Gill R: Effect of a maldistribution of microvascular blood flow on capillary O(2) extraction in sepsis. Am J Physiol Heart Circ Physiol
35. Razavi HM, Wang L, Weicker S, Quinlan GJ, Mumby S, McCormack DG, Mehta S: Pulmonary oxidant stress in murine sepsis is due to inflammatory cell nitric oxide. Crit Care Med
36. Rudkowski JC, Barreiro E, Harfouche R, Goldberg P, D'Orleans-Juste P, Labonté J, Lesur O, Hussain SNA: Roles of iNOS and nNOS in sepsis-induced pulmonary apoptosis. Am J Physiol (Lung)
37. Meyer J, Traber LD, Nelson S, Lentz CW, Nakazawa H, Herndon DN, Noda H, Traber DL: Reversal of hyperdynamic response to continuous endotoxin administration by inhibition of NO synthesis. J Appl Physiol
38. Kilbourn RG, Gross SS, Jubran A, Adams J, Griffith OW, Levi R, Lodato RF: NG
-methyl-l-arginine inhibits tumor necrosis factor-induced hypotension: implications for the involvement of nitric oxide. Proc Natl Acad Sci U S A
39. Lorente JA, Landin L, De Pablo R, Renes E, Liste D: l-Arginine pathway in the sepsis syndrome. Crit Care Med
40. Petros A, Lamb G, Leone A, Moncada S, Bennett D, Vallance P: Effects of a nitric oxide synthase inhibitor in humans with septic shock. Cardiovasc Res
41. Avontuur JA, Tutein Nolthenius RP, van Bodegom JW, Bruining HA: Prolonged inhibition of nitric oxide synthesis in severe septic shock: a clinical study. Crit Care Med
42. Grover R, Zaccardelli D, Colice G, Guntupalli K, Watson D, Vincent JL: An open-label dose escalation study of the nitric oxide synthase inhibitor, N
)-methyl-l-arginine hydrochloride (546C88), in patients with septic shock. Glaxo Wellcome International Septic Shock Study Group. Crit Care Med
43. Cobb JP: Use of nitric oxide synthase inhibitors to treat septic shock: the light has changed from yellow to red. Crit Care Med
44. Lamontagne F, Meade M, Ondiveeran HK, Lesur O, Robichaud AE: Nitric oxide donors in sepsis: a systematic review of clinical and in vivo preclinical data. Shock
45. Goya T, Morisaki T, Torisu M: Immunologic assessment of host defense impairment in patients with septic multiple organ failure: relationship between complement activation and changes in neutrophil function. Surgery
46. Linares E, Giorgio S, Mortara RA, Santos CX, Yamada AT, Augusto O: Role of peroxynitrite in macrophage microbicidal mechanisms in vivo revealed by protein nitration and hydroxylation. Free Radic Biol Med
47. Rosen H, Crowley JR, Heinecke JW: Human neutrophils use the myeloperoxidase-hydrogen peroxide-chloride system to chlorinate but not nitrate bacterial proteins during phagocytosis. J Biol Chem
48. Lopez A, Lorente JA, Steingrub J, Bakker J, McLuckie A, Willatts S, Brockway M, Anzueto A, Holzapfel L, Breen D, et al: Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: effect on survival in patients with septic shock. Crit Care Med
49. Cobb JP, Danner RL: Nitric oxide and septic shock. JAMA
50. Benjamim CF, Hogaboam CM, Kunkel SL: The chronic consequences of severe sepsis. J Leukoc Biol
51. Wen H, Dou Y, Hogaboam CM, Kunkel SL: Epigenetic regulation of dendritic cell-derived interleukin-12 facilitates immunosuppression after a severe innate immune response. Blood
52. Nathan C: Neutrophils and immunity: challenges and opportunities. Nat Rev Immunol
53. Welbourn CR, Goldman G, Paterson IS, Valeri CR, Shepro D, Hechtman HB: Pathophysiology of ischaemia reperfusion injury: central role of the neutrophil. Br J Surg
54. Windsor AC, Mullen PG, Fowler AA, Sugerman HJ: Role of the neutrophil in adult respiratory distress syndrome. Br J Surg
55. Jimenez MF, Watson RW, Parodo J, Evans D, Foster D, Steinberg M, Rotstein OD, Marshall JC: Dysregulated expression of neutrophil apoptosis in the systemic inflammatory response syndrome. Arch Surg
132:1263-1269; discussion 1269-1270, 1997.
56. Lesur O, Kokis A, Hermans C, Fulop T, Bernard A, Lane D: Interleukin-2 involvement in early acute respiratory distress syndrome: relationship with polymorphonuclear neutrophil apoptosis and patient survival. Crit Care Med
57. Guo RF, Sun L, Gao H, Shi KX, Rittirsch D, Sarma VJ, Zetoune FS, Ward PA: In vivo regulation of neutrophil apoptosis by C5a during sepsis. J Leukoc Biol
58. Van Dervort AL, Yan L, Madara PJ, Cobb JP, Wesley RA, Corriveau CC, Tropea MM, Danner RL: Nitric oxide regulates endotoxin-induced TNF-alpha production by human neutrophils. J Immunol
59. Moffat FL Jr, Han T, Li ZM, Peck MD, Jy W, Ahn YS, Chu AJ, Bourguignon LY: Supplemental l-arginine HCl augments bacterial phagocytosis in human polymorphonuclear leukocytes. J Cell Physiol
60. Alves-Filho JC, Tavares-Murta BM, Barja-Fidalgo C, Benjamim CF, Basile-Filho A, Arraes SM, Cunha FQ: Neutrophil function in severe sepsis. Endocr Metab Immune Disord Drug Targets
61. Bath PM: The effect of nitric oxide-donating vasodilators on monocyte chemotaxis and intracellular cGMP concentrations in vitro. Eur J Clin Pharmacol
62. Bath PM, Hassall DG, Gladwin AM, Palmer RM, Martin JF: Nitric oxide and prostacyclin. Divergence of inhibitory effects on monocyte chemotaxis and adhesion to endothelium in vitro. Arterioscler Thromb
63. Fernandez-Ruiz V, Gonzalez A, Lopez-Moratalla N: Effect of nitric oxide in the differentiation of human monocytes to dendritic cells. Immunol Lett
64. Filep JG, Beauchamp M, Baron C, Paquette Y: Peroxynitrite mediates IL-8 gene expression and production in lipopolysaccharide-stimulated human whole blood. J Immunol
65. Fiorucci S, Mencarelli A, Distrutti E, Baldoni M, del Soldato P, Morelli A: Nitric oxide regulates immune cell bioenergetic: a mechanism to understand immunomodulatory functions of nitric oxide-releasing anti-inflammatory drugs. J Immunol
66. Peck G, Andrades M, Lorenzi R, da Costa M, Petronilho F, Moreira JC, Dal-Pizzol F, Ritter C: Serum-induced macrophage activation is related to the severity of septic shock. Inflamm Res
67. Wishah K, Malur A, Raychaudhuri B, Melton AL, Kavuru MS, Thomassen MJ: Nitric oxide blocks inflammatory cytokine secretion triggered by CD23 in monocytes from allergic, asthmatic patients and healthy controls. Ann Allergy Asthma Immunol
68. Zouki C, Jozsef L, Ouellet S, Paquette Y, Filep JG: Peroxynitrite mediates cytokine-induced IL-8 gene expression and production by human leukocytes. J Leukoc Biol
69. Rios-Santos F, Alves-Filho JC, Souto FO, Spiller F, Freitas A, Lotufo CM, Soares MB, Dos Santos RR, Teixeira MM, Cunha FQ: Down-regulation of CXCR2 on neutrophils in severe sepsis is mediated by inducible nitric oxide synthase-derived nitric oxide. Am J Respir Crit Care Med
70. Clements MK, Siemsen DW, Swain SD, Hanson AJ, Nelson-Overton LK, Rohn TT, Quinn MT: Inhibition of actin polymerization by peroxynitrite modulates neutrophil functional responses. J Leukoc Biol
71. Klink M, Bednarska K, Jastrzembska K, Banasik M, Sulowska Z: Signal transduction pathways affected by nitric oxide donors during neutrophil functional response in vitro. Inflamm Res
72. Thom SR, Bhopale VM, Mancini DJ, Milovanova TN: Actin S
-nitrosylation inhibits neutrophil beta2 integrin function. J Biol Chem
73. Rohn TT, Nelson LK, Sipes KM, Swain SD, Jutila KL, Quinn MT: Priming of human neutrophils by peroxynitrite: potential role in enhancement of the local inflammatory response. J Leukoc Biol
74. Hoesel LM, Neff TA, Neff SB, Younger JG, Olle EW, Gao H, Pianko MJ, Bernacki KD, Sarma JV, Ward PA: Harmful and protective roles of neutrophils in sepsis. Shock
75. Skidgel RA, Gao XP, Brovkovych V, Rahman A, Jho D, Predescu S, Standiford TJ, Malik AB: Nitric oxide stimulates macrophage inflammatory protein-2 expression in sepsis. J Immunol
76. Sparkman L, Boggaram V: Nitric oxide increases IL-8 gene transcription and mRNA stability to enhance IL-8 gene expression in lung epithelial cells. Am J Physiol Lung Cell Mol Physiol
77. Ribeiro FP, Furlaneto CJ, Hatanaka E, Ribeiro WB, Souza GM, Cassatella MA, Campa A: mRNA expression and release of interleukin-8 induced by serum amyloid A in neutrophils and monocytes. Mediators Inflamm
78. Reis J, Tan X, Yang R, Rockwell CE, Papasian CJ, Vogel SN, Morrison DC, Qureshi AA, Qureshi N: A combination of proteasome inhibitors and antibiotics prevents lethality in a septic shock model. Innate Immun
79. Gordon S: The macrophage: past, present and future. Eur J Immunol
80. Martinez FO, Sica A, Mantovani A, Locati M: Macrophage activation and polarization. Front Biosci
81. Gonzalez-Roldan N, Ferat-Osorio E, Aduna-Vicente R, Wong-Baeza I, Esquivel-Callejas N, Astudillo-de la Vega H, Sanchez-Fernandez P, Arriaga-Pizano L, Villasis-Keever MA, Lopez-Macias C, et al: Expression of triggering receptor on myeloid cell 1 and histocompatibility complex molecules in sepsis and major abdominal surgery. World J Gastroenterol
82. Abe R, Hirasawa H, Oda S, Sadahiro T, Nakamura M, Watanabe E, Nakada TA, Hatano M, Tokuhisa T: Up-regulation of interleukin-10 mRNA expression in peripheral leukocytes predicts poor outcome and diminished human leukocyte antigen-DR expression on monocytes in septic patients. J Surg Res
83. Sinistro A, Almerighi C, Ciaprini C, Natoli S, Sussarello E, Di Fino S, Calo-Carducci F, Rocchi G, Bergamini A: Downregulation of CD40 ligand response in monocytes from sepsis patients. Clin Vaccine Immunol
84. Pachot A, Cazalis MA, Venet F, Turrel F, Faudot C, Voirin N, Diasparra J, Bourgoin N, Poitevin F, Mougin B, et al: Decreased expression of the fractalkine receptor CX3CR1 on circulating monocytes as new feature of sepsis-induced immunosuppression. J Immunol
85. Giamarellos-Bourboulis EJ, Routsi C, Plachouras D, Markaki V, Raftogiannis M, Zervakis D, Koussoulas V, Orfanos S, Kotanidou A, Armaganidis A, et al: Early apoptosis of blood monocytes in the septic host: is it a mechanism of protection in the event of septic shock? Crit Care
86. Antonopoulou A, Raftogiannis M, Giamarellos-Bourboulis EJ, Koutoukas P, Sabracos L, Mouktaroudi M, Adamis T, Tzepi I, Giamarellou H, Douzinas EE: Early apoptosis of blood monocytes is a determinant of survival in experimental sepsis by multi-drug-resistant Pseudomonas aeruginosa
. Clin Exp Immunol
87. Peck-Palmer OM, Unsinger J, Chang KC, McDonough JS, Perlman H, McDunn JE, Hotchkiss RS: Modulation of the bcl-2 family blocks sepsis-induced depletion of dendritic cells and macrophages. Shock
88. Matata BM, Galinanes M: Peroxynitrite is an essential component of cytokines production mechanism in human monocytes through modulation of nuclear factor-kappa B DNA binding activity. J Biol Chem
89. Vallet B: Microthrombosis in sepsis. Minerva Anestesiol
90. Vallet B, Wiel E: Endothelial cell dysfunction and coagulation. Crit Care Med
91. Hattori Y, Kasai K, Gross SS: NO suppresses while peroxynitrite sustains NF-kappaB: a paradigm to rationalize cytoprotective and cytotoxic actions attributed to NO. Cardiovasc Res
92. Fan H, Cook JA: Molecular mechanisms of endotoxin tolerance. J Endotoxin Res
93. Kobayashi K, Hernandez LD, Galan JE, Janeway CA Jr, Medzhitov R, Flavell RA: IRAK-M is a negative regulator of Toll-like receptor signaling. Cell
94. del Fresno C, Soler-Rangel L, Soares-Schanoski A, Gomez-Pina V, Gonzalez-Leon MC, Gomez-Garcia L, Mendoza-Barbera E, Rodriguez-Rojas A, Garcia F, Fuentes-Prior P, et al: Inflammatory responses associated with acute coronary syndrome up-regulate IRAK-M and induce endotoxin tolerance in circulating monocytes. J Endotoxin Res
95. del Fresno C, Gomez-Garcia L, Caveda L, Escoll P, Arnalich F, Zamora R, Lopez-Collazo E: Nitric oxide activates the expression of IRAK-M via the release of TNF-alpha in human monocytes. Nitric Oxide
96. Hellberg CB, Boggs SE, Lapetina EG: Phosphatidylinositol 3-kinase is a target for protein tyrosine nitration. Biochem Biophys Res Commun
97. Llovera M, Pearson JD, Moreno C, Riveros-Moreno V: Impaired response to interferon-gamma in activated macrophages due to tyrosine nitration of STAT1 by endogenous nitric oxide. Br J Pharmacol
98. Shibuya A, Wada K, Nakajima A, Saeki M, Katayama K, Mayumi T, Kadowaki T, Niwa H, Kamisaki Y: Nitration of PPARgamma inhibits ligand-dependent translocation into the nucleus in a macrophage-like cell line, RAW 264. FEBS Lett
99. Natal C, Modol T, Oses-Prieto JA, Lopez-Moratalla N, Iraburu MJ, Lopez-Zabalza MJ: Specific protein nitration in nitric oxide-induced apoptosis of human monocytes. Apoptosis
100. Lopez-Bravo M, Ardavin C: In vivo induction of immune responses to pathogens by conventional dendritic cells. Immunity
101. Wen H, Schaller MA, Dou Y, Hogaboam CM, Kunkel SL: Dendritic cells at the interface of innate and acquired immunity: the role for epigenetic changes. J Leukoc Biol
102. Wesche DE, Lomas-Neira JL, Perl M, Chung CS, Ayala A: Leukocyte apoptosis and its significance in sepsis and shock. J Leukoc Biol
103. Hotchkiss RS, Tinsley KW, Swanson PE, Grayson MH, Osborne DF, Wagner TH, Cobb JP, Coopersmith C, Karl IE: Depletion of dendritic cells, but not macrophages, in patients with sepsis. J Immunol
104. Tinsley KW, Grayson MH, Swanson PE, Drewry AM, Chang KC, Karl IE, Hotchkiss RS: Sepsis induces apoptosis and profound depletion of splenic interdigitating and follicular dendritic cells. J Immunol
105. Scumpia PO, McAuliffe PF, O'Malley KA, Ungaro R, Uchida T, Matsumoto T, Remick DG, Clare-Salzler MJ, Moldawer LL, Efron PA: CD11c+ dendritic cells are required for survival in murine polymicrobial sepsis. J Immunol
106. Efron PA, Martins A, Minnich D, Tinsley K, Ungaro R, Bahjat FR, Hotchkiss R, Clare-Salzler M, Moldawer LL: Characterization of the systemic loss of dendritic cells in murine lymph nodes during polymicrobial sepsis. J Immunol
107. Flohe SB, Agrawal H, Schmitz D, Gertz M, Flohe S, Schade FU: Dendritic cells during polymicrobial sepsis rapidly mature but fail to initiate a protective Th1-type immune response. J Leukoc Biol
108. Flohe SB, Agrawal H, Flohe S, Rani M, Bangen JM, Schade FU: Diversity of interferon gamma and granulocyte-macrophage colony-stimulating factor in restoring immune dysfunction of dendritic cells and macrophages during polymicrobial sepsis. Mol Med
109. Falcone S, Perrotta C, De Palma C, Pisconti A, Sciorati C, Capobianco A, Rovere-Querini P, Manfredi AA, Clementi E: Activation of acid sphingomyelinase and its inhibition by the nitric oxide/cyclic guanosine 3',5'-monophosphate pathway: key events in Escherichia coli
-elicited apoptosis of dendritic cells. J Immunol
110. Corinti S, Pastore S, Mascia F, Girolomoni G: Regulatory role of nitric oxide on monocyte-derived dendritic cell functions. J Interferon Cytokine Res
111. Morita R, Uchiyama T, Hori T: Nitric oxide inhibits IFN-alpha production of human plasmacytoid dendritic cells partly via a guanosine 3',5'-cyclic monophosphate-dependent pathway. J Immunol
112. Unsinger J, Herndon JM, Davis CG, Muenzer JT, Hotchkiss RS, Ferguson TA: The role of TCR engagement and activation-induced cell death in sepsis-induced T cell apoptosis. J Immunol
113. Venet F, Chung CS, Monneret G, Huang X, Horner B, Garber M, Ayala A: Regulatory T cell populations in sepsis and trauma. J Leukoc Biol
114. van Schaik SM, Abbas AK: Role of T cells in a murine model of Escherichia coli
sepsis. Eur J Immunol
115. Enoh VT, Lin SH, Lin CY, Toliver-Kinsky T, Murphey ED, Varma TK, Sherwood ER: Mice depleted of alphabeta but not gammadelta T cells are resistant to mortality caused by cecal ligation and puncture. Shock
116. Martignoni A, Tschop J, Goetzman HS, Choi LG, Reid MD, Johannigman JA, Lentsch AB, Caldwell CC: CD4-expressing cells are early mediators of the innate immune system during sepsis. Shock
117. Tschop J, Martignoni A, Goetzman HS, Choi LG, Wang Q, Noel JG, Ogle CK, Pritts TA, Johannigman JA, Lentsch AB, et al: Gammadelta T cells mitigate the organ injury and mortality of sepsis. J Leukoc Biol
118. Flierl MA, Rittirsch D, Gao H, Hoesel LM, Nadeau BA, Day DE, Zetoune FS, Sarma JV, Huber-Lang MS, Ferrara JL, et al: Adverse functions of IL-17A in experimental sepsis. FASEB J
119. Saito K, Wagatsuma T, Toyama H, Ejima Y, Hoshi K, Shibusawa M, Kato M, Kurosawa S: Sepsis is characterized by the increases in percentages of circulating CD4+CD25+ regulatory T cells and plasma levels of soluble CD25. Tohoku J Exp Med
120. Scumpia PO, Delano MJ, Kelly KM, O'Malley KA, Efron PA, McAuliffe PF, Brusko T, Ungaro R, Barker T, Wynn JL, et al: Increased natural CD4+CD25+ regulatory T cells and their suppressor activity do not contribute to mortality in murine polymicrobial sepsis. J Immunol
121. Nagaraj S, Gupta K, Pisarev V, Kinarsky L, Sherman S, Kang L, Herber DL, Schneck J, Gabrilovich DI: Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer. Nat Med
122. Liew FY: Nitric oxide in infectious and autoimmune diseases. Ciba Found Symp
195:234-239; discussion 239-244, 1995.
123. Brito C, Naviliat M, Tiscornia AC, Vuillier F, Gualco G, Dighiero G, Radi R, Cayota AM: Peroxynitrite inhibits T lymphocyte activation and proliferation by promoting impairment of tyrosine phosphorylation and peroxynitrite-driven apoptotic death. J Immunol
124. Kong SK, Yim MB, Stadtman ER, Chock PB: Peroxynitrite disables the tyrosine phosphorylation regulatory mechanism: lymphocyte-specific tyrosine kinase fails to phosphorylate nitrated cdc2(6-20)NH2 peptide. Proc Natl Acad Sci U S A
125. Mahidhara RS, Hoffman RA, Huang S, Wolf-Johnston A, Vodovotz Y, Simmons RL, Billiar TR: Nitric oxide-mediated inhibition of caspase-dependent T lymphocyte proliferation. J Leukoc Biol
126. Amin AR, Attur M, Vyas P, Leszczynska-Piziak J, Levartovsky D, Rediske J, Clancy RM, Vora KA, Abramson SB: Expression of nitric oxide synthase in human peripheral blood mononuclear cells and neutrophils. J Inflamm
127. MacMicking J, Xie QW, Nathan C: Nitric oxide and macrophage function. Annu Rev Immunol
128. West MA, Heagy W: Endotoxin tolerance: a review. Crit Care Med
129. Caille V, Bossi P, Grimaldi D, Vieillard-Baron A: [Physiopathology of severe sepsis]. Presse Med
33:256-261; discussion 269, 2004.
130. McCall CE, Yoza BK: Gene silencing in severe systemic inflammation. Am J Respir Crit Care Med
131. Docke WD, Hoflich C, Davis KA, Rottgers K, Meisel C, Kiefer P, Weber SU, Hedwig-Geissing M, Kreuzfelder E, Tschentscher P, et al: Monitoring temporary immunodepression by flow cytometric measurement of monocytic HLA-DR expression: a multicenter standardized study. Clin Chem
132. Pachot A, Monneret G, Brion A, Venet F, Bohe J, Bienvenu J, Mougin B, Lepape A: Messenger RNA expression of major histocompatibility complex class II genes in whole blood from septic shock patients. Crit Care Med
33:31-38; discussion 236-237, 2005.
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