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Originally published online as doi:10.1189/jlb.0206123 on June 12, 2006

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(Journal of Leukocyte Biology. 2006;80:237-244.)
© 2006 by Society for Leukocyte Biology

The central role of adrenomedullin in host defense

Enrique Zudaire1, Sergio Portal-Núñez and Frank Cuttitta

Cell and Cancer Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

1Correspondence: Cell and Cancer Biology Branch, NCI, NIH, Bldg. 10, Room 13N262, Bethesda, MD 20892. E-mail: zudairee{at}mail.nih.gov


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ABSTRACT
 
Thirteen years after the isolation of adrenomedullin (AM) from a human pheochromocytoma, the literature is awash with reports describing its implication in countless physiological and disease mechanisms ranging from vasodilatation to cancer promotion. A growing body of evidence illustrates AM as a pivotal component in normal physiology and disease with marked beneficial effects in the host defense mechanism. Exogenous administration of AM as well as its ectopic overexpression and the use of drugs, which potentiates its activity, are promising strategies for treatment of septic shock and several other pathogen-related disorders. Although major progress toward this end has been achieved over the past few years, our further understanding of the pleiotropic mechanisms involved with AM as a protective peptide is paramount to maximize its clinical application.

Key Words: PAMP • AMBP-1 • septic shock


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ADRENOMEDULLIN (AM) GENE AND PROTEIN STRUCTURE
 
AM was isolated originally by Kitamura et al. [1 ] from a human pheochromocytoma, based on its ability to elevate intracellular cyclic adenosine monophosphate (cAMP) in rat platelets and to cause strong hypotension. The AM gene is located at the short arm of human chromosome 11 (p11.1-3) and is made up of four exons and three intercalated introns [2 ]. It encodes a 185-amino acid preprohormone (Fig. 1 ), which after cleavage of the 21-residue N-terminal signal peptide, generates a 164-amino acid peptide known as pro-AM. This prohormone is processed further into two biologically active peptides: AM, which is entirely located at the fourth exon, and PAMP, encoded by exons two and three. A third fragment derived from the AM precursor, pro-AM 45–92, has recently been identified [3 ]. This peptide is produced in stoichiometric amounts to AM and PAMP and contrary to them, is apparently inactive and stable. The AM gene undergoes alternative splicing, resulting in two mRNAs variants, which in turn, codify two different preprohormones. The shortest mRNA form includes Exons 1–4 and generates AM and PAMP peptides. In the longest mRNA form, the third intron is incorporated, which contains an early termination codon in its sequence. As a consequence, only PAMP gets translated [4 ].


Figure 1
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  		Figure 1. Schematic representation of the AM preprohormone. Pro-AM N-terminal 20 peptide (PAMP) is shown in red and AM in green. Some important structural aspects have also been highlighted: amino acids in blue represent Gly, where PAMP and AM are amidated once the preprohormone is processed. Peptidyl glycine {alpha}-amidating monooxigenase (PAM) is an enzyme complex, which converts the {alpha}-amine of Gly to the amide of the carboxy terminal amino acid of AM and PAMP (Tyr and Arg, respectively). Amino acids cleaved by carboxypeptidases are shown in yellow. Note the presence of a disulfide bond between two Cys on the AM sequence.

The characterization of purified AM showed that it contains 52 amino acids with a tyrosine amide at its C terminus and a single disulfide linkage (between amino acids 16 and 21) forming a six-residue ring structure [1 ]. The mature form of AM is processed by enzymatic amidation from a glycine-extended precursor. Although both forms coexist in plasma, most of the circulating, free AM consists of the glycine-extended form, probably reflecting the process of production in tissue [5 ] or a preferential binding pattern to its plasma-binding protein (see below). AM shares a slight homology with calcitonin gene-related peptide (CGRP [6 ]) and amylin [7 ], and the intramolecular disulfide bridge and the C-terminal amide structure are conserved. These facts, together with similar biological and pharmacological activities, place AM in the CGRP family of peptides [8 ]. Although the secondary structure of AM has not yet been resolved, several prediction algorithms converge, showing an {alpha}-helix region from residues 31 to 33 [9 ]. The second product of pro-AM is PAMP, an amidated, 20-amino acid-long peptide. Its secondary structure has been resolved recently by nuclear magnetic resonance and consists of an {alpha}-helix for residues 2–20. Recent reviews have compiled the state of the art on AM [10 , 11 ]. As a result of the diverse actions of AM in disease states, a potential clinical use as a therapeutic target has been proposed for this peptide [12 ].


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COMPLEMENT FACTOR H IS AN AM-BINDING PROTEIN 1
 
In 1999, our group identified an AM binding protein (AMBP-1) in the plasma of several species including humans [13 ]. Nonradioactive ligand-blotting assay together with high-pressure liquid chromatography/sodium dodecyl sulfate-polyacrylamide gel electrophoresis purification techniques permitted the isolation of AMBP-1, which by database comparison, was subsequently identified as complement factor H, an inhibitor of the classic and alternative pathways of the complement cascade [14 ]. The AM-AMBP-1 complex cannot be dissociated in vitro under acidic or high salt conditions, supporting a strong interaction between both molecules. In fact, interaction between AM with its binding protein interferes with its quantification by radioimmunoassay (RIA) and other immunoassays. Several alternatives have been proposed to avoid this problem including quantification of midregional pro-AM by immunoluminometric assay [3 , 15 , 16 ]. The resulting AM factor H complex regulates the bioactivity of both molecules. It is interesting that AMBP-1 does not alter the affinity of AM for its receptor but rather, seems to protect it against enzymatic degradation [17 ], which could explain why the addition of AMBP-1 enhances AM-induced cAMP production in Rat-2 cells [18 ] and AM-induced growth in the breast cancer cell line T-47D. AM also regulates factor H activity as a complement modulator by increasing the ability of this molecule to facilitate the cleavage of C3b in the presence of Factor I [14 ].


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AM AND PAMP ARE POTENT, ANTIMICROBIAL PEPTIDES
 
Many antimicrobial peptides are produced by mucosal epithelia in mammals. The expression and accumulation of AM in epithelia surfaces (skin, lung, genitourinary tract, digestive system, and others) and body fluids (plasma, sweat, milk, saliva, amniotic fluid, and others) [11 ] soon pointed to its possible role as an antimicrobial agent. In a seminal paper, Allaker and coworkers [19 ] tested the sensitivity of several members of the human skin, oral, respiratory tract, and gut microflora to AM by disc diffusion and broth microdilution assays. All Gram-positive and Gram-negative strains tested were equally susceptible to AM-induced lysis, although no effect was observed on the yeast Candida albicans. Furthermore, exposure of oral keratinocytes to several commonly isolated microorganisms from the mouth resulted in up-regulation of AM, and no effect was observed after exposure to C. albicans [20 ]. These two reports not only demonstrated the antimicrobial activity of AM but identified a pathway by which microbial products enhance the mucosal defense mechanism through up-regulation of antimicrobial peptides such as AM itself. Some concerns have been expressed in the literature as to whether the levels of AM present in epithelial surfaces and body fluids reach a sufficient concentration to function as an antimicrobial peptide [21 ]. Recently, gene expression profiling followed by real-time polymerase chain reaction analysis has succeeded in detecting AM up-regulation in carious pulpal tissue [22 ]. In a functionally related paper, RIA measurements have shown that AM is present in gingival crevicular fluid at levels consistent with antimicrobial activity [23 ]. These reports confirm that AM expression is enhanced after polymicrobial insult and that microenviromental levels of AM reach an appropriate concentration to be effective as an antimicrobial peptide. Marutsuka et al. [24 ] studied the presence of AM immunoreactivity in mucosal and glandular epithelia of the gastrointestinal, respiratory, reproductive, and auditory systems. It is worth reiterating that given the genomic structure of the AM gene, the two possible spliced transcripts should generate equimolecular amounts of AM and PAMP or only PAMP. Therefore, without taking into consideration possible differences in translation rates of both transcripts and different degradation rates of both peptides, the presence of the AM peptide should implicate PAMP production at the same mucosal epithelia where AM is expressed. The presence of PAMP in such areas encouraged Marutsuka and coworkers [24 ] to test its antimicrobial activity. Using colony count assay, the authors demonstrated that PAMP has stronger antimicrobial activity against Escherichia coli than AM or other known antimicrobial peptides such as neutrophilic peptide-1 [24 ]. Additional proof that AM functions as an antimicrobial agent results from its up-regulation after exposure to various pathogens in an in vivo animal model [25 ]. Recently, we have gained some insight into the antimicrobial mechanism of action of AM [9 ]. Ultrastructural analyses have shown cell-wall disruption shortly after (within 30 min) treatment with AM in E. coli. Alternatively, abnormal septum formation with no cell-wall disruption was observed in Staphylococcus aureus. It is interesting that carboxy terminal fragments of AM were shown to be more active than the whole molecule, suggesting that this region is required for optimal antimicrobial activity. This model could give further insight to explain the inhibitory effect of AMBP-1 on the antimicrobial action of AM [14 ]. Two AM-binding regions (high- and low-affinity, respectively) have been described in factor H, which do not colocalize with the C3b-binding site [26 ]. Although the three-dimensional structure of the AM-AMBP-1 dimer remains unknown, complex formation prevents AM cleavage by matrix metalloproteinase 2 in several regions of the molecule [17 ], which suggests that AMBP-1 masks at least a portion of the AM peptide, making it unavailable for interaction with other molecules. In this sense, AMBP-1 acts as a chaperone, creating steric interferences impeding AM interaction with other molecules. This could prevent the interaction of AM with the bacterial wall, resulting in decreased antimicrobial activity.


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ROLE OF AM IN SEPTIC RESPONSE
 
Intravenous (i.v.) infusion of lipopolysaccharide (LPS) into rats results in a dramatic elevation of AM in the plasma and tissue viscera of the challenged animal [27 ]. Successive reports have corroborated these findings in a variety of animal models [28 , 29 ] and have determined that the small intestine is an important source of plasma AM during sepsis [30 ]. Recent findings suggest that AM levels in plasma and various tissues during sepsis are influenced by multiple factors such as circulating levels of LPS [31 ], decrease in clearance, and enhanced synthesis by multiple organ dysfunction [32 ] and are also regulated by expression and activity of neutral endopeptidases [33 ]. Several studies have shown elevated levels of plasma AM in patients during septic sock, implicating a potential role of AM in this disease state [32 , 34 ]. The cecal ligation and puncture (CLP) model has been used to further investigate the action of AM in septic animals [35 ]. Similar to what is seen in blood-borne, pathogen-infected patients, the septic response in animals with CLP is biphasic with an early hyperdynamic phase, which takes place between 2 and 10 h after CLP and a late hypodynamic phase starting 16 h after CLP. Using this model, the authors described elevation in plasma AM as early as 2 h after CLP (simultaneous with the onset of the hyperdynamic phase), a progressive increase from 5 to 20 h thereafter, and sustained, elevated levels 30 h after the onset of sepsis. These results stimulated subsequent studies aimed to elucidate AM as a causal agent of the hyperdynamic phase. AM i.v. infusion in rats mimicked the hyperdynamic parameters typical of early sepsis (cardiac output, stroke volume, and microvascular blood flow in the liver, small intestine, kidney, and spleen increased; total peripheral resistance decreased), whereas administration of anti-AM antibodies prevented the occurrence of the hyperdynamic response [35 ], demonstrating that AM plays a pivotal role in producing a hyperdynamic response during early sepsis. Studies in different animal models have further supported the role of AM as a causal agent of the hyperdynamic circulation early in sepsis [36 ]. It is surprising that transition to the late hypodynamic phase occurs in the presence of steady high levels of plasma AM. In a subsequent publication, Wang and coworkers [37 ] addressed this apparently paradoxical phenomenon. The responsiveness to AM in thoracic aorta rings shows no change at 5–10 h after CLP but significantly decreased 20 h after the onset of sepsis. Authors proposed that reduced vascular responsiveness to AM might be responsible for the transition between early hyperdynamic and late hypodynamic phases in the course of polymicrobial sepsis and that maintenance of vascular AM responsiveness by pharmacological agents could be a novel approach for preventing or delaying the hypodynamic phase and eventually, septic shock. Consistent with this hypothesis, a follow-up study showed that administration of pentoxifylline (PTX) early after the onset of sepsis preserves the macro- and microvascular responsiveness to AM, although it did not affect its expression after CLP. However, tumor necrosis factor {alpha} (TNF-{alpha}), interleukin (IL)-1ß, and IL-6 expression was attenuated by PTX administration, suggesting a link between maintenance of AM responsiveness and down-regulation of these cytokines [38 ].

A number of publications have reported beneficial effects of exogenous AM in different aspects of the sepsis onset. Endothelial hyperpermeability and deterioration in vascular reactivity are hallmarks of sepsis and are believed to be responsible for the transition from hyperdynamic to the hypodynamic phase. AM has been found to prevent vascular leakage in vitro [39 ] and to protect ileum by reducing {alpha}-toxin-induced microcirculatory disturbances and by stabilizing the endothelial barrier function [40 ]. As AM has an overall protective effect in sepsis, molecules that enhance its activity should prove beneficial as treatments of this pathology. Recently, we have identified and partially characterized several positive small molecule regulators of the AM function using a neutralizing antibody-based screening strategy [41 , 42 ]. Future planned studies will address the appropriateness of these nonpeptidic molecules in the treatment of sepsis.

As noted above, the genomic organization of the AM gene results in equimolecular amounts of AM and PAMP (when no early termination codon is incorporated in the mRNA). Although several factors, including differential protease degradation rates, could result in different levels of AM and PAMP in plasma and tissues, given the expression pattern of AM in sepsis, it seems logical to speculate that PAMP should be increased after endotoxic insult. Moreover, given the parallelisms reported previously in the antimicrobial activity of both peptides [43 44 45 46 ], it would certainly be interesting to study possible implications of PAMP in sepsis. It is surprising that little is known about the role of PAMP in sepsis, and to our knowledge, only a single study has assessed the levels of PAMP in a rat model of endotoxic shock. As expected, PAMP is elevated in plasma and parallels AM expression pattern in several tissues after LPS challenge. Differences in PAMP levels between the control and the LPS-challenged group were lower than those observed for AM. Further studies are necessary to uncover any relevance of PAMP during sepsis progression.


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BENEFICIAL EFFECTS OF AM-AMBP-1 ON THE SEPSIS OUTCOME
 
The bulk of the data presented so far suggests a protective role of AM during sepsis and renders it an attractive molecule for the treatment of septic shock. Several studies have shown that AM gene delivery protects against multiple disorders including hypertension, cerebral ischemic injury, myocardial infraction, and renal injury [47 48 49 50 ]. More definitive proof of the beneficial actions of AM in septic shock and validation of its use as treatment in sepsis come from its administration or ectopic overexpression alone or in combination with its binding protein AMBP-1 in sepsis models. As expected, transgenic mice overexpressing AM in vascular endothelial and smooth muscle cells exhibited significantly lower blood pressure than their wild-type littermates. It is interesting that LPS challenge elicited less-severe organ damage in AM transgenic mice, which showed a significantly higher 24-h survival rate than wild-type animals [51 ]. In this transgenic model, administration of the nitric oxide (NO) inhibitor NG-monomethyl-L-arginine decreased the survival advantage conveyed by overexpression of AM, suggesting that AM-induced NO expression contributed to the protective effect of AM against shock.

As mentioned before, vascular responsiveness decreases 20 h after CLP [37 ], and it is interesting that a concomitant reduction in the amount of AMBP-1 was observed by Western blot analysis [52 ]. In vitro addition of AMBP-1 successfully restored the vascular relaxation induced by AM, suggesting that a reduction in AMBP-1 could be responsible for the vascular AM hyporesponsiveness observed during the hypodynamic phase of sepsis. Yang and coworkers [53 ] demonstrated on a CLP rat model that administration of AM/AMBP-1 reduces the overall 10-day mortality rate from 57% to 7%, whereas administration of either factor alone failed to reproduce the results. In the same work, the authors showed a decrease in the measured systemic and regional hemodynamic parameters 20 h after the onset of sepsis, together with attenuated, hepatic damage and prevention in hemoconcentration. Vascular endothelial cell apoptosis occurs in the late stage of sepsis and is linked to a decrease in Blc-2 expression. Coadministration of AM and AMBP-1 early after sepsis significantly reduces the number of apoptotic endothelial cells in aortic and pulmonary tissue, and this effect is associated with a recovery in Bcl-2 expression in endothelial cells together with a decrease in the proapoptotic factor Bax [54 ]. These results suggest that administration of AM/AMBP-1 delays or prevents the transition from the early, hyperdynamic phase to the later, hypodynamic phase in sepsis.


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AM IN IMMUNE SYSTEM CELLS: COREGULATION OF AM AND INFLAMMATORY CYTOKINES IN SEPSIS
 
Although little is known about the biology of AM in cells of the immune system, a few reports have recently began to define its role in immune cell function. Neutrophils are usually the first cells arriving to inflammatory sites and represent cardinal cellular effectors of the innate host response [55 ]. AM is produced by neutrophils [22 ] and significantly potentiates accumulation of this cell type in skin through an IL-1ß-dependent mechanism [56 ]. However, AM suppresses formyl-Met-Leu-Phe-induced up-regulation of the adhesion molecule CD11b in human neutrophils through a cAMP-mediated mechanism, suggesting that it acts to inhibit neutrophil activation and migration potential [57 ]. The inhibitory potential of AM on neutrophil migration has also been proposed in the context of ischemic brain injury [58 ]. Based on these results, it seems that the effect of AM on neutrophil biology could be dependent on tissue environment and disease state. AM up-regulation has been reported in leukocytes in newborn infants with severe hypoxic-ischemic encephalopathy [59 ]. Also, it has been shown that AM is a critical factor for the survival of antigen-activated T cells [60 ]. Of special interest for our understanding of the biology of sepsis are publications focused on the role of AM in mast cell (MC) regulation. The pivotal role of MC during sepsis has only been recognized recently [61 62 63 64 65 66 67 68 69 ]. Yoshida and coworkers [70 ] demonstrated that PAMP and AM cause rat peritoneal MC degranulation. A recent study by our group shows that degranulation of human (h)MC is a receptor-independent mechanism, which occurs only in the presence of high concentrations of AM (µM range). However, AM at nanomolar concentrations acts as a chemotactic agent and is able to induce the expression of proangiogenic factors in MC, which supports that receptor-mediated actions also occur [71 ]. It is interesting that hypoxic insult, a condition known to enhance AM expression in multiple cell types through a hypoxia-inducible factor-1{alpha}-dependent mechanism [72 ], fails to drive AM expression in undifferentiated hMC. Exposure to the differentiation agent phorbol ester seems to equip hMC with the necessary cellular machinery to drive AM expression [71 ]. These collective data support a complex and tight regulation of AM expression in MC and a wide involvement of AM in MC function, which could potentially be relevant in sepsis.

Monocytes and macrophages are broadly recognized as one of the key cellular components in the sepsis onset [73 ]. Multiple studies over the last decade have demonstrated the ability of in vitro-cultured and animal-isolated macrophages from different anatomical locations to produce and secrete AM [74 75 76 77 78 79 ]. Macrophage-derived AM is regulated by a number of naturally occurring factors as well as man-made drugs implicated in multiple mechanisms involved in the host defense system. Several substances known to induce differentiation and/or activation of monocytes/macrophages, such as phorbol ester, retinoic acid, LPS, and interferon-{gamma}, were shown to induce AM in these cell types [75 , 80 ]. Conversely, dexamethasone, hydrocortisone, estradiol, transforming growth factor-ß, and IL-6 decreased AM production in cultured macrophages [75 ]. Toll-like receptor 4 (TLR4) is involved in LPS-dependent AM induction in macrophages, as AM expression is not found in TLR4 mutant C3H HeJ mice after exposure to LPS [81 ]. In addition, AM has been shown to inhibit the secretion of cytokine-induced neutrophil chemoattractant from rat alveolar macrophages via a cAMP-dependent mechanism [82 ]. The complexity of the cytokine-mediated regulation of AM expression in different cell types and the effect of AM on the expression of inflammatory cytokines have been made apparent by several recently published studies [83 84 85 86 ]. Cumulative data suggest that the regulation of the AM gene by inflammatory cytokines is cell type- or even species-dependent. The effect of AM in the expression of these factors seems to be equally multifaceted. Provided that in-depth studies are required to understand the biology of AM in different cell types and in the context of multiple tissue-specific environmental conditions, in vivo experiments have proven informative to understand the global coregulation of AM and inflammatory cytokines as it relates to sepsis progression. For instance, one of the possible mechanisms responsible for the protective effect of AM/AMBP-1 in sepsis is the down-regulation of proinflammatory cytokines. In vitro experiments have shown that coadministration of AM and AMBP-1 effectively suppresses LPS-induced TNF-{alpha} expression and release in primary-cultured rat Kupffer cells [87 ]. In agreement with these results, i.v. administration of AM/AMBP-1 5 h after CLP reduced plasma concentrations of TNF-{alpha}, IL-1ß, and IL-6 at 20 h after the onset of sepsis [88 ].

A recent study addresses the effect of AM on proinflammatory and anti-inflammatory cytokines on in vitro-cultured rat macrophages [89 ]. In agreement with previous reports, AM was shown to potently suppress LPS-induced TNF-{alpha} production on macrophages. It is interesting that in this in vitro model, AM up-regulates the production of the anti-inflammatory cytokine IL-6 in nonstimulated and LPS-stimulated macrophages [90 ]. AM is known to induce IL-6 production in the mouse fibroblast cell line Swiss 3T3 [91 ]. Up-regulation of IL-6 and down-regulation of TNF-{alpha} support a role of AM as an anti-inflammatory factor that suppresses the progression of inflammation. Conversely, the same work shows that AM significantly increases the production of migratory inhibitory factor (MIF) and IL-1ß. As MIF and IL-1ß are potent mediators of inflammation, these results suggest that AM may also have a role as a proinflammatory factor. In a recent study by our group, we emphasize the role of AM as a molecule that regulates MC function-enhancing inflammation during human carcinogenesis [71 ]. These conflicting results exemplify the complex story surrounding the interactions of AM with the immune system and support the need for additional studies in this area to precisely define the possible therapeutic role of AM in septic shock.


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EVOLUTIONARY ASPECTS: AM AS A NEURO/ANTIMICROBIAL PEPTIDE
 
Coevolution of genetically diverse pathogens and the first eukariotic organisms provided a platform for the development of innate immunity, a first-line host defense based on a variety of clever mechanical, cellular, and chemical mechanisms aimed to limit infection in the early hours after exposure to microorganisms [92 ]. In evolved eukariotic organisms, innate immunity is often powered by external epithelial structures, which represent the first barrier against pathogenic infections. Epithelia are not only the simplest form of mechanical protection but also highly evolved, biologically active barriers whose cellular units are capable of synthesizing, storing, and secreting key molecules needed in innate immunity, the antimicrobial peptides [93 ]. Antimicrobial molecules are a diverse group of typically short (12–50 amino acids long), cationic (+2 to +7 net charge) peptides characterized by spatially separated hydrophobic and charged regions, which allow bacterial membrane intercalation [94 ]. The above-discussed protein structure for AM and PAMP certainly resembles the basic description of an antimicrobial peptide. A combination of immunohistochemistry, molecular biology techniques, and the advancement in the capability to decode entire genomes from different species has proven successful in demonstrating the presence of AM and AM-like epitopes in species from the Cambrian period [95 ] to the recent times. AM is an ancient gene that shows a remarkable degree of conservation in genomic organization and peptide structure from fish to humans [96 , 97 ]. This high degree of conservation through evolutionary adaptation supports its critical role in species survival. It is interesting that so far, the first known appearance of AM in evolution occurs in the nerves of the basiepithelial plexus of cardiac and pyloric stomachs and the pyloric caecanervous system of the starfish, which suggests its role in regulation of muscle movement and neurotransmission [95 ]. However, it is worth noting that the interactions between the immune and nervous systems appear to have a long, evolutionary history [98 , 99 ]. It is interesting that the structural and physicochemical similarities among neuropeptides, peptide hormones, and cationic antimicrobial peptides have been long known [98 , 100 ]. This intimate relationship between immune and nervous systems is well-exemplified in a set of molecules that function as antimicrobial and neuropeptides. Several antimicrobial peptides, particularly defensins, are produced in the central nervous system of many species [101 102 103 ]. In a recently published review, AM is recognized as a locally produced neuropeptide with direct antimicrobial function [98 , 100 ]. Certain evolutionary interest rises to test the hypothesis that rather than being an ancillary function, host defense together with neurotransmission could have been the major purpose of AM since ancient species.


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CONCLUDING REMARKS
 
Over the past decade, a growing body of evidence has implicated AM, AMBP-1, and PAMP as important pleiotropic effectors of the host defense mechanism. AM is quickly mobilized by the epithelium upon polymicrobial injury and together with PAMP, participates in the first line of defense, exerting a potent, antimicrobial action. Although it is still too early to predict the possible clinical benefit AM may offer septic shock patients, a growing body of evidence suggests that combined AM/AMBP-1 therapy could prevent hyperdynamic-to-hypodynamic-phase transition, protect against polymicrobial sepsis-induced cell damage, and ultimately, lower mortality rates. Given this possibility, small molecule enhancers of AM activity should be considered as an attractive, therapeutic strategy for sepsis.

Received February 28, 2006; revised April 11, 2006; accepted April 13, 2006.


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