Plasma Levels Of Serum Amyloid Research Articles

Key charged residues influence the amyloidogenic propensity of the helix-1 region of serum amyloid A

Increased plasma levels of serum amyloid A (SAA), an acute-phase protein that is secreted in response to inflammation, may lead to the accumulation of amyloid in various organs thereby obstructing their functions. Severe cases can lead to a systemic disorder called AA amyloidosis. Previous studies suggest that the N-terminal helix is the most amyloidogenic region of SAA. Moreover, computational studies implicated a significant role for Arg-1 and the residue-specific interactions formed during the fibrillization process. With a focus on the N-terminal region of helix-1, SAA1–13, mutational analysis was employed to interrogate the roles of the amino acid residues, Arg-1, Ser-5, Glu-9, and Asp-12. The truncated SAA1–13 fragment was systematically modified by substituting the key residues with alanine or uncharged but structurally similar amino acids. We monitored the changes in the amyloidogenic propensities, associated conformational markers, and morphology of the amyloids resulting from the mutation of SAA1–13. Mutating out Arg-1 resulted in much reduced aggregation propensity and a lack of detectable β-structures alluding to the importance of salt-bridge interactions involving Arg-1. Our data revealed that by systematically mutating the key amino acid residues, we can modulate the amyloidogenic propensity and alter the time-dependent conformational variation of the peptide. When the behaviors of each mutant peptide were analyzed, they provided evidence consistent with the aggregation pathway predicted by MD simulation studies. Here, we detail the important temporal molecular interactions formed by Arg-1 with Ser-5, Glu-9, and Asp-12 and discuss its mechanistic implications on the self-assembly of the helix-1 region of SAA.

Regulation of the Innate Immune System as a Therapeutic Approach to Supporting Respiratory Function in ALS

Amyotrophic lateral sclerosis (ALS) is a clinical diagnosis used to define a neurodegenerative process that involves progressive loss of voluntary muscle function and leads to death within 2-5 years after diagnosis, in most cases because of respiratory function failure. Respiratory vital capacity (VC) measurements are reproducible and strong predictors of survival. To understand the role of the innate immune response in progressive VC loss we evaluated ALS clinical trial and biomarker results from a 6-month phase 2 study of NP001, a regulator of innate immune function. All ALS baseline values were similar between treated and controls except for those > 65 years old who were excluded from analysis. Treated patients with plasma CRP ≥ 1.13 mg/L (high CRP) showed a 64% slower rate of VC decline compared with placebo and those with plasma CRP < 1.13 mg/L (low CRP) who showed no response. High CRP patients showed no age associated loss of VC whereas low CRP patients showed an age dependent loss of VC function. Plasma levels of serum amyloid A (SAA) were similarly elevated in high CRP patients consistent with ongoing innate immune activation. Plasma TGFB1 in high CRP treated patients was 95% higher than placebo at 6-months, confirming the activation and release of this anti-inflammatory factor by the innate immune alpha 2 macroglobulin (A2M) system. This report is the first to link a biomarker confirmed regulation of the innate immune system with a therapeutic approach for controlling VC loss in ALS patients.

Effects of mineral oil administration on the pharmacokinetics, metabolism and pharmacodynamics of atorvastatin and pravastatin in mice and dogs

We investigated the effects of mineral oil on statin pharmacokinetics and inflammatory markers in animal models. A new synthesis strategy produced regioisomers that facilitated the characterization of the main metabolite (M1) of atorvastatin, a lipophilic statin, in C57BL/6NCrl mice. The chemical structure of M1 in mice was confirmed as ortho-hydroxy β-oxidized atorvastatin. Atorvastatin and M1 pharmacokinetics and inflammatory markers were assessed in C57BL6/J mice given atorvastatin 5 mg/kg/day or 10 mg/kg/day, as a single dose or for 21 days, with or without 10 µL or 30 µL mineral oil. No consistent differences in plasma exposure of atorvastatin or M1 were observed in mice after single or repeat dosing of atorvastatin with or without mineral oil. However, mice administered atorvastatin 10 mg/kg with 30 µL mineral oil for 21 days had significantly increased plasma levels of serum amyloid A (mean 9.6 µg/mL vs 7.9 µg/mL without mineral oil; p < 0.01) and significantly increased proportions of C62Lhigh B cells (mean 18% vs 12% without mineral oil; p = 0.04). There were no statistically significant differences for other inflammatory markers assessed. In dogs, pharmacokinetics of atorvastatin, its two hydroxy metabolites and pravastatin (a hydrophilic statin) were evaluated after single administration of atorvastatin 10 mg plus pravastatin 40 mg with or without 2 g mineral oil. Pharmacokinetics of atorvastatin, hydroxylated atorvastatin metabolites or pravastatin were not significantly different after single dosing with or without mineral oil in dogs. Collectively, the results in mice and dogs indicate that mineral oil does not affect atorvastatin or pravastatin pharmacokinetics, but could cause low-grade inflammation with chronic oral administration, which warrants further investigation.

Correlation Study of the Long-Term Prognosis of Venous Thromboembolism and Inflammatory Gene Polymorphisms.

BackgroundVenous thromboembolism (VTE) is the third most common cause of cardiovascular death worldwide, following coronary heart disease and stroke, and many risk factors for VTE are not yet clear. Our study investigated the association between multiple inflammatory gene polymorphisms and VTE prognosis, aiming to find a new predictor of VTE prognosis.MethodsBased on our previous studies, we detected the plasma levels of serum amyloid A protein (SAA), interleukin-1 (IL-1) and tumor necrosis factor-a (TNF-a) and their 8 gene polymorphisms by ELISA and a multiplex ligation detection reaction (iMLDR) method in 284 patients with VTE. All subjects were followed up for 5 years.ResultsThe 5-year follow-up results of this study showed that 62 of the 284 patients (21.83%) had reached the endpoint (all-cause death). Kaplan–Meier survival analyses revealed that the mortality rate of VTE patients with a high Simplified Pulmonary Embolism Severity Index (SPESI) score and carrying IL-1 rs1800587 mutation genotypes was significantly increased (log-rank p=0.000 and 0.034 respectively). The multifactor Cox regression results confirmed that the mortality rate of patients who carrying IL-1 rs1800587 mutation genotypes was significantly increased (HR=2.982; 95% CI: 1.681–5.100). The mortality rate of those carrying IL-1 rs1143634 mutation genotypes was significantly decreased (HR=0.294; 95% CI: 0.132–0.652). There were no significant differences in mortality rates between wild-type and mutant genotypes of IL-1 rs1143634, IL-1 rs2234650, SAA rs11603089, and TNF-α rs1800629 (P>0.05).ConclusionA high SPESI score and the presence of the IL-1 rs1800587 mutant genotype predict shorter survival in patients with VTE, whereas the IL-1 rs1143634 genotype is associated with a lower mortality rate. Screening for mutations in inflammation-related genes has prognostic value in the clinical management of VTE.

Correlation study of venous thromboembolism with SAA, IL-1, and TNF-a levels and gene polymorphisms in Chinese population.

The relationship between inflammation and venous thromboembolism (VTE) has not been fully elucidated. Based on our previous studies, we detected the plasma levels of serum amyloid A protein (SAA), interleukin-1 (IL-1), and tumor necrosis factor-a (TNF-a) and their 8 gene polymorphisms by ELISA and a multiplex ligation detection reaction (iMLDR) method in 284 patients with VTE and 268 healthy controls. Levels of SAA (P=0.032), IL-1 (P=0.045), and TNF-a (P=0.040) were significantly higher in the VTE group than in the control group. Recessive model analysis of the IL-1 rs1800587 variant showed that the risk of VTE in patients with the GG + GA genotype was significantly higher than that in patients with the AA genotype [odds ratio (OR): 4.444; 95% CI: 1.466-13.470]. Recessive model analysis of the IL-1 rs2234650 polymorphism showed that the risk of VTE in patients with the CC + CT genotype was significantly lower than that in patients with the TT genotype (OR: 0.500; 95% CI: 0.268-0.934). Multivariate logistic regression analysis showed that the TT genotype at IL-1 rs2234650 (OR: 2.086; 95% CI: 1.091-3.985) was an independent risk factor for VTE. The AA genotype of IL-1 rs1800587 (OR: 0.226; 95% CI: 0.074-0.890) was an independent protective factor against VTE. In summary, an intrinsic relationship may exist between inflammatory activation and the occurrence of VTE.

Comparative Study on Hyaluronic Acid Binding to Murine SAA1.1 and SAA2.2

Persistently high plasma levels of serum amyloid A (SAA) may induce AA amyloidosis in various organs causing their dysfunction. Although SAA isoforms share a high degree of homology, only the SAA1.1 isoform is found in amyloid deposits. SAA1.1 misfolding is a nucleation-dependent process with dimer and trimer formation playing a major role in SAA fibril formation through self-catalyzed recruitment of native SAA molecules. Yet, a structural model of initial SAA oligomerization is still missing. In this study, we constructed a loosely associated model for murine SAA1.1 and SAA2.2 dimers in the presence or absence of hyaluronic acid as an exemplary glycosaminoglycan, a factor known to facilitate SAA fibril formation. Molecular dynamics simulations predicted that hyaluronic acid finally stabilized in a different binding pocket of the pathogenic SAA1.1 dimer compared to the nonpathogenic SAA2.2 dimer. Besides, Markov state modeling points to dynamic behavioral differences between the linker region of SAA1.1 and SAA2.2 and identifies a state unique to pathogenic SAA1.1 while bound to hyaluronic acid. The presence or absence of hyaluronic acid, as well as the dimer interface switch, affects dynamic behavior and possible oligomeric states, proposing a conceivable clue to the deviant pathogenicity of the two SAA isoforms.

Course of serum amyloid A (SAA) plasma concentrations in horses undergoing surgery for injuries penetrating synovial structures, an observational clinical study

BackgroundInjuries penetrating synovial structures are common in equine practice and often result in septic synovitis. Significantly increased plasma levels of serum amyloid A (SAA) have been found in various infectious conditions in horses including wounds and septic arthritis. Plasma SAA levels were found to decrease rapidly once the infectious stimulus was eliminated. The purpose of the current study was to investigate the usefulness of serial measurements of plasma SAA as a monitoring tool for the response to treatment of horses presented with injuries penetrating synovial structures. In the current study plasma SAA concentrations were measured every 48 hours (h) during the course of treatment.ResultsA total of 19 horses with a wound penetrating a synovial structure were included in the current study. Horses in Group 1 (n = 12) (injuries older than 24 h) only needed one surgical intervention. Patients in this group had significantly lower median plasma SAA levels (P = 0.001) between 48 h (median 776 mg/L) and 96 h (median 202 mg/L) after surgery. A significant decrease (P = 0.004) in plasma SAA levels was also observed between 96 h after surgery (median 270 mg/L) and 6 days (d) after surgery (median 3 mg/L). Four horses (Group 2) required more than one surgical intervention. In contrast to Group 1 patients in Group 2 had either very high initial plasma concentrations (3378 mg/L), an increase or persistently high concentrations of plasma SAA after the first surgery (median 2525 mg/L). A small group of patients (n = 3) (Group 3) were admitted less than 24 h after sustaining a wound. In this group low SAA values at admission (median 23 mg/L) and peak concentrations at 48 h after surgery (median 1016 mg/L) were observed followed by a decrease in plasma SAA concentration over time.ConclusionsA decrease in plasma SAA concentrations between two consecutive time points could be associated with positive response to treatment in the current study. Therefore, serial measurements of plasma SAA could potentially be used as an additional inexpensive, quick and easy tool for monitoring the treatment response in otherwise healthy horses presented with injuries penetrating synovial structures. However further studies will be necessary to ascertain its clinical utility.

Factor XI Deficiency Alters the Cytokine Response and Activation of Contact Proteases during Polymicrobial Sepsis in Mice.

Sepsis, a systemic inflammatory response to infection, is often accompanied by abnormalities of blood coagulation. Prior work with a mouse model of sepsis induced by cecal ligation and puncture (CLP) suggested that the protease factor XIa contributed to disseminated intravascular coagulation (DIC) and to the cytokine response during sepsis. We investigated the importance of factor XI to cytokine and coagulation responses during the first 24 hours after CLP. Compared to wild type littermates, factor XI-deficient (FXI-/-) mice had a survival advantage after CLP, with smaller increases in plasma levels of TNF-α and IL-10 and delayed IL-1β and IL-6 responses. Plasma levels of serum amyloid P, an acute phase protein, were increased in wild type mice 24 hours post-CLP, but not in FXI-/- mice, supporting the impression of a reduced inflammatory response in the absence of factor XI. Surprisingly, there was little evidence of DIC in mice of either genotype. Plasma levels of the contact factors factor XII and prekallikrein were reduced in WT mice after CLP, consistent with induction of contact activation. However, factor XII and PK levels were not reduced in FXI-/- animals, indicating factor XI deficiency blunted contact activation. Intravenous infusion of polyphosphate into WT mice also induced changes in factor XII, but had much less effect in FXI deficient mice. In vitro analysis revealed that factor XIa activates factor XII, and that this reaction is enhanced by polyanions such polyphosphate and nucleic acids. These data suggest that factor XI deficiency confers a survival advantage in the CLP sepsis model by altering the cytokine response to infection and blunting activation of the contact (kallikrein-kinin) system. The findings support the hypothesis that factor XI functions as a bidirectional interface between contact activation and thrombin generation, allowing the two processes to influence each other.

Metabolites of arachidonic acid acting in the small intestine mediate systemic and vascular inflammation in LDLR null mice (832.13)

We previously reported that a Western Diet increased levels of free arachidonic acid (AA) and its metabolites in the small intestine and plasma of LDLR null mice and increased plasma levels of serum amyloid A (SAA). To determine the role of AA metabolites in initiating inflammation, LDLR null mice on a chow diet were or were not administered 15‐hydroxyeicosatetraenoic acid (15‐HETE) at a dose of 5 μg/day (mixed into the chow) or the mice received 5 μg/day subcutaneously (SQ). After two weeks the mice were bled, perfused with saline to remove any remaining blood and the heart was harvested. Plasma levels of SAA were determined by ELISA and levels of free AA and its metabolites were determined in plasma by LC‐ESI‐MS/MS. Plasma SAA levels increased from 6.4 ± 1.9 ug/mL on chow without 15‐HETE to 15 ± 7 ug/mL with oral 15‐HETE (p&lt;0.0001) and 15 ± 8 µg/mL with SQ (p = 0.0004). Plasma levels of free AA increased from 2435 ± 420 ng/mL on chow to 3274 ± 517 ng/mL with oral 15‐HETE (p&lt;0.0001) and 2712 ± 479 ng/mL with SQ (p = 0.001). Three hours after the last SQ dose, plasma 15‐HETE levels were 0.9 ± 0.4 ng/mL on chow, 2.7 ± 1.5 ng/mL after oral (p&lt;0.0001) and 1.5 ± 0.3 ng/mL after SQ 15‐HETE (p&lt;0.0001). 5‐HETE and 12‐HETE levels also increased (p&lt;0.001) and the magnitude of the changes were similar whether the 15‐HETE was administered orally or SQ. We conclude i) 15‐HETE administration increases plasma SAA, and free AA levels to a similar degree whether administered orally or SQ; ii) These results suggest that AA metabolites such as 15‐HETE can act in the small intestine to regulate systemic inflammation.Grant Funding Source: NIH

Intraocular Expression of Serum Amyloid A and Interleukin-6 in Proliferative Diabetic Retinopathy

Because serum amyloid A can regulate angiogenesis, we searched for an association between serum amyloid A and interleukin-6 (IL-6), as proinflammatory factors, and proliferative diabetic retinopathy (PDR). Retrospective, comparative study. Seventy-six patients (76 eyes) with PDR and 31 patients (31 eyes) with nondiabetic ocular disease (control group), including idiopathic epiretinal membranes (8 eyes) and idiopathic macular holes (23 eyes), were enrolled. Enzyme-linked immunosorbent assay, dual-color immunofluorescence staining, and semiquantitative reverse-transcription polymerase chain reaction were used to examine the serum amyloid A and IL-6 levels in vitreous and plasma, expression of protein and mRNA of serum amyloid A in the excised membranes, respectively. Vitreous serum amyloid A and IL-6 levels in the study group were significantly higher than those in the control group (both P < .001), whereas the plasma concentrations of serum amyloid A and IL-6 did not vary significantly between the groups (P = .555 and P = .621, respectively). A significant correlation was observed between the vitreous and plasma levels of serum amyloid A in subjects with PDR (r = 0.525; P < .001). In fibrovascular membranes of the study group, colocalization of endothelial marker CD31 with serum amyloid A and colocalization of fibrillar structure markers fibronectin with serum amyloid A were observed. Expression of serum amyloid A mRNA was significantly higher in fibrovascular membranes with PDR than in idiopathic epiretinal membranes (P = .004). Serum amyloid A and IL-6 may be involved with the inflammatory process in the development of PDR. Local expression of serum amyloid A may exist in PDR.

Secondary bacterial infection in plasma endotoxin levels and the acute‐phase response of mice infected withTrypanosoma brucei brucei

Murine Trypanosoma brucei brucei infection leads to elevated plasma endotoxin-like activity levels not related to parasitaemia levels accompanied by the development of acute-phase response and increased plasma levels of serum amyloid P (SAP) and haptoglobin (Hp). To determine the source of the endotoxin-like activity and role of secondary bacterial infection in the pathogenesis of trypanosomosis, infected mice were treated with the antibiotic ciprofloxacin. Plasma endotoxin-like activity levels, irrespective of treatment, were elevated three- to fourfold, beginning 7 days after infection. Plasma protein concentrations increased markedly following infection from 7 days after infection (DAI). Peak Hp and SAP concentrations in ciprofloxacin-treated and -untreated infected mice were attained 7 and 14 DAI, respectively. Thereafter, both protein levels gradually declined until the end of the experiment, but Hp levels for non-treated mice declined up to 21 DAI and thereafter significantly increased on 28 and 35 DAI. Whole-trypanosome lysate and the membrane-enriched fraction demonstrated endotoxin-like activity, with the former having higher levels. The results suggest that the endotoxin-like activity in trypanosome fractions and plasma of infected mice is due to the trypanosome. Further elevation of haptoglobin during the late stages of infection in non-treated mice suggests the involvement of secondary bacterial infection.

Serum Amyloid A Protein and C-Reactive Protein in Normal Pregnancy and Preeclampsia

Aims: To study plasma levels of serum amyloid A protein and C-reactive protein in pregnant women with and without preeclampsia and non-pregnant women. Plasma levels of haptoglobin, orosomucoid and ceruloplasmin were also analyzed. Methods: The study included 295 women with uncomplicated pregnancies, 57 women diagnosed with preeclampsia, and 58 healthy non-pregnant women. Plasma concentrations of acute phase proteins were analyzed by particle-enhanced immunoassays. Non-parametric Kruskal-Wallis and Mann-Whitney U tests were used to test differences between the groups. Results: Plasma levels of C-reactive protein and ceruloplasmin were increased in pregnant women with and without preeclampsia compared to non-pregnant women. Plasma levels of serum amyloid A protein and C-reactive protein were not elevated in women with preeclampsia compared to women with normal pregnancy. Conclusion: The description of preeclampsia as a systemic inflammatory state was not reflected in the plasma levels of serum amyloid A protein and C-reactive protein.

Reduced antioxidant capacity and diet-induced atherosclerosis in uncoupling protein-2-deficient mice

Vascular dysfunction in response to reactive oxygen species (ROS) plays an important role in the development and progression of atherosclerotic lesions. In most cells, mitochondria are the major source of cellular ROS during aerobic respiration. Under most conditions the rates of ROS formation and elimination are balanced through mechanisms that sense relative ROS levels. However, a chronic imbalance in redox homeostasis is believed to contribute to various chronic diseases, including atherosclerosis. Uncoupling protein-2 (UCP2) is a mitochondrial inner membrane protein shown to be a negative regulator of macrophage ROS production. In response to a cholesterol-containing atherogenic diet, C57BL/6J mice significantly increased expression of UCP2 in the aorta, while mice lacking UCP2, in the absence of any other genetic modification, displayed significant endothelial dysfunction following the atherogenic diet. Compared with wild-type mice, Ucp2(-/-) mice had decreased endothelial nitric oxide synthase, an increase in vascular cell adhesion molecule-1 expression, increased ROS production, and an impaired ability to increase total antioxidant capacity. These changes in Ucp2(-/-) mice were associated with increased aortic macrophage infiltration and more numerous and larger atherosclerotic lesions. These data establish that in the vasculature UCP2 functions as an adaptive antioxidant defense to protect against the development of atherosclerosis in response to a fat and cholesterol diet.

SAA and PLTP activity in plasma of periodontal patients before and after full‐mouth tooth extraction

To assess whether treatment of advanced periodontal disease affects plasma levels of serum amyloid A (SAA) and phospholipid transfer protein (PLTP) activity. We measured the levels of SAA and PLTP activity in plasma of 66 patients with advanced periodontal disease before and after treatment by full-mouth tooth extraction (FME). At baseline, median SAA levels in our study population were within the normal range (2.7 microg ml(-1)) but SAA was elevated (>5 microg ml(-1)) in 18% of periodontitis patients. Three months after FME, SAA levels were significantly reduced (P = 0.04). SAA did not correlate with any of the periodontal disease parameters. PLTP activity was elevated in patients with periodontitis, compared to the PLTP activity reference group (age-matched systemically healthy adults, n = 29; 18 micromol ml(-1) h(-1)vs 13 micromol ml(-1) h(-1), respectively, P = 0.002). PLTP activity inversely correlated with average periodontal pocket depth (PPD) per tooth (r(s) = -0.372; P = 0.002). Three months after FME, median PLTP activity did not change significantly. Full-mouth tooth extraction significantly reduces SAA, a marker of inflammation, while it does not affect plasma PLTP activity. However, the inverse correlation between PLTP activity and average PPD suggests that increased PLTP activity may limit periodontal tissue damage.

The Relationship Between Acute Phase Serum Amyloid A (SAA) Protein Concentrations and Left Ventricular Systolic Function in Acute Myocardial Infarction Patients Treated With Primary Coronary Angioplasty

Our study was planned to investigate the relationship between plasma levels of serum amyloid A protein (SAA) concentrations and the subsequent left ventricular systolic function in patients with acute myocardial infarction (AMI) treated with primary coronary angioplasty. Reperfusion by primary percutaneous coronary intervention was successful in 486 consecutive AMI patients who were admitted within 12 hours of onset. Plasma SAA concentrations were evaluated 24 hours after onset. Left ventricular (LV) function was serially determined by left ventriculography performed in the acute (soon after recanalization) and chronic phases (6 months after onset). (I) There was no significant correlation between SAA concentration and acute phase left ventricular ejection fraction (LVEF) or regional wall motion (RWM). (II) The SAA concentration was significantly correlated with both highly sensitive C-reactive protein (hs-CRP) and the peak-CK value (hs-CRP: r = 0.69, P < 0.0001, peak-CK: r = 0.21, P = 0.0003). (III) SAA was significantly negatively correlated with both LVEF and RWM in the chronic phase (LVEF: r = -0.42, P = 0.001; RWM: r = -0.41, P = 0.007). (IV) The plasma level of SAA also showed a significant negative correlation with the differences in LVEF between the 2 stages (delta-LVEF) (r = -0.43, P = 0.02). In the setting of AMI, plasma SAA concentrations may be closely related to subsequent left-ventricular systolic dysfunction.

Down-Regulation of Endothelial Adhesion Molecules and Leukocyte Adhesion by Treatment with Superoxide Dismutase Is Beneficial in Chronic Immune Experimental Colitis

Modulation of adhesion molecule expression that govern trafficking of leukocytes into the inflamed intestine is envisioned as a new strategy for treatment of inflammatory bowel disease (IBD). This study was designed to determine the impact of reducing oxidative stress on adhesion molecules expression and leukocyte recruitment in experimental chronic colitis. For that purpose, colitic interleukin-10 knockout and wild-type mice were studied. Groups of animals were treated with Cu/Zn superoxide dismutase (SOD1) 13 mg/kg/d or vehicle for either 7 or 14 days. Expression of vascular cell adhesion molecule-1 and mucosal addressin cell adhesion molecule-1 were determined; leukocyte-endothelial cell interactions in colonic venules were studied with intravital microscopy; and changes in colon pathology and biomarkers of colitis severity were determined. Development of colitis was associated with a marked increase in endothelial vascular cell adhesion molecule-1 and mucosal addressin cell adhesion molecule-1 expression, which were significantly reduced by treatment with SOD1. The increase in leukocyte rolling and adhesion in colonic venules of colitic mice were significantly reduced by administration of SOD1. This treatment markedly reduced colonic lipid hydroperoxidation, myeoloperoxidase activity, and plasma levels of serum amyloid A protein and resulted in significant, although modest, reductions in histologic damage score. The therapeutic value of SOD1 when administered prophylactically was assessed in the dextran sulfate sodium model of colitis with similar positive results. These results indicate that SOD1 affords significant amelioration of colonic inflammatory changes in experimental colitis. Down-regulation of adhesion molecule expression, reduction of lipid hydroperoxidation, and recruitment of leukocytes into the inflamed intestine contribute to this beneficial effect.

Prognostic Value of Serum Amyloid A Protein in Patients With Acute Myocardial Infarction

The relationship between plasma levels of serum amyloid A protein (SAA) concentrations and clinical course (including mortality) was investigated in patients with acute myocardial infarction (AMI). The study enrolled 280 consecutive AMI patients who were admitted within 10 h of onset and were successfully reperfused by primary percutaneous coronary intervention. Plasma SAA concentrations were evaluated at 24 h after onset. The threshold of the upper quintile (325 mug/dl) was used to divide patients into 2 groups: either a high SAA (H group: > or =325 mug/dl; n=56) or low SAA (L group: <325 microg/dl; n=224). (I) Left ventricular (LV) ejection fraction in the chronic phase was significantly less in the H group than in the L group (52+/-14% vs 57+/-13%, p=0.03). (II) There were significantly more major complications in the H group than in the L group (cardiac rupture: p=0.0007, cardiogenic shock: p<0.0001; subacute thrombosis: p=0.0007; cardiac death: p=0.0003). (III) Multivariate analysis identified SAA as an independent predictor of 6-month mortality in AMI patients (risk ratio: 5.8, 95%confidence interval: 1.3-27.7, p=0.03). In the setting of AMI, plasma SAA concentrations may be closely related to LV systolic dysfunction and poor patient outcomes, including mortality.

Green Tea Polyphenol Extract Attenuates Inflammation in Interleukin-2–Deficient Mice, a Model of Autoimmunity

Green tea polyphenols (GrTP) have been previously shown to decrease endotoxin-induced tumor necrosis factor-alpha production and lethality in mice. Our present studies demonstrate that GrTP inhibit inflammatory responses and may be useful in treating chronic inflammatory states, such as inflammatory bowel disease. In this preliminary study, we examined whether GrTP decrease disease activity in interleukin-2-deficient (IL-2(-/-) mice. Eight-week old IL-2(-/-) C57BL/6J mice who were fed nonpurified diet were randomly assigned to receive water with GrTP (5 g/L) or water alone (control) for up to 6 wk. After 1 wk, explant colon and lamina propria lymphocyte (LPL) cultures were established from a subgroup of mice and supernatants collected. Culture supernatants from GrTP-treated mice showed decreased spontaneous interferon-gamma and tumor necrosis factor-alpha secretion compared with that of controls. At 6 wk, the GrTP group had less severe colitis as demonstrated by lower histologic scores and wet colon weights. This was associated with lower plasma levels of serum amyloid A, increased weight gain and improved hematocrits. These results show that GrTP attenuated inflammation in IL-2(-/-) mice and suggest a role for GrTP in treating chronic inflammatory diseases such as inflammatory bowel disease.

Neuropeptide regulation of inflammatory and immunologic responses. The capacity of alpha-melanocyte-stimulating hormone to inhibit tumor necrosis factor and IL-1-inducible biologic responses.

Administration of the pituitary hormone alpha-melanocyte-stimulating hormone (alpha-MSH) to mice was found to inhibit a number of IL-1 and TNF-inducible biologic responses in situ. The ability of either IL-1 or TNF to cause fever, enhance plasma levels of acute phase proteins, and increase the numbers of peripheral blood neutrophils was inhibited by the simultaneous peripheral administration of this neuropeptide. In addition, alpha-MSH reversed the depressive influences of IL-1 or TNF on the effector phase of contact hypersensitivity (CH) responses in animals given an adoptive transfer of primed lymphocytes from hapten-sensitized donors. Intracerebral injection of nanogram quantities of alpha-MSH inhibited the ability of peripherally administered IL-1 or TNF to induce both fever and neutrophilia without affecting the increase in plasma levels of serum amyloid P and fibrinogen. Also, nanogram quantities of alpha-MSH given intracerebrally to normal mice did not reverse the depressed CH responses observed after peripheral IL-1 or TNF administration. These findings suggest that both fever and neutrophilia are linked to the direct action of IL-1 or TNF on the brain. This was supported by the observation that an intracerebral injection of IL-1 or TNF in low doses increased core body temperature and circulating neutrophil numbers without affecting plasma levels of acute phase proteins or CH responsiveness. Our results provide additional support for the hypothesis that bidirectional control exists between elements of the neuroendocrine and immune systems.