Chronic heart failure (CHF) patients with edema have elevated plasma concentrations of bacterial endotoxin (lipopolysaccharide [LPS], with significant activation of the immune system (1, 2) The LPS acts on systemic immune-competent cells to potently stimulate the production of proinflammatory cytokines (PICs) (3). Some PICs, such as tumor necrosis factor-α (TNF-α) and nitrous oxide (NO), are also cardiosuppressors, which may also exacerbate the course of the disease. Both LPS and the subsequent inflammatory response can alter the permeability of the gut, allowing more LPS to leak into the blood (4-7). This endogenous LPS further stimulates inflammatory responses and results in a positive feedback loop that may perpetuate the chronic inflammatory state and its associated depression of cardiac function. Although inflammation in heart disease is now well documented (8, 9), the role of LPS in heart disease is poorly delineated, and published data are often conflicting. In CHF patients, both desensitization to LPS with a concomitant decrease in the inflammatory response (10), and an increase in sensitivity to LPS with an increase in TNF-α production and a decrease in HLA-DR (a major histocompatibility complex, class II, cell surface receptor) expression in monocytes (11) have been observed. More recently, human studies suggest that enterically derived LPS drives inflammation: decontamination of the gut being associated with both a reduction in intestinal LPS and a decline in CD14+ monocyte levels (12). In addition, selective digestive decontamination of the gut before cardiopulmonary bypass reduced the level of LPS and PICs (13) and improved postoperative outcome (14).
In this review, we put forward the argument that LPS is an underestimated and important contributor to the pathophysiology of CHF. In addition, we propose that agents that can either neutralize or decrease systemic LPS and lower the chronic inflammation observed in CHF patients would limit progression of heart disease and have a positive impact on patient mortality.
HEART FAILURE AND THE SYSTEMIC INFLAMMATORY RESPONSE
Low-grade systemic inflammation is a feature of both acute and chronic heart failure (15), with elevation in circulating PIC levels (16), such as TNF-α (17), interleukin (IL)-6 (15), and IL-1 (18), being associated with worsening of symptoms, hospital readmission, and even mortality (19). Increasing evidence indicates that this association may be causal. The PICs suppress myocardial contractility (20-25), a process in which cytokine-stimulated generation of local NO through increased expression of inducible NO synthase (20, 26-28) may play a key role. This leads to a depression of excitation-contraction coupling (29) and thus maximum extent and peak velocity of cardiomyocyte shortening (21)-effects due, at least in part, to alterations in mitochondrial respiration (21, 26, 30-36). Additional associated reductions in muscle resting membrane potential and sodium-potassium gradient (37) and mitochondrial density (37), impaired cellular substrate metabolism (37), a rise in the expression of matrix metalloproteinases and a fall in expression of their inhibitors (27), the potentiation of leukocyte adhesion (38), tissue hypoxia and cell death through apoptosis or necrosis (39), and a failure of adrenergic responsiveness (40, 41) contribute to such cardiac impairment.
In this regard, TNF-α and IL-6 may be especially potent. The TNF-α is produced directly by the failing heart (42-44) and systemically in response to other PICs. Elevated circulating levels of TNF-α are correlated to the severity of heart disease (45-48). The TNF-α is cardiodepressant through a number of pathways: (1) sphingosine release and suppression of the calcium transient (49, 50); (2) inhibition of the phosphoinositide pathway and of pyruvate dehydrogenase activity that reduces mitochondrial function (51); and (3) enhancing peroxynitrite production and the levels of matrix metalloproteinase 2 while reducing tissue inhibitor of matrix metalloproteinase 4 in the heart (52). The TNF-α may also engender peripheral tissue decompensation, stimulating inducible NO synthase, and thus NO, skeletal muscle apoptosis, and muscle wasting through the ATP-dependent ubiquitin-protease pathway that degrades proteins (53). Elevated levels of TNF-α result in upregulation of two TNF-α receptors (TNFRs), TNFR-1 and TNFR-2, with the former predominating and thus a good predictor of short-term (54) and long-term (19) prognosis in CHF patients (55). The plasma levels of both these receptors are also correlated with the degree of impairment of systemic ventricular function (56). The TNF-α is thus implicated in β-receptor uncoupling from adenylate cyclase, cardiomyocyte apoptosis, cardiac dysfunction, and systemic effects, including endothelial dysfunction, reduced skeletal muscle blood flow, and the development of anorexia and cachexia (57-59). Elevated TNF-α levels are thus inversely related to functional capacity and peak oxygen consumption (60).
Meanwhile, the PIC IL-6 is induced by diverse inflammatory stimuli and their associated hormonal and cytokine responses (16, 61, 62). Produced by activated leukocytes, fibroblasts, endothelial cells (63), and adipose tissue (64), it is the only cytokine that stimulates the synthesis of all the acute-phase proteins (63, 65-67) and thus has pleiotropic actions on cardiac function, inflammatory cell recruitment, lipid metabolism, and endothelial function (68). Interleukin 6 also causes cardiac adrenergic refractoriness (40, 41) and cardiomyocyte apoptosis (69), and depresses myocardial function (25, 41). Indeed, IL-6 is viewed by some as the most potent cytokine depressor of myocardial function of all (22). Circulating IL-6 levels are elevated in asymptomatic (70) and symptomatic (71, 72) CHF and correlate with impaired functional class, poorer left ventricular function, an increase in length of hospital stay (42, 73-75), and mortality (19, 55, 76). Levels of IL-6 and LPS have been shown to correlate with the severity of heart disease in adults (56). Several recent studies have also shown that levels of IL-6 are correlated invariably to the severity of heart disease (45-48).
THERAPY TARGETED TO INFLAMMATION
Chronic heart failure is accompanied by an elevation in levels of PICs and an inadequate parallel elevation in anti-inflammatory mediators. This imbalance of cytokines has been implicated in the development and progression of CHF, and in the last decade, attempts have been made to modulate this dysregulation (8). Except for one large mortality/morbidity study (77), with a subsequent substudy (78), all studies of immunomodulatory therapy in CHF have used small numbers of patients and have yielded inconclusive results (79, 80). Meanwhile, recent studies of i.v. immunoglobulin, thalidomide, and pentoxifylline highlight the potential benefits of immunomodulation in CHF patients and emphasize the need for larger, placebo-controlled mortality studies of immunomodulatory therapies in CHF (9).
LIPOPOLYSACCHARIDE AND INFLAMMATION
Thus, PIC levels are elevated in both acute (81) and chronic heart failure (19, 82) and may be causative in disease and symptom progression. Although the driving factors, which chronically provoke such synthesis, have yet to be fully understood, a growing corpus of work implicates LPS that may be derived from the gut in this capacity. Gram-negative bacteria can comprise around 109 of the 1012 total bacteria colonizing the healthy gastrointestinal tract (83). The LPS is the major glycolipid constituent of their outer membranes. The gastrointestinal tract thus contains sufficient LPS (~200- 300 mg) to kill the host many times over as indicated from the lethal range of nanogram per kilogram in the rabbit model (84, 85). The LPS potently induces the expression of PICs (86, 87), including TNF-α (88) and IL-6 (89-93), partly through the activation of the nuclear transcription factor nuclear factor (NF)-κB (94). The stimulation of NF-κB by both LPS and TNF-α results in a positive feedback loop of PIC generation (Fig. 1). This results in a spiraling cycle of inflammation, cardiodepression, ischemia, and damage of the villi, causing leakage of LPS, and then more inflammation (Fig. 1). This vicious cycle is exacerbated by LPS or gram-negative bacteria that can act directly on the intestine to increase its permeability and promote further leakage of LPS (4-7).
Recently, the toll-like receptor (TLR) (and TLR-4, in particular) has been implicated as a key component of the innate response in the heart (95). The TLRs are a family of receptors that recognize molecular patterns associated with pathogens, and several exogenous and endogenous ligands have been identified, including LPS (96, 97), fibrinogen (98), hyaluronan, fibronectin, and minimally modified low-density lipoprotein (99) and heat shock protein 60 (100). Ligand binding leads to the activation of several kinases and NF-κB. Enhanced monocyte and macrophage expression of costimulatory molecules, including B7-1 and B7-2, and PICs, including IL-1β, IL-6, IL-12, and TNF-α, have been demonstrated as downstream effects of TLR activation (101, 102). In this way, such ligands may initiate a powerful immune response even in the absence of infection.
Although the importance of TLRs in innate immune responses to microbes is well established, their role in heart disease processes is not well understood. An enhanced in vitro response of monocytes to LPS has been demonstrated in patients with recurrent unstable angina (103) and a role for TLR-4 in outward arterial remodeling (104). It has also recently been shown that there is an expansion of circulating TLR-4-positive monocytes in patients with acute coronary syndrome (105). We therefore reason that TLR-4 and LPS may have an important role in the pathophysiology of heart disease.
THE ROLE OF MONOCYTES IN INFLAMMATION
Chemokines have a critical role in basal and inflammatory leukocyte trafficking, and their main targets are cells derived from bone marrow (106, 107). In addition to recruitment of blood cells, chemokines also induce responses beyond the immune system. For example, there is activation of endothelial cells that can result in angiogenic or angiostatic effects (108) and various responses in smooth muscle cells, fibroblasts, neurons, and epithelial cells. Produced in response to a proinflammatory stimulus, the chemokine CCL2/monocyte chemoattractant protein 1 recruits monocytes locally and induces them to leave the bloodstream and enter the surrounding tissue, becoming tissue macrophages. Other mediators such as complement, tissue growth factor-β, free radicals, and other CC chemokines may also have a role in regulating monocyte infiltration. The CC chemokines or β chemokines have two adjacent cysteines near the amino terminus of the protein and bind to CC chemokine receptors, of which 10 have been discovered to date, designated CCR1 to CCR10. These receptors are expressed on the surface of different cell types, allowing their specific attraction by the chemokines. The CC chemokines induce the migration of monocytes and other cell types, such as natural killer cells and dendritic cells. There are two principle subsets of human monocytes, the CD14+/CD16− and CD14lo/CD16+, which raises the possibility that different chemokine profiles elicited by the inflammatory response may recruit distinct subsets of monocytes in heart disease (109).
Stimulated monocytes and macrophages, T cells, and mast cells synthesize a variety of PICs that include IL-1β, IL-6, and TNF-α. Cytokines upregulate endothelial cell adhesion molecules, recruit leukocytes, and induce smooth muscle cell migration and proliferation (110). Cytokines act systemically to initiate the acute-phase response, upregulating proteins involved in inflammation and hemostasis and resulting in a proinflammatory and prothrombotic state. Expression of tissue factor by inflammatory cells potently induces thrombus formation upon plaque rupture, leading to acute coronary syndromes. Inflammatory biomarkers, including C-reactive protein, complement proteins, IL-6, and white blood cell count predict the development of acute coronary syndromes. The C-reactive protein has been widely studied and consistently predicts future acute coronary syndrome events.
HOW DOES LPS TRIGGER INFLAMMATION?
An understanding of the structure of LPS and the molecular pathways involved in the triggering of inflammation may further aid in the development of anti-LPS therapeutics to study LPS in CHF patients and to develop effective immunotherapeutics to limit progression of CHF. The LPS binding protein (LBP) and CD14 play key roles in promoting innate immunity to gram-negative bacteria by transferring LPS to the signaling receptor complex, MD-2/TLR-4 (111, 112). In the absence of plasma, LPS binds poorly to leukocytes and only provokes a response at very high concentrations (113, 114). This is because LPS is an amphipathic molecule that forms aggregates in aqueous buffers with the lipid A on the inside and unable to bind to cells and trigger inflammation (Fig. 2) (115-117).
In plasma, two mutually exclusive proteins interact with LPS and modulate its biological activity. One of these, the LBP disassociates a single molecule of LPS from the aggregated LPS (Fig. 3). This LPS:LBP complex then interacts with the CD14 protein, possibly in combination with albumin (118, 119), TLR-4 (96, 101, 121), and MD-2 (122) proteins to initiate the inflammatory response (123, 124) (Fig. 3). The LPS:LBP complex also transfers LPS monomers to high-density lipoprotein particles and clearance of plasma LPS via the liver (125, 126) (Fig. 3). The other, bactericidal/permeability-increasing protein (BPI) also interacts with LPS aggregates, but unlike LBP, it stabilizes LPS aggregates and blocks the binding of LBP (127), and averts the inflammatory response mediated by LPS (128, 129).
LIPOPOLYSACCHARIDE IN HEART FAILURE
In CHF, there is reduced cardiac output that decreases the flow of blood to the tissues (130). The gut is particularly affected as it has a high demand for oxygen (up to 20% of the whole body's requirement) and thus readily becomes hypoxic (131). The CHF-associated gut mucosal edema further compromises gut function (1). The architecture of the gut mucosal microvasculature exposes the tip of the villus to the highest risk of ischemia in low flow states (132, 133). This causes necrosis and apoptosis of the epithelial cells at the tip of the villi (134, 135). The integrity of the mucosal epithelium is compromised and intestinal barrier dysfunction (136) ultimately allows translocation of endotoxin and gut bacteria (137-139). Even surgical anesthesia can cause mild ischemia of the gut and translocation of LPS (140). The possibility that LPS triggers inflammation and cytokine production in heart failure was first proposed by Anker et al. (2). Since then, elevated levels of LPS in CHF have been reported in many studies (1, 56, 88, 141). The amount of LPS in the circulation is sufficient to cause increased levels of PICs and the symptoms observed in CHF patients (56, 141). It has also been shown, at least in children, that the severity of the clinical outcome increases with higher levels of plasma LPS (142). Significant myocardial depression has been demonstrated in experimental human endotoxemia (143) by i.v. infusion with 4 ng/kg body weight of reference endotoxin from Escherichia coli 0113 (144). This dose of the reference endotoxin is a safe and well-recognized method of modeling the cardiovascular manifestations of sepsis and septic shock in healthy human volunteers (145).
Evidence for the role of endogenous LPS derived from the gut in inflammation has been obtained from a pilot study where patients with severe CHF had bacterial decontamination of the gut. This reduced intestinal LPS and decreased the inflammatory state (12). Decontamination of the gut before cardiopulmonary bypass was found to be associated with reduced levels of LPS and PICs (13), a finding that has been associated to an improved outcome when used in the postoperative period (14).
INTERVENTION THERAPY AGAINST LPS
Because we propose that endogenous LPS may be an important factor responsible for the underlying chronic inflammation seen in CHF, immunotherapeutic intervention strategies targeted to LPS may be beneficial to CHF patients. However, such strategies have only been applied to the treatment of sepsis, where the administration of antibodies, or passive immunization, to reduce levels of LPS gave variable and disappointing findings (146-149). An analysis of these trials revealed that many of them lacked detailed follow-up assessments of serum antibody and LPS levels to establish the sufficiency of antibodies administered and their ability to reduce plasma LPS levels (148). Thus, a benefit may have been achieved if sufficient anti-LPS antibodies had been administered-a conclusion supported by the findings that endotoxemic patients had a poorer prognostic outcome when their anti-LPS antibodies were depleted before subtoxic levels of plasma LPS were attained (150-154).
Other factors that would influence the efficacy of the antibody therapy are the target site, or epitope, and strength of binding. The epitopes of the monoclonal antibodies (mAbs) E5 (Xoma, Berkley, Calif) and HA-1 A (Centocor, Malvern, Pa) used in these trials were in the lipid A, as the concept was to neutralize the toxicity of LPS by blocking the binding of lipid A to cells (155). Unbelievably, subsequent in vitro analyses of mAbs E5 and HA-1A revealed that they exhibited weak binding to LPS (156), neutralized LPS poorly (157, 158), bound nonspecifically to hydrophobic ligands, such as lipoproteins and cardiolipin (159), and to a variety of human B-cell and erythrocyte proteins (160, 161), and were toxic in a canine model of septic shock (162).
In contrast, anti-LPS antibodies with epitopes in the hydrophilic outer domain of the LPS have the potential to have very high affinities that are in the nanomolar range. For example, the antimeningococcal LPS mAb 9-2-L379 that targets the hydrophilic domain has a binding affinity, with a dissociation constant of 7.5 nM (163). The binding affinity was accurately determined by us using real-time kinetic analysis with a resonant mirror biosensor (164). Thus, we propose that the lack of demonstrable effect of the anti-LPS strategies to date represents inappropriate immunotherapeutics with poorly designed preclinical evaluation.
Alternatively, various other substances (some of which are licensed for use in humans) have been shown to neutralize or limit the inflammatory effects of LPS, for example, BPI or synthetic peptides derived from BPI (165-168) can be tested in animal models to establish an association between LPS and the heart. If such as association is established in the animal model, clinical trials on heart patients could be initiated because BPI is licensed for human use.
CAN NEW ANTI-LPS IMMUNOTHERAPEUTICS BE SUCCESSFUL?
The lessons that can be learned from the trials of anti-LPS immunotherapeutics to treat sepsis are that antibodies with poor binding affinity and insufficient specificity are unlikely to be effective. In addition, trials should be carefully designed to determine their efficacy and to establish whether sufficient levels of antibody were administered to reduce levels of systemic LPS. We postulate that high-affinity and specific antibodies that target LPS could be developed if their epitope lies in the immunogenic hydrophilic portion of LPS (169, 170) as opposed to the hydrophobic lipid A moiety used in the past. This proposal is supported by a human trial of active immunization against LPS sepsis, where a reduction in mortality was achieved with human antiserum raised by vaccinating with the core region of E. coli LPS (171). Most of the polyclonal antibody population would have been against the core hydrophilic sugars of the LPS with only a smaller subset against the less immunogenic lipid A moiety. A subsequent study in mice and rabbit infection models by Kirkland and Ziegler (172) showed that a mAb to an oligosaccharide determinant of LPS from E. coli 0111:B4 could protect from gram-negative infection. Active immunization of mice with the core of LPS from four gram-negative bacterial strains that colonize the gut: E. coli K12, E. coli R1, Pseudomonas aeruginosa PAC608, and Bacteroides fragilis showed protection against a lethal challenge of E. coli O18 LPS (173). Vaccines have also been developed against E. coli J5 (174), Shigella sonnei and Shigella flexneri 2a (175, 176), Salmonella typhimurium (177), and Vibrio cholerae (178), as well as to other human pathogens such as P. aeruginosa (179), Pasteurella multocida (180), Brucella melitensis (181), and Francisella tularensis (182). The efficacy of a single mAb targeted to a hydrophilic oligosaccharide protection of the LPS has yet to be confirmed in human trials.
Although these vaccination studies indicate that effective anti-LPS antibodies can be generated, the use of LPS as a vaccine component may be problematic because it is poorly immunogenic and as little as 4 ng/kg body mass can be toxic. The LPS may also mimic human antigens to camouflage the bacterium from host defenses and thus has the potential to raise autoimmune responses (183, 184). In an alternative strategy toward the development of safer anti-LPS vaccines, we have used peptide mimics of LPS. These were identified by direct interaction with a functional high-affinity mAb (163) with known specificity and whose epitope is within the core region of LPS that is accessible in the intact organism and does not include the toxic lipid A (185, 186).
To date, these anti-LPS immunotherapeutic strategies have only been tested against sepsis-with levels of systemic LPS that are much higher than in the inflammatory state observed in heart disease. Before such studies are extended to CHF patients, anti-LPS antibodies need to be developed that bind to LPS specifically and with high affinity. Using these immunotherapeutics to reduce systemic LPS will then allow the role of LPS in heart disease to be established in a suitable animal model, for example, in rabbits, as they are the only rodents with LPS sensitivities similar to humans. The potential of anti-LPS immunotherapeutics that can clear LPS rapidly and safely from the circulation can be determined. Subsequently, they may then need to be refined and licensed for human clinical trials. For example, if these antibodies were produced in an animal, they could be humanized by replacement with a human antibody constant (Fc) domain (187).
Chronic heart failure afflicts millions of people worldwide. Despite modern pharmacotherapy, mortality remains high: 40% die within a year of diagnosis, and a similar percentage of those worst affected annually thereafter. Similarly, associated morbidity is also high: annually, CHF accounts for 2% of all hospital inpatient days and 5% of all emergency medical admissions to hospital. Hospital admissions due to heart failure are projected to rise by 50% during the next 25 years mainly caused by the aging of the population. This does not include the rising tide of obesity in developed countries that is an important risk factor of heart disease. The health care costs per patient increase from 8 to 30 times in cases of severe disease compared with those with mild symptoms. Additional social and financial burdens to patient, carers, family, and state are likely to be even greater.
Many processes are activated in CHF but the causal role for LPS has yet to be established, and no effective anti-LPS intervention therapy for any disease has been developed, despite evidence to show that it will be beneficial and is an intensive research in this area. Preliminary studies on gut decontamination that reduces systemic LPS are beginning to reveal tantalizing evidence for a role of LPS in CHF. We propose that the development of safe anti-LPS immunotherapeutics that can reduce LPS and inflammation is within our grasp and that these will pave the way to elucidate the role of LPS in the pathophysiology of heart disease. These immunotherapeutics coupled with the potential that agents such as BPI (that can limit LPS-mediated inflammation) may have on heart disease will provide new technological platforms for intervention studies that can limit the progression of heart disease and reduce mortality.
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