Rainbow trout Oncorhynchus mykiss (Walbaum) type IV ice-structuring protein LS-12 in the acute-phase response to Flavobacterium psychrophilum infection.

A previous proteomic study examining the plasma acute-phase response of rainbow trout to sterile inflammation highlighted an unidentified 9.5-kDa spot using 2D-PAGE, which was dramatically increased. The 15 amino acid sequence obtained from this protein spot allowed rapid amplification of cDNA ends PCR to generate a 443-bp nucleotide sequence that was 98.6% similar to type-4 ice-structuring protein LS-12 from Atlantic salmon Salmo salar Linnaeus. Quantitative reverse translation PCR and an ELISA were used to measure gene expression and plasma concentrations of LS-12 following experimental intraperitoneal injection of rainbow trout with either 106 or 108 colony-forming units (CFU) of Flavobacterium psychrophilum. There was no significant change in the plasma concentration of LS-12 up to 15 days post-infection in any group. Hepatic LS-12 gene expression was significantly reduced at 3 and 6 days (p < 0.001) post-infection in fish injected with 108 CFU of F. psychrophilum relative to control fish, while branchial or head kidney expression was unchanged. Infected fish had significantly increased hepatic gene expression of serum amyloid A, confirming an acute-phase response. Under the conditions used, LS-12 is not a positive acute-phase protein in rainbow trout.

THE ACUTE-PHASE AND HEMOSTATIC RESPONSE IN DROMEDARY CAMELS ( CAMELUS DROMEDARIUS).

Acute-phase reactants indicate inflammation and are increasingly used in veterinary medicine to indicate and to monitor progression of disease. Hemostasis and inflammation have interconnected pathophysiologic pathways and influence each other on different levels. This study established observed normal ranges for acute-phase reactants and for coagulation and thromboelastographic (TEG) parameters in 49 dromedary camels ( Camelus dromedarius) and assessed the response to chronic and acute inflammation. Chronically infected animals suffering from lymph abscessation due to Corynebacterium spp. had significantly higher concentrations of the acute-phase reactants haptoglobin ( P < 0.005) and fibrinogen ( P < 0.013) and an increased clot strength characterized by an increase of the TEG parameters MA ( P < 0.039), representing the maximum amplitude of the clot strengths, and G, the global clot strength ( P < 0.022), compared to healthy animals. When the acute-phase and hemostatic responses of 10 males receiving a gonadotropin-releasing hormone vaccine and of 9 males that were surgically castrated over 7 days were studied, haptoglobin proved to be a minor positive acute-phase protein, with moderate levels in healthy animals. It increased significantly after both vaccination and castration and remained elevated 7 days postinsult. The negative reactant iron significantly decreased over the 7-day period after castration, whereas a similar decrease following vaccination lasted less than 3 days. Fibrinogen reacted as a positive, minor reactant, with a significant increase and a peak on days 3-5, with higher values seen after castration. Prothrombin time showed a slight shortening at days 5-7, and the TEG parameters MA and G showed significantly increased values, similar to fibrinogen. The acute-phase protein serum amyloid A showed poor repeatability, suggesting that the assay was not reliable.

Microbial Translocation Associated with an Acute-Phase Response and Elevations in MMP-1, HO-1, and Proinflammatory Cytokines in Strongyloides stercoralis Infection.

Microbial translocation, characterized by elevated levels of lipopolysaccharide (LPS) and related markers, is a common occurrence in HIV and some parasitic infections. This is usually associated with extensive inflammation and immune activation. To examine the occurrence of microbial translocation and the associated inflammatory response in asymptomatic Strongyloides stercoralis infection, we measured the plasma levels of LPS and other microbial translocation markers, acute-phase proteins, inflammatory markers, and proinflammatory cytokines in individuals with (infected [INF]) or without (uninfected [UN]) S. stercoralis infections. Finally, we also measured the levels of all of these markers in INF individuals following treatment of S. stercoralis infection. We show that INF individuals exhibit significantly higher plasma levels of microbial translocation markers (LPS, soluble CD14 [sCD14], intestinal fatty acid-binding protein [iFABP], and endotoxin core IgG antibody [EndoCAb]), acute-phase proteins (α-2 macroglobulin [α-2M], C-reactive protein [CRP], haptoglobin, and serum amyloid protein A [SAA]), inflammatory markers (matrix metalloproteinase 1 [MMP-1] and heme oxygenase 1 [HO-1]), and proinflammatory cytokines (interleukin-6 [IL-6], IL-8, monocyte chemoattractant protein 1 [MCP-1], and IL-1ß) than do UN individuals. INF individuals exhibit significantly decreased levels of tissue inhibitor of metalloproteinases 4 (TIMP-4). Following treatment of S. stercoralis infection, the elevated levels of microbial translocation markers, acute-phase proteins, and inflammatory markers were all diminished. Our data thus show that S. stercoralis infection is characterized by microbial translocation and accompanying increases in levels of acute-phase proteins and markers of inflammation and provide data to suggest that microbial translocation is a feature of asymptomatic S. stercoralis infection and is associated with an inflammatory response.

Dietary ß-glucan stimulate complement and C-reactive protein acute phase responses in common carp (Cyprinus carpio) during an Aeromonas salmonicida infection.

The effect of ß-glucans as feed additive on the profile of C-reactive protein (CRP) and complement acute phase responses was studied in common carp Cyprinus carpio after exposition to a bacterial infection with Aeromonas salmonicida. Carp were orally administered with ß-glucan (MacroGard®) for 14 days with a daily ß-glucan intake of 6 mg per kg body weight. Fish were then intraperitoneally injected with either PBS or 1 × 108 bacteria per fish and sampled at time 0, 6, 12, 24, 48, 72, 96 and 120 h post-injection (p.i.) for serum and head kidney, liver and mid-gut tissues. CRP levels and complement activity were determined in the serum samples whilst the gene expression profiles of CRP and complement related genes (crp1, crp2, c1r/s, bf/c2, c3 and masp2) were analysed in the tissues by quantitative PCR. Results obtained showed that oral administration of ß-glucan for 14 days significantly increased serum CRP levels up to 2 fold and serum alternative complement activity (ACP) up to 35 fold. The bacterial infection on its own (i.e. not combined with a ß-glucan feeding) did have significant effects on complement response whilst CRP was not detectably induced during the carp acute phase reaction. However, the combination of the infection and the ß-glucan feeding did show significant effects on both CRP and complement profiles with higher serum CRP levels and serum ACP activity in the ß-glucan fed fish than in the control fed fish. In addition, a distinct organ and time dependent expression profile pattern was detected for all the selected genes: a peak of gene expression first occurred in the head kidney tissue (6 h p.i. or 12 h p.i.), then an up-regulation in the liver several hours later (24 h p.i.) and finally up- or down-regulations in the mid-gut at 24 h p.i. and 72 h p.i. In conclusion, the results of this study suggest that MacroGard® stimulated CRP and complement responses to A. salmonicida infection in common carp.

Location-specific activation of the paraventricular nucleus of the hypothalamus by localized inflammation.

The existence of an immunological homunculus has been proposed, but evidence for location-specific response of the central nervous system to immunological stimulation is lacking. In this study, we show that inflammation induced by injection of casein into one of the causes c-fos expression in the paraventricular nucleus of the hypothalamus (PVN) in an asymmetrical manner: much stronger activation is always induced in the contralateral PVN. Unilateral sciatic nerve transection abolished the casein-induced PVN activation if casein was injected into the hindlimb with the nerve transection, but had no effect if casein was injected into the hindlimb with intact nerve innervation. Injection of casein into one the forelimbs also caused contralateral PNV activation. Further, stronger PVN activation was found in the anterior PVN after the forelimb injection, but in the posterior PVN after the hindlimb injection. Casein-induced PVN activation is absent in IL-1R1 KO, IL-6 KO, TNFα KO, and in C3H/HeJ (TLR4 mutant) animals. In comparison, injection of LPS, a systemic inflammagen, into one hindlimb induced bilateral PVN activation but injection of live Escherichia coli into one hindlimb induced contralateral PVN activation. These results support the notion that local inflammation may activate the PVN by neural routes in a location-specific manner.

The acute-phase response impairs host defence against Enterococcus faecium peritonitis.

Enterococcus faecium is an emerging pathogen that causes infections in hospitalized patients with various co-morbid diseases. These underlying diseases are often associated with an acute-phase response that renders patients vulnerable to nosocomial infections. To study the influence of the acute-phase response induced by sterile tissue injury on host defence against E. faecium, mice were injected subcutaneously with either turpentine or casein 1 day before intraperitoneal infection with E. faecium. Control mice were subcutaneously injected with saline or sodium bicarbonate, respectively. Turpentine and casein induced an acute-phase response as reflected by increases in the plasma concentrations of interleukin-6, serum amyloid P and C3. A pre-existent acute-phase response in mice was associated with a strongly reduced capacity to clear E. faecium, resulting in prolonged bacteraemia for several days. The inflammatory response to E. faecium was impaired in mice with an acute-phase response, as shown by reduced capacity to mount a neutrophilic leucocytosis in peripheral blood and by decreased local cytokine concentrations. These data indicate that the acute-phase response impairs host defence against E. faecium, suggesting that this condition may contribute to the increased vulnerability of critically ill patients to enterococcal infections.

Regulation of low-density lipoprotein cholesterol by intestinal inflammation and the acute phase response.

Systemic inflammation, induced by disease or experimental intervention, is well established to result in elevated levels of circulating triglycerides, and reduced levels of high-density lipoprotein-cholesterol (HDL-C), in most mammalian species. However, the relationship between inflammation and low-density lipoprotein-cholesterol (LDL-C) concentrations is less clear. Most reports indicate that systemic inflammation, as observed during sepsis or following high dose experimental endotoxaemia, lowers total, and LDL-C in man. However, isolated reports have suggested that certain inflammatory conditions are associated with increased LDL-C. In this review, we summarize the emerging evidence that low-grade inflammation specifically of intestinal origin may be associated with increased serum LDL-C levels. Preliminary insights into potential mechanisms that may mediate these effects, including those connecting inflammation to trans-intestinal cholesterol efflux (TICE), are considered. We conclude that this evidence supports the potential downregulation of major mediators of TICE by inflammatory mediators in vitro and during intestinal inflammation in vivo. The TICE-inflammation axis therefore merits further study in terms of its potential to regulate serum LDL-C, and as a readily druggable target for hypercholesterolaemia.

Acute-phase response alters the disposition kinetics of cefepime following intravenous administration to rabbits.

The effect of experimentally induced fever on the pharmacokinetics of cefepime administered intravenously at a dose of 75 mg/kg bw was studied in six healthy rabbits. The study was conducted in two consecutive phases, separated by a washout period of 2 weeks. Infection was induced by the intravenous inoculation of 5 x 10(8) cfu of Escherichia coli 24 h before the pharmacokinetic investigation was carried out. Serial blood samples for cefepime concentration determination were obtained for 48 h following drug administration. The concentrations of cefepime in the plasma were determined by a quantitative microbiological assay using an agar-gel diffusion method employing Bacillus subtilis ATCC 6633 as the test organism, with a level of detectability of approximately 0.10 microg/ml. Cefepime plasma concentrations versus time were evaluated by non-compartmental methods using WinNonLin. Cefepime was well tolerated and no serious adverse events were observed. Rectal temperature increased 1 degree C 24 h post injection in infected animals. Highly significant differences in the blood plasma concentrations of cefepime were observed between febrile and healthy animals at all the sampling times. This could explain the greater area under the plasma level-time curve of the drug in febrile compared with healthy animals. The results from pharmacokinetic calculations showed that both the distribution volume at steady state (V (dss)) and body clearance (CL(tot)) were affected in febrile as compared to healthy animals. The mean values of V (dss) and CL(tot) of cefepime in healthy rabbits were 1.168 L/kg and 0.303 L/kg/h, respectively. As compared with healthy animals, the mean estimates of V (dss) (0.917 L/kg) and CL(tot) (0.205 L/kg per h) of cefepime were significantly lower, whereas t (1/2lambda), MRT and AUMC were significantly higher in febrile rabbits. It is concluded that, although experimental infection had an effect on the disposition kinetics of cefepime in healthy and febrile rabbits, this was not sufficiently pronounced to require alteration of the dosage during disease.

Paraoxonases and infectious diseases.

The paraoxonases (PON1, PON2 and PON3) are an enzyme family with a high structural homology. All of them have lactonase activity and degrade lipid peroxides in lipoproteins and cells. As such, they play a role in protection against oxidation and inflammation. Infectious diseases are often associated with oxidative stress and an inflammatory response. Infection and inflammation trigger a cascade of reactions in the host, known as the acute-phase response. This response is associated with dramatic changes in serum proteins and lipoproteins, including a decrease in serum PON1 activity. These alterations have clinical consequences for the infected patient, including an increased risk for cardiovascular diseases, and an impaired protection against the formation of antibiotic-resistant bacterial biofilms. Several studies have investigated the value of serum PON1 measurement as a biomarker of the infection process. Low serum PON1 activities are associated with poor survival in patients with severe sepsis. In addition, preliminary studies suggest that serum PON1 concentration and/or enzyme activity may be useful as markers of acute concomitant infection in patients with an indwelling central venous catheter. Investigating the associations between paraoxonases and infectious diseases is a recent, and productive, line of research.

Study of the immunomodulatory properties of gamithromycin and dexamethasone in a lipopolysaccharide inflammation model in calves.

The aim of this study was to define the in vivo immunomodulatory properties of the macrolide antibiotic gamithromycin in calves, with respect to the acute phase response. Additionally, the corticosteroid dexamethasone was included as a positive control immunomodulatory drug. Both drugs, as well as their combination,were studied in a previously developed inflammation model,which was initiated by an intravenous lipopolysaccharide (LPS) challenge (0.5 µg/kg body weight). Twenty-four 4-week-old male Holstein Friesian calves were randomized into four groups: no pharmacological treatment (n = 6) or a pharmacological treatment with gamithromycin (n= 6), dexamethasone (n= 6) or their combination (n= 6) 1 h prior to LPS administration. Blood collection and clinical scoring were performed at regular time points until 72 h post LPS challenge. Plasma concentrations of selected cytokines (tumour necrosis factor-α (TNF-α) and interleukin 6 (IL-6)) and acute phase proteins (serum amyloid A and haptoglobin) were subsequently determined. Gamithromycin did not have any beneficial effect on the LPS-induced clinical signs (dyspnea, fever, anorexia and depression), nor on the studied inflammatory mediators. In the dexamethasone and combination groups, the occurrence of dyspnea and fever was not prominently influenced, although the calves recovered significantly faster from the challenge. Moreover, dexamethasone significantly inhibited the levels of TNF-α and IL-6, suggesting a key role for these cytokines in sickness behaviour. In conclusion, unlike dexamethasone, gamithromycin did not directly reduce cytokine release in an LPS inflammation model in calves.

Interleukin 6, serum amyloid A and haptoglobin as markers of treatment efficacy in pigs experimentally infected with Actinobacillus pleuropneumoniae.

The possibility to use acute phase proteins to monitor the elimination of a bacterial infection in pigs would facilitate an objective assessment of treatment with various antimicrobial substances. To examine this possibility, the acute phase response (IL-6, serum amyloid A (SAA), and haptoglobin) elicited by Actinobacillus pleuropneumoniae and its reduction on treatment with various antibiotics was studied in serum from specific pathogen free (SPF) pigs. Pigs were infected intranasally with A. pleuropneumoniae serotype 2, and either left as non-treated control pigs or treated with different antibiotics intramuscularly at onset of respiratory disease (20h post-infection). Pigs responded to the infection with prominent increases in activity and concentrations of IL-6, SAA, and haptoglobin. These responses were to a certain extent overlapping and covered the time span from a few hours after infection until development of detectable levels of specific antibodies (7-10 days post-infection in untreated pigs). The haptoglobin response lasted until the end of the study on day 17 and thereby partly coincided with the antibody response. Treatment with antimicrobials that effectively reduced establishment of the infection with A. pleuropneumoniae also reduced the duration of all three acute phase responses, and reduced the concentration of serum haptoglobin. In contrast, less efficacious treatments did not reduce these acute phase responses. Thus, acute phase reactants can be applied to monitor therapeutic effects of antimicrobial drugs in the pig and measurements of IL-6, SAA and haptoglobin could add valuable information about the stage of infection during a disease outbreak.

Chlortetracycline modulates acute phase response of ex vivo perfused pig livers, and inhibits TNF-alpha secretion by isolated Kupffer cells.

Tetracyclines have been shown to have anti-inflammatory effects in addition to their antimicrobial action. We investigated the effects of in vivo administration of chlortetracycline (CTC) on ex vivo perfused pig livers. The retention and clearance of Salmonella choleraesuis, production of acute phase proteins C-reactive protein (CRP), and haptoglobin (HPG) by whole livers were studied. The in vitro modulation by CTC of TNF-alpha secretion by pig Kupffer cells (KC) was also studied. Pigs were dosed orally with CTC for three days, and given injections of Salmonella LPS 24 h before removal of the liver. Salmonella retention and clearance by livers of pigs given CTC was lower than by control livers (p < 0.01 and p < 0.05, respectively). We demonstrated an increase of CRP and HPG by livers from control pigs after a three-hour perfusion while pigs from CTC pretreated pigs varied in this response. Further, CTC decreased the secretion of TNF-alpha by cultured KC incubated in vitro with LPS. Modulation of TNF-alpha production by CTC suggests a potential for attenuating the inflammatory response. However, this possible beneficial action of CTC was accompanied by a significant decline in the antimicrobial effect of the liver.

Acute phase response to Salmonella in a pig liver perfusion model.

Livers from 7- to 14-day old pigs were maintained on a perfusion apparatus for 3 h. The perfused livers maintained physiologic and immunologic functions during perfusion. The perfused livers retained 78-94% of a non-recirculating inoculum of approximately 1-5 x 10(8) Salmonella choleraesuis (Scs), and cleared 94.9 +/- 1.7% of the retained (Scs) during the 3-h perfusion period. When the acute phase response (APR) was induced in liver donor pigs 24 h before liver perfusion, the perfused livers had diminished capability to retain, and greatly diminished capability to clear Scs. When sterile, filtered, and concentrated liver perfusate (LP) from previous, LPS-perfused livers was added to the perfusion fluid (PF) at 50 min of Scs perfusion (passive APR), Scs clearance was inhibited. When sterile, filtered LP from previously Scs perfused livers was added to the system, liver clearance was abolished, and Scs always grew in such livers during the 3 h perfusion period. The LP of livers perfused with Scs enhanced growth of Scs in an in vitro assay. These observations suggest that products of the acute phase response favor growth of Scs in vitro and in vivo.

A non-competitive chemiluminescence enzyme immunoassay for the equine acute phase protein serum amyloid A (SAA) -- a clinically useful inflammatory marker in the horse.

A non-competitive chemiluminescence enzyme immunoassay for measuring serum amyloid A (SAA) in equine serum was developed. A polyclonal anti-equine-amyloid A antiserum specific for equine SAA was utilized, and the assay was standardized using highly purified equine SAA. An acute phase horse serum was calibrated against the purified SAA and was used as standard when running the assay. Serum SAA concentrations in the range of 3-1210 mg/l could be measured. The reference range of SAA in clinically healthy adult horses was <7 mg/l. The clinical validation of the assay comprised the SAA responses after surgery and experimentally induced aseptic arthritis, and those associated with viral and bacterial infections. The SAA response after surgery (castration) was consistent, with peak concentrations on day 2 and a return to normal SAA concentrations within eight days. The aseptic arthritis produced an SAA response with a pattern similar to that seen after surgery, with peak concentrations of SAA 36-48 h after induction. Seven horses showed a biphasic pattern, with a second rise in SAA concentrations on day 4 and 5. All animals had SAA levels <7 mg/l on day 15. All horses with viral and bacterial infections had SAA concentrations above 7 mg/l. The ranges of SAA concentrations following the different types of inflammation overlap, being consistent with the unspecific nature of the SAA response. This study revealed that SAA is a sensitive and unspecific marker for inflammation, and describes the dynamics of the SAA response after standardized and well defined tissue damage.

Biology of fetal repair: the presence of bacteria in fetal wounds induces an adult-like healing response.

The minimal acute inflammatory response to tissue injury is one of the most dramatic differences between fetal and adult wound healing. Considering the prominent role of inflammation in adult tissue repair, this study tested the hypothesis that the minimal fetal inflammatory response to tissue injury plays a central role in the "scarless" fetal repair process. Sponge implants were treated with lethally irradiated or live bacteria and placed subcutaneously in fetal rabbits to test the ability of the fetus to mount an acute inflammatory response to bacterial antigens present at the wound site and to analyze the effects of this inflammatory response on fetal fibroplasia and neovascularization. After harvest, these implants were examined histologically for inflammation, fibroblast infiltration, collagen deposition, and neovascularization, and collagen deposition was measured using hydroxyproline quantitation by high-performance liquid chromatography. Bacteria-treated implants showed dose-dependent acute inflammatory responses and significant increases in collagen deposition compared with control sponges. Implants containing live bacteria demonstrated maximal fibroplasia and neovascularization. These findings suggest that, despite neutropenia and immaturity of the fetal immune system, the fetus is capable of mounting an acute inflammatory response to avirulent bacteria present at the wound site. Fetal inflammatory cells which respond to this bacterial stimulus appear capable of initiating an adult-like healing response. Thus, by failing to provide a bacterial stimulus for leukocyte recruitment at the site of tissue injury, the sterile fetal environment appears to play a role in effecting "scarless" fetal wound healing.

Acute phase response in naturally occurring coliform mastitis.

Changes in the activities of serum cytokines and in acute phase response were observed in dairy cows with naturally occurring coliform mastitis. Seven cows with severe mastitis showed systemic and mammary inflammatory response throughout the observation period, and 11 cows with mild mastitis recovered and were able to be milked within 3 days of onset of mastitis. Serum interleukin (IL)-I and tumor necrosis factor (TNF) activities were higher in the severe group than in the mild group at the first appearance of symptoms. Elevated IL-1 activity was evident in the severe group throughout the observation period. Serum alpha-1-acidglycoprotein (alpha1AG) concentration began to rise with the beginning of mastitis in the severe group, and peaked at 9 days. Serum haptoglobin (Hp) concentrations peaked at 3 days, and decreased gradually after 3 days in the severe group. These results showed that there are dynamic changes in serum IL-1 activity and in serum alpha1AG and Hp concentrations in cows with severe coliform mastitis.

Periodontal disease and cardiovascular disease: epidemiology and possible mechanisms.

BACKGROUND: Many early epidemiologic studies reported an association between periodontal disease and cardiovascular disease. However, other studies found no association or nonsignificant trends. This report summarizes the evidence from epidemiologic studies and studies that focused on potential contributing mechanisms to provide a more complete picture of the association between periodontal and heart disease. TYPES OF STUDIES REVIEWED: The authors summarize the longitudinal studies reported to date, because they represent the highest level of evidence available regarding the connection between periodontal disease and heart disease. The authors also review many of the case-control and cross-sectional studies published, as well as findings from clinical, animal and basic laboratory studies. RESULTS: The evidence suggests a moderate association--but not a causal relationship--between periodontal disease and heart disease. Results of some case-control studies indicate that subgingival periodontal pathogenic infection may be associated with myocardial infarction. Basic laboratory studies point to the biological plausibility of this association, since oral bacteria have been found in carotid atheromas and some oral bacteria may be associated with platelet aggregation, an event important for thrombosis. Animal studies have shown that atheroma formation can be enhanced by exposure to periodontal pathogens. CONCLUSIONS: The accumulation of epidemiologic, in vitro, clinical and animal evidence suggests that periodontal infection may be a contributing risk factor for heart disease. However, legitimate concerns have arisen about the nature of this relationship. These are early investigations. Since even a moderate risk contributed by periodontal disease to heart disease could contribute to significant morbidity and mortality, it is imperative that further studies be conducted to evaluate this relationship. One particularly important study to be carried out is the investigation of a possible clinically meaningful reduction in heart disease resulting from the prevention or treatment of periodontal disease.

Hepatocyte-specific mutation of both NF-κB RelA and STAT3 abrogates the acute phase response in mice.

The acute phase response is an evolutionarily conserved reaction in which physiological stress triggers the liver to remodel the blood proteome. Although thought to be involved in immune defense, the net biological effect of the acute phase response remains unknown. As the acute phase response is stimulated by diverse cytokines that activate either NF-κB or STAT3, we hypothesized that it could be eliminated by hepatocyte-specific interruption of both transcription factors. Here, we report that the elimination in mice of both NF-κB p65 (RelA) and STAT3, but neither alone, abrogated all acute phase responses measured. The failure to respond was consistent across multiple different infectious, inflammatory, and noxious stimuli, including pneumococcal pneumonia. When the effects of infection were analyzed in detail, pneumococcal pneumonia was found to alter the expression of over a thousand transcripts in the liver. This outcome was inhibited by the combined loss of RelA and STAT3. Moreover, this interruption of the acute phase response increased mortality and exacerbated bacterial dissemination during pneumonia, possibly as a result of acute humoral enhancement of macrophage opsonophagocytosis, which was impaired in the mutant mice. Thus, we conclude that RelA and STAT3 are essential for stress-induced transcriptional remodeling in the liver and the subsequent activation of the acute phase response, whose functional role includes compartmentalization of local infection.

Acute phase response to Mycoplasma haemofelis and 'Candidatus Mycoplasma haemominutum' infection in FIV-infected and non-FIV-infected cats.

The pathogenicity of Haemoplasma spp. in cats varies with 'Candidatus Mycoplasma haemominutum' (CMhm) causing subclinical infection while Mycoplasma haemofelis (Mhf) often induces haemolytic anaemia. The aims of this study were to characterise the acute phase response (APR) of the cat to experimental infection with Mhf or CMhm, and to determine whether chronic feline immunodeficiency virus (FIV) infection influences this response. The acute phase proteins serum amyloid A (SAA), haptoglobin (Hp) and α-1-acid glycoprotein (AGP) concentrations were measured pre-infection and every 7-14 days up to day 100 post-infection (pi) in cats infected with either Mhf or CMhm. Half of each group of cats (6/12) were chronically and subclinically infected with FIV. Marbofloxacin treatment was given on days 16-44 pi to half of the Mhf-infected cats, and on days 49-77 pi to half of the CMhm-infected cats. FIV-infected animals had significantly lower AGP concentrations, and significantly greater Hp concentrations than non-FIV-infected cats when infected with CMhm and Mhf, respectively. Both CMhm and Mhf infection were associated with significant increases in SAA concentrations, while AGP concentrations were only significantly increased by Mhf infection. Mhf-infected cats had significantly greater SAA concentrations than CMhm-infected animals. Both Mhf and CMhm infections were associated with an APR, with Mhf infection inducing a greater response. Chronic FIV infection appeared to modify the APR, which varied with the infecting Haemoplasma species.

The role of tumour necrosis factor-alpha (TNF-alpha) in fever and the acute phase reaction in rabbits.

We investigated the role of tumour necrosis factor-alpha (TNF-alpha) in fever and the acute phase reaction using a specific type-IV phosphodiesterase inhibitor, rolipram, that inhibits the production of TNF-alpha. The body temperatures and serum iron concentrations of rabbits were measured following injections of lipopolysaccharide (LPS) or Staphylococcus aureus (S. aureus) with either rolipram, diclofenac sodium or the appropriate control solutions. Rolipram significantly (P<0.05) inhibited the first phase of both LPS and Staphylococcal fever, but had no effect on the second phase. The fall in serum iron concentration was not significantly affected by the injection of rolipram together with LPS or S. aureus. These results suggest that TNF-alpha is a pyrogen that plays a role during the first phase of fever, at least. However, TNF-alpha appears not to mediate the fall in serum iron concentration during the acute phase reaction.