内质网应激偶联炎性反应研究进展

内质网是真核细胞蛋白合成和折叠的主要细胞器,当内质网内蛋白合成或折叠负担增加,引起未折叠或错误折叠蛋白增多时,可激活内质网几条特定信号通路,启动未折叠蛋白反应,这对维持细胞稳态有重要意义。越来越多研究表明,多种炎性反应疾病与内质网应激有密切联系。一方面,内质网应激引起的未折叠蛋白反应可以诱发或者抑制炎症,另一方面,炎性反应也能影响蛋白折叠,从而促进或缓解内质网应激。2型糖尿病、肿瘤和动脉粥样硬化等多种重大疾病的病理机制都涉及内质网应激与炎性反应的相互作用,对该问题的深入研究不仅能加深人们对这些疾病发病机制的理解,也有助于相关药物的研发。     

D-Dimer Improves the Prognostic Value of Combined Clinical and Laboratory Data in Equine Gastrointestinal Colic

The discriminating ability of 15 parameters alone or in combinations, including results from analysis of plasma endotoxin, the Nycomed plasma D-Dimer test and phospholipase A₂, were analyzed to predict morbidity and mortality in equine gastrointestinal colic. Endotoxaemia was a characteristic feature of the colic horses. The problem of adequately predicting non-survivors among colic horses required several parameters to be included in the logistic model: if the “classical parameters”, (heart rate, respiratory rate, PCV, anion gap) were included in the model, addition of plasma D-dimer, phospholipase A₂, and Cl^- significantly improved the predictive value of the logistic model. Increasing heart rate and D-dimer together with decreasing chloride was a risk factor for nonsurvival. The sensitivity of this three-parameter logistic model to predict nonsurvival was 78% and specificity 77%. The Nycomed D-Dimer test is recommended as a horse-site test to predict disseminated intravascular coagulation and nonsurvival in equine colic.     

Suppurative Inflammation of Apocrine Sweat Glands (Suppurative Hidradenitis) in the Dog: A Retrospective Clinicopathological Analysis of 100 Cases

Résumé— Une analyse rétrospective clinicopathologique a été menée chez 100 chiens présentant une hydradénite suppurative diagnostiquée par biopsie cutanée. Aucune prédisposition d'âge, de race ou de sexe n'a été mise en évidence. Tous les chiens présentaient cliniquement une folliculite bactérienne, ou une furonculose, ou les deux, qu'elle soit primaire ou secondaire à d'autres dermatoses. Aucene lésion clinique n'était pathognomonique d'hidradénite suppurative. Chez 73 chiens, l'hidradénite suppurative était associée microscopiquement à des degrés variables d'inflammation du follicule pileux. Chez 27 chiens, l'hidradénite suppurative était la seule évidence histologique d'inflammation annexielle. L'observation histopathologique d'hidradénite suppurative suggère l'existence sur le plan clinique d'une folliculite bactérienne, d'une furonculose, ou des 2. [Scott, D.W. Suppurative inflammation of apocrine sweat glands (suppurative hidradentis) in the dog: a retrospective clinicopathological analysis of 100 cases (inflammation suppurative des glandes sudorales apocrines (hidradénite suppurative) chez le chien: une analyse rétrospective clinicopathologique de 100 cas). Resumen— Se llevó a cabo un estudio clinicopatológico retrospectivo en 100 perros con hidradenitis supurativa diagnosticada mediante biopsia cutánea. No se detectó predominancia alguna de raza, sexo o edad. A todes los perros se les habia diagnosticado clinicamente foliculitis o furunculosis bacteriana, o ambas, ya sea de forma primaria o secundaria a otras dermatosis. No se encontraron lesiones clinicas especificas indicativas de hidradenitis supurativa. En 73 animales, la hidradenitis supurativa estaba asociada con varios grados de inflamación folicular a nivel microscópico. En los 27 casos restantes, los anejos presentaban unicamente hidradenitis supurativa. La presencia de hidradenitis supurativa a nivel microscópico sugiere la existencia de foliculitis o furunculosis bacteriana clinicas, o de ambas. [Scott, D.W. Suppurative inflammation of apocrine sweat glands (suppurative hidradenitis) in the dog: a retrospective clinicopathological analysis of 100 cases (inflamación supurativa de las glándulas sudoriparas apocrinas (hidradenitis supurativa) en el perro: estudio clinicopatológico retrospectivo de 100 casos). Abstract— A retrospective clinicopathological study was conducted on 100 dogs with suppurative hidradenitis as determined by skin biopsy. No apparent age, breed, or sex predilections were recognized. All dogs had been given a clinical diagnosis of bacterial folliculitis, furunculosis, or both of these, whether primary or secondary to other dermatoses. There were no clinical lesions that uniquely suggested the presence of suppurative hidradenitis. In 73 dogs, suppurative hidradenitis occurred in conjunction with varying degrees of hair follicle inflammation microscopically. In 27 dogs, suppurative hidradenitis was the only histological evidence of adnexal inflammation. The histopathologic finding of suppurative hidradenitis suggests the existence of clinical bacterial folliculitis, furunculosis, or both of these.     

Preliminary observations on the effects of Meloxicam in a new model for acute intra-articular inflammation in dogs

The effects of intra-articular injection, on two occasions, 3 weeks apart, of the contrast agent Urografin on the cytological and biochemical characteristics of synovial fluid (SF) were examined in two studies in dogs. The first study provided baseline data in two non-medicated dogs. The second study used a cross-over design whereby 4 dogs received a 7-day oral treatment with either a placebo or meloxicam (0.2 mg/kg body weight daily) with a washout period of 3 weeks, in order to determine the effect of this new non-steroidal anti-inflammatory drug (NSAID) on the response to Urografin injection. SF samples were collected under general anaesthesia prior to and at 24 and 72 h after each Urografin injection. The volume, relative viscosity, white blood cell count and concentrations of protein, lactate dehydrogenase (LDH) and hyaluronic acid of these samples were determined.The results from both studies indicate that intra-articular injection of Urografin provoked a mild local transient inflammatory response, the most dramatic evidence of which was an increase in the white blood cell count in the SF after 24 h. In the second study, comparison of the synovial fluid measurements of the placebo-treated dogs at 24 h after Urografin injection with those prior to injection revealed significant increases in SF volume, white blood cell count, protein concentration and LDH activity and a significant reduction in relative viscosity. At 72 h after injection, only the white blood cell count and relative viscosity were significantly different from the pre-injection values. All of these measurements were, however, associated with high coefficients of variation, which must be taken into account in assessing the usefulness of the model for drug-testing purposes. Nevertheless, the administration of meloxicam significantly reduced the SF volume and white blood cell count at 24 h relative to the effects of concurrent placebo treatment. The general health status of the animals was not disturbed at any time as assessed by clinical and haematological observations. No adverse reactions were observed.Abbreviations LDH lactate dehydrogenase - NSAID non-steroidal anti-inflammatory drug - SF synovial fluid - WBC white blood cell count     

Morphologic evaluation of acute endometritis in mares with differing resistance to uterine infections

The study was designed to determine differences between normal mares and mares with endometrial pathology in the inflammatory response after bacterial challenge. Six normal mares (biopsy category I) and 4 mares with pathological endometrial changes (biopsy category II) were given an intrauterine infusion of β-hemolytic streptococci on the second day of estrus. All mares had a similar kind of inflammatory response after the bacterial inoculation as assessed by rectal and vaginal examinations. There were no significant differences in the amount of discharge, uterine tone, uterine size and cervical relaxation between the groups. Leukocytic response, as determined by endometrial smears and biopsies, was of the same magnitude in both groups. Two mares from the pathological group were not able to eliminate the infection, but had vaginal discharge and bacteriologically positive uterine swabs until the end of the experiment. It is concluded that the inability of some mares to clear uterine infections cannot be explained by a deficient inflammatory response.     

Neutrophilic myeloperoxidase index and mean light absorbance in neonatal septic and nonseptic foals

Background: Two neutrophilic indices reported by the ADVIA 120 Hematology Analyzer, neutrophilic myeloperoxidase index (MPXI), and mean light absorbance (neutrophil X mean [NXM]) have been proposed as indicators of systemic inflammatory disease in horses and of neutrophil activation in coronary ischemic syndromes in people. Objective: The aim of this study was to evaluate NXM and MPXI in healthy, sick nonseptic, and sick septic foals to determine whether conditions likely associated with neutrophil activation result in decreases in these variables. Methods: In this retrospective study, CBC data from 61 neonatal foals presented to the Equine Teaching Hospital of Barcelona were evaluated for correlations between MPXI, NXM, percentage of large unstained cells, neutrophil count, and percentage of band neutrophils. Results obtained in septic (n=32), sick nonseptic (n=22), and healthy foals (n=7) were compared. In addition, results recorded in septic/neutropenic (n=12), septic/non‐neutropenic (n=20), nonseptic/neutropenic (n=8), nonseptic/non‐neutropenic (n=14), and healthy foals (n=7) were also compared. Results: A weak negative correlation was found between MPXI and neutrophil count and between NXM and percentage of band neutrophils. Septic/neutropenic foals had significantly higher MPXI values (median 17.9, minimum–maximum 4.7–42.5) than did septic/non‐neutropenic (1.5, ?24.4 to 22.3), nonseptic/neutropenic (6.6, 0.6–17.9), and nonseptic/non‐neutropenic foals (8.8, ?10.1 to 16.8) but did not differ significantly from controls (12.8, ?8.5 to 20.4). Conclusions: Significant differences in NXM or MPXI were not found when disease groups were compared with controls; however, septic/neutropenic foals had significantly higher median MPXI than other groups of sick foals. Further prospective studies are needed to clarify if this finding is related to decreased neutrophil function or activation in septic/neutropenic foals.     

Evaluation of a point-of-care test for canine C-reactive protein

Background: In veterinary medicine, there is increasing interest in measuring C‐reactive protein (CRP) as a tool for diagnosis and monitoring of inflammatory diseases. Reported CRP concentrations for healthy dogs have ranged from 0 to 8.9 mg/L. Objectives: The aims of this study were to evaluate a canine‐specific point‐of‐care (POC) lateral flow immunoassay for qualitative CRP measurement in healthy and diseased dogs and to compare results with those obtained by a quantitative ELISA. Methods: Blood samples from 73 client‐owned dogs were available for testing: 16 healthy dogs and 57 dogs with a variety of infectious, inflammatory, or neoplastic diseases. CRP was measured in heparinized whole blood samples and serum with the TECOmedical Dog CRP‐visual POC test. A red line develops in the POC device if CRP is ≥5 mg/L, and results are scored as negative or positive. An ELISA validated previously for canine serum was used as the reference method. Results: For all dogs, serum CRP concentrations measured by the ELISA ranged from 0.1 to ≥350 mg/L (median=38 mg/L). Percentages of the CRP POC test results that agreed with the ELISA results were 98.6% for whole blood and 97.3% for serum samples. For serum samples, sensitivity of the POC test was 96.4% and specificity was 81.3%. For whole blood, sensitivity was 94.7% and specificity was 93.8%. Conclusions: The POC test had very good agreement with the ELISA test and had high sensitivity and specificity; therefore, it can be used as a qualitative test to screen for increases in CRP concentrations.     

Laminar inflammatory gene expression in the carbohydrate overload model of equine laminitis

Reasons for performing study: There is a need to assess the laminar inflammatory response in a laminitis model that more closely resembles clinical cases of sepsis‐related laminitis than the black walnut extract (BWE) model. Objectives: To determine if a similar pattern of laminar inflammation, characterised by proinflammatory cytokine expression, occurs in the CHO model of laminitis as has been previously reported for the BWE model. Methods: Sixteen horses administered 17.6 g of starch (85% corn starch/15% wood flour)/kg bwt via nasogastric (NG) tube were anaesthetised either after developing a temperature >38.9°C (DEV group, n = 8) or at onset of Obel grade 1 lameness (OG1 group, n = 8). Control horses (CON group, n = 8) were anaesthetised 24 h after NG administration of 6 l of deionised water. Laminar tissue was collected from horses while under anaesthesia, followed by humane euthanasia. Real time‐quantitative PCR was used to assess laminar mRNA concentrations of genes involved in inflammatory signalling. Results: Increased mRNA concentrations (P<0.05) for IL‐1β, IL‐6, IL‐12p35, COX‐2, E‐selectin and ICAM‐1 were present in laminae from horses with OG1 lameness but not at the DEV time, when compared to the CON horses. No differences between the groups were found for IL‐2, IL‐4, IL‐10, TNF‐α, IFN‐γ or COX‐1 at either the DEV or OG1 time points. Conclusions: There was a notable difference in the temporal pattern of inflammatory events between the BWE and CHO models, with the majority of laminar inflammatory events appearing to occur at or near the onset of lameness in the CHO model, whereas many of these events peak earlier in the developmental stages in the BWE model. This suggests that, in addition to circulating inflammatory molecules, there may be a local phenomenon in the CHO model resulting in the simultaneous onset of multiple laminar events including endothelial activation, leucocyte emigration and proinflammatory cytokine expression. Potential relevance: The similar (although somewhat delayed) inflammatory response in the CHO model of laminitis indicates that inflammatory signalling is a consistent entity in the pathophysiology of laminitis.     

Plasma interleukin-6 response is predictive for severity and mortality in canine systemic inflammatory response syndrome and sepsis

BACKGROUND: Sepsis is still a major cause of death in both human and veterinary medicine. Early diagnosis is essential for appropriate treatment. Identification of patients at risk for developing sepsis is already possible in human medicine through the measurement of plasma interleukin-6 (IL-6) levels. In veterinary medicine, however, this has been investigated only in canine experimental models. OBJECTIVES: The purpose of this study was to measure IL-6 plasma levels in dogs with naturally occurring systemic inflammatory response syndrome (SIRS) and sepsis and to analyze the value of IL-6 as a predictive parameter for severity and mortality. METHODS: Included in the study were 79 dogs that had been admitted to the small animal clinics of Munich and Berlin from July 2004 to July 2005 and that satisfied the diagnostic criteria for SIRS and sepsis as defined using established parameters. Measurement of plasma IL-6 levels on days 0, 1, and 2 was performed by the use of a colorimetric bioassay based on IL-6-dependent cell growth. RESULTS: Septic foci were identified in 43 patients (septic group), and 36 patients were enrolled in the SIRS group. The frequency of positive blood cultures was 11%. The overall mortality rate was 48%. Higher plasma IL-6 levels on the day of admission were significantly correlated with a more severe degree of disease, increased mortality rate, and earlier fatality. CONCLUSIONS: Plasma IL-6 concentration is predictive of outcome in canine SIRS and sepsis and may be a valuable laboratory parameter for assessing critically ill dogs.     

Dietary fatty acids and inflammation in the vertebral column of Atlantic salmon, Salmo salar L., smolts: a possible link to spinal deformities

Vegetable oils (Vo) are an alternative to fish oil (Fo) in aquaculture feeds. This study aimed to evaluate the effect of dietary soybean oil (Vo diet), rich in linoleic acid, and of dietary fish oil (Fo diet) on the development of spinal deformities under bacterial lipopolysaccharide (LPS)‐induced chronic inflammation conditions in Atlantic salmon, Salmo salar L. Fish [25 g body weight (BW)] were fed the experimental diets for 99 days. On day 47 of feeding (40 g BW), fish were subjected to four experimental regimes: (i) intramuscular injections with LPS, (ii) sham‐injected phosphate‐buffered saline (PBS), (iii) intraperitoneally injected commercial oil adjuvant vaccine, or (iv) no treatment. The fish continued under a common feeding regime in sea water for 165 more days. Body weight was temporarily higher in the Vo group than in the Fo group prior to immunization and was also affected by the type of immunization. At the end of the trial, no differences were seen between the dietary groups. The overall prevalence of spinal deformities was approximately 14% at the end of the experiment. The Vo diet affected vertebral shape but did not induce spinal deformities. In groups injected with LPS and PBS, spinal deformities ranged between 21% and 38%, diet independent. Deformed vertebrae were located at or in proximity to the injection point. Assessment of inflammatory markers revealed high levels of plasma prostaglandin E₂ (PGE₂) in the Vo‐fed and LPS‐injected groups, suggesting an inflammatory response to LPS. Cyclooxigenase 2 (COX‐2) mRNA expression in bone was higher in fish fed Fo compared to Vo‐fed fish. Gene expression of immunoglobulin M (IgM) was up‐regulated in bone of all LPS‐injected groups irrespective of dietary oil. In conclusion, the study suggests that Vo is not a risk factor for the development of inflammation‐related spinal deformities. At the same time, we found evidence that localized injection‐related processes could trigger the development of vertebral body malformations.