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The quantification, localization, production, function, and regulation of irisin/FNDC5 in camel species have not been previously studied. The objective of this study was to detect the irisin content in Arabian camel blood and tissues and study the gene expression of FNDC5 and PGC-1α in camel skeletal muscles and white adipose tissue depots under basal conditions. To monitor if exercise influences blood and tissue irisin protein levels as well as FNDC5 and PGC-1α gene expression levels, we analyzed irisin concentrations in the serum, skeletal muscles (soleus and gastrocnemius), and white adipose tissues (hump, subcutaneous, visceral, epididymal, and perirenal) in both control (n = 6) and exercised group (n = 6) using ELISA and determined the cellular localization of irisin/FNDC5 and the mRNA levels of FNDC5 and PGC-1α in skeletal muscles and adipose tissues via immunohistochemistry and real-time PCR, respectively. The possible regulatory roles of exercise on some hormones and metabolites as well as the detection of links between serum irisin and other circulating hormones (insulin, leptin, and cortisol) and metabolites (glucose, free fatty acids, triglycerides, and ATP) were explored for the first time in camels. Our results indicated that exercise induces tissue-specific regulation of the camel irisin, FNDC5, and PGC-1α levels, which subsequently regulates the circulating irisin level. Significant associations were detected between the levels of irisin/FNDC5/PGC-1α in camels and the metabolic and hormonal responses to exercise. Our study suggested that irisin regulates, or is regulated by, glucose, FFA, insulin, leptin, and cortisol in camels. The novel results of the present study will serve as baseline data for camels.

To arrange multidisciplinary treatment for esophageal cancer, a simple and accurate predictive marker for prognosis is required. The current multicenter prospective study aims to validate the prognostic significance of fibrinogen and albumin score (FA score) for esophageal cancer patients. Patients who were planned to undergo surgical resection for esophageal cancer at four participating institutions were enrolled in this study. Patient background, clinicopathological factors, and blood concentration of plasma fibrinogen and albumin were collected. Patients with elevated fibrinogen and decreased albumin levels were allocated a score of 2; those with only one of these abnormalities were allocated a score of 1; and those with neither of these abnormalities were allocated a score of 0. Recurrence-free survival (RFS) and overall survival (OS) were evaluated as a primary endpoint. From four participating institutions, 133 patients were registered for the current analysis. The distribution of FA score of 0/1/2 was 84 (63%)/34 (26%)/15 (11%), respectively. In the analysis of primary endpoint, the preoperative FA score significantly classified RFS (FA score 1/2: HR 2.546, p = 0.013/6.989, p

Children with leukemia treated with methotrexate (MTX) may develop MTX-induced leukoencephalopathy, which can present as seizures or focal neurological deficits. However, the precise pathophysiology has not been fully elucidated. Differences in cytokine/chemokine profiles in cerebrospinal fluid (CSF) between children with MTX-induced leukoencephalopathy and those with posterior reversible encephalopathy syndrome (PRES), an acute neurological condition associated with hypertension, were investigated. Interleukin (IL)-1β, 2, 4, 5, 6, 7, 8, 10, 12, 13, and 17, tumor necrosis factor-alpha, interferon-gamma, granulocyte monocyte colony-stimulating factor, granulocyte colony-stimulating factor, macrophage inflammatory protein-1β, and monocyte chemoattractant protein-1 concentrations were measured in CSF supernatants from 3 children with acute leukemia with MTX-induced leukoencephalopathy, 3 children with acute leukemia with PRES, 6 children with acute leukemia without neurological complications, and 8 children with acute encephalopathy. CSF IL-6 concentrations were higher in children with MTX-induced leukoencephalopathy than in children with acute leukemia with PRES, with acute leukemia without neurological complications, and with acute encephalopathy. We concluded that IL-6 may be involved in the pathogenesis of MTX-induced leukoencephalopathy.

Chemoattractant receptor homologous with T-helper cell type 2 cells (CRTH2), a receptor for prostaglandin D2, is preferentially expressed on T-helper cell type 2 lymphocytes, group 2 innate lymphoid cells, eosinophils, and basophils, and elicits the production of type 2 cytokines, including profibrotic IL-13. We hypothesized that lack of CRTH2 might protect against fibrotic lung disease, and we tested this hypothesis using a bleomycin-induced lung inflammation and fibrosis model in CRTH2-deficient (CRTH2-/-) or wild-type BALB/c mice. Compared with wild-type mice, CRTH2-/- mice treated with bleomycin exhibited significantly higher mortality, enhanced accumulation of inflammatory cells 14-21 days after bleomycin injection, reduced pulmonary compliance, and increased levels of collagen and total protein in the lungs. These phenotypes were associated with decreased levels of IFN-γ, IL-6, IL-10, and IL-17A in BAL fluid. Adoptive transfer of splenocytes from wild-type, but not CRTH2-/-, mice 2 days before injection of bleomycin resolved the sustained inflammation as well as the increased collagen and protein accumulation in the lungs of CRTH2-/- mice. We consider that the disease model is driven by γδT cells that express CRTH2; thus, the adoptive transfer of γδT cells could ameliorate bleomycin-induced alveolar inflammation and fibrosis.

Background Despite much evidence supporting the monitoring of the divergence of transcutaneous partial pressure of carbon dioxide (tcPCO2) from arterial partial pressure carbon dioxide (artPCO2) as an indicator of the shock status, data are limited on the relationships of the gradient between tcPCO2 and artPCO2 (tc-artPCO2) with the systemic oxygen metabolism and hemodynamic parameters. Our study aimed to test the hypothesis that tc-artPCO2 can detect inadequate tissue perfusion during hemorrhagic shock and resuscitation. Methods This prospective animal study was performed using female pigs at a university-based experimental laboratory. Progressive massive hemorrhagic shock was induced in mechanically ventilated pigs by stepwise blood withdrawal. All animals were then resuscitated by transfusing the stored blood in stages. A transcutaneous monitor was attached to their ears to measure tcPCO2. A pulmonary artery catheter (PAC) and pulse index continuous cardiac output (PiCCO) were used to monitor cardiac output (CO) and several hemodynamic parameters. The relationships of tc-artPCO2 with the study parameters and systemic oxygen delivery (DO2) were analyzed. Results Hemorrhage and blood transfusion precisely impacted hemodynamic and laboratory data as expected. The tc-artPCO2 level markedly increased as CO decreased. There were significant correlations of tc-artPCO2 with DO2 and COs (DO2: r = − 0.83, CO by PAC: r = − 0.79; CO by PiCCO: r = − 0.74; all P 2crit) was 11.72 mL/kg/min according to transcutaneous partial pressure of oxygen (threshold of 30 mmHg). Receiver operating characteristic curve analyses revealed that the value of tc-artPCO2 for discrimination of DO2crit was highest with an area under the curve (AUC) of 0.94, followed by shock index (AUC = 0.78; P 2), and lactate (AUC = 0.65; P 2). Conclusions Our observations suggest the less-invasive tc-artPCO2 monitoring can sensitively detect inadequate systemic oxygen supply during hemorrhagic shock. Further evaluations are required in different forms of shock in other large animal models and in humans to assess its usefulness, safety, and ability to predict outcomes in critical illnesses.

Acute mesenteric ischemia (AMI) is challenging to diagnose in the early phase. We tested the hypothesis that blood levels of cell-free DNA would increase early after AMI. In addition, proteome analysis was conducted as an exploratory analysis to identify other potential diagnostic biomarkers.Mesenteric ischemia, abdominal sepsis, and sham model were compared in Sprague-Dawley rats. The abdominal sepsis model was induced by cecum puncture and mesenteric ischemia model by ligation of the superior mesenteric artery. Blood levels of cell-free DNA were measured 2 h and 6 h after wound closure. Shotgun proteome analysis was performed using plasma samples obtained at the 2 h timepoint; quantitative analysis was conducted for proteins detected exclusively in the AMI models.Blood cell-free DNA levels at 2 h after wound closure were significantly higher in the AMI model than in the sham and the abdominal sepsis models (P0.05). Cell-free DNA was positively correlated with the pathologic ischemia severity score (correlation coefficient 0.793-0.834, P0.001). Derivative proteome analysis in blood at 2-h time point revealed higher intensity of paraoxonase-1 in the AMI models than in the abdominal sepsis models; the significantly high blood paraoxonase-1 levels in the AMI models were confirmed in a separate quantitative analysis (P = 0.015).Cell-free DNA was demonstrated to be a promising biomarker for the early diagnosis of mesenteric ischemia in a rat model of AMI. Paraoxonase-1 may also play a role in the differential diagnosis of mesenteric ischemia from abdominal sepsis. The current results warrant further investigation in human studies.

Testicular steroidogenesis is depressed by adrenal-secreted corticosterone (CORT) under stress. However, the mechanisms are not well understood. This study investigated the details of testicular steroidogenesis depression during fasting. Blood levels of adrenocorticotropic hormone secreted from the pituitary glands increased, but blood CORT was not changed in rats that fasted for 96 h, in spite of the rats being severely stressed. CORT in fasting adult male rats increased more than three times in the testis, but reduced testicular testosterone (T) and blood T levels to 5% and 2% of the control, respectively, was observed. The contents of T precursor (except PGN) were drastically reduced in the fasted-rat testes. Testicular CORT levels were elevated, but the enzymatic activity of cytochrome P45011β, which produces CORT, remained unchanged. The enzymatic activities of 3β-hydroxysteroid dehydrogenase (3β-HSD), mediating the conversion of pregnenolone to progesterone, decreased in the fasted-rat testes. Thus, fasting suppressed testicular steroidogenesis by affecting the enzyme activity of 3β-HSD in the testes and drastically reduced T and increased CORT synthesis. It can be considered that T synthesis involved in cell proliferation is suppressed due to lack of energy during fasting. Conversely, 11β-hydroxylase enzyme activity was induced and CORT synthesis is increased to cope with the fasting stress. Hence, it can be concluded that CORT synthesis in the testes plays a role in the local defense response.

Diethylstilbestrol (DES) is a synthetic oestrogen known to disrupt the endocrine system and to cause reproductive toxicity mediated via the hypothalamic-pituitary-adrenal axis; however, its molecular mechanism of action is poorly understood. In the present study, we found that, after only 1 week of exposure to DES, blood testosterone dramatically decreased and that this decrease was associated with a strong induction of prolactin (PRL). Even with the increase in PRL, the luteinising hormone and follicle-stimulating hormone mRNAs slightly decreased. Our results show that, after 48 hours of a single dose of DES, there was a six-fold increase in PRL expression. After exploring the upstream mechanisms, we determined that dopamine, which inhibits PRL secretion in male rats, did not decrease in the pituitary gland of DES-treated rats, whereas vasoactive intestinal peptide (VIP), which mediates the acute release of PRL, was elevated. Serotonin (5-HT) increased in the brain of male rats 24 hours after a single DES treatment; however, PRL, VIP or 5-HT was not induced by DES in female rats. Our results indicate that DES induces the expression of pituitary PRL in male rats by stimulating VIP in the hypothalamus and 5-HT in the central nervous system.

Background The incidence of biliary tract infection (BTI), especially healthcare-associated cholangitis, is increasing. However, there are few reports concerning biomarkers of acute cholangitis. We therefore performed an exhaustive investigation of several biomarkers. Methods We retrospectively measured eleven cytokines, six chemokines and procalcitonin (PCT), and endotoxin activity assay (EAA) values (IRB: 110512019) of sixty-one samples with acute cholangitis. Result The 28-day mortality rate was 9.8%. The levels of most cytokines and chemokines were significantly correlated with each other. A low IL-7 level was found to predict of blood culture positivity. Low IL-7 level was also found to predict DIC. Low IL-7 levels and a high PCT level were found to be predictors of severe cholangitis. The 28-day mortality in the group of patients with an IL-7 level of ≤6.0 and a PCT level of >0.5 was 18.2%. It was significantly higher than in the other group. Conclusion The combined use of IL-7 and PCT may be useful for evaluating severe acute cholangitis; these results may suggest that severe acute cholangitis is affected by immunosuppressive changes. This article is protected by copyright. All rights reserved.

Haptoglobin exerts renal protective function by scavenging free hemoglobin from the urine and blood stream in patients with hemolytic disorders. Recent studies elucidate the relationships between haptoglobin and inflammation. In addition, coagulopathy is often induced by systemic inflammation characterized by the presence of vascular endothelial damage. We hypothesize that haptoglobin might have an anti-inflammatory effect and affect hypercoagulability using rat burn model. Thirty anesthetized rats of six-weeks of age received over 30% full-thickness scald burn on the dorsal skin surface. All rats were injected with either haptoglobin (Hpt) or normal saline (NS) intraperitoneally. The rats were divided into three groups: 1) control group (NS 20 mL/kg); 2) low concentration of Hpt group, L-Hpt, (Hpt 4 mL (80 U) /kg+NS 16 mL/kg); and 3) high concentration of Hpt group, H-Hpt, (Hpt 20 mL (400 U) /kg). While under anesthesia, all rats were euthanized by exsanguination at 6 hours (N=5) and 24 hours (N=5). Inflammatory and anti-inflammatory cytokines were measured and whole-blood viscoelastic tests were performed by thromboelastometry (ROTEM). Haptoglobin significantly reduced free hemoglobin 24 hours after the injury. Improvement of hematuria was confirmed in the H-Hpt group. There were no differences in thrombin-antithrombin complex and plasmin-α2 plasmin inhibitor complex. The haptoglobin tended to decrease interferon-gamma (IFN-γ) in H-Hpt group. ROTEM findings of the L-Hpt group showed significantly higher clot firmness and shorter time to maximum clot formation velocity than the control group. Haptoglobin reduced INF-γ, and accelerated speed of clot formation in acute phase of severe burn.

We report the case of a baby with low birthweight born by emergency caesarean section at 33 weeks 2 days' gestation due to placental abruption. High-mobility group box-1 (HMGB-1) and interleukin-17 concentration in the umbilical cord blood were high at 55.7 ng/mL and 50.7 pg/mL, respectively. On immunostaining of umbilical cord and amniotic epithelium, HMGB-1 was identified in the nuclei of vascular endothelial cells and cytoplasm of the surrounding cells in the umbilical cord. This suggests that, in the present case of placental abruption and subsequent ischemic placenta and fetus, the high level of HMGB-1 observed was due to the release of HMGB-1 into the umbilical cord blood from the vascular endothelial cells of the umbilical cord.

Direct hemoperfusion with a polymyxin B-immobilized column (PMX-DHP) adsorbs endotoxin and has been used for the treatment of septic shock. Yet, the mechanisms by which PMX-DHP acts on acute kidney injury are only partially understood.Rats were anesthetized, tracheostomized, and placed on mechanical ventilation. The animals were randomized to three groups: a cecal ligation and puncture (CLP) + dummy-DHP group (n = 10), a CLP + PMX-DHP group (n = 10), and a sham group (n = 4). Four hours after CLP, a dummy-DHP or PMX-DHP was performed for 1 h. The heart rate, mean arterial pressure, arterial blood gases, and plasma concentrations of creatinine, lactate, potassium, interleukin (IL)-6, and IL-10 were measured at 0 h and 8 h. Eight hours after CLP, the kidney was harvested, and histopathologic examination was performed. The expressions of cleaved poly (ADP-ribose) polymerase (PARP) and nuclear factor (NF)-κB p65 were examined by immunohistochemistry. A terminal deoxynucleotide transferase dUTP nick-end labeling assay was performed to detect apoptotic nuclei in kidney sections.PMX-DHP maintained hemodynamics and the acid-base balance and significantly (P0.05) decreased the plasma concentrations of lactate, creatinine, potassium, IL-6, and IL-10 compared with dummy-DHP. PMX-DHP significantly (P0.001) attenuated the expressions of cleaved PARP and NF-κB p65 in renal tubular cells and renal tubular cell apoptosis compared with dummy-DHP.These findings suggest that PMX-DHP may protect against acute kidney injury not only by inhibiting the NF-κB signaling pathway but also by preventing renal tubular cell apoptosis.

Chemoattractant receptor homologous with T-helper cell type 2 cells (CRTH2), a receptor for prostaglandin D

Promising results have been reported with blood purification as adjuvant treatment; however, the immunological mechanisms remain unclear. We have been developing a new blood purification system for regulating excessive immune reactions in severe sepsis and septic shock using a granulocyte adsorbing column (Adacolumn [Ada]), and a cytokine-adsorbing hemofilter (AN69ST hemofilter [AN69]). Fresh porcine blood was circulated for 6 h in five experimental groups including Ada and AN69 to assess the effects of leukocyte adsorption, phagocytic activity and adhesiveness of granulocytes. In the present study, we found that Ada mainly adsorbed granulocytes and monocytes, but not lymphocytes. The phagocytic activity level of granulocytes decreased, and adhesiveness increased, but the number of CD11b-positive cells markedly decreased in the current system. Elevated cytokine levels (IL-1β, IL-8 and IL-10) at the outlet of Ada were significantly lower than at the outlet of AN69 due to cytokine adsorption. Further studies are needed to better understand cellular interactions.

Haemangiosarcoma (HSA) is an important malignant neoplasm of dogs that originates from vascular endothelial cells. This study explored the suitability of using serum big endothelin-1 (ET-1) as a tumour marker for canine spontaneous HSA. Serum big ET-1 was measured in dogs with splenic HSA (n = 14), splenic malignant tumours other than HSA (n = 10), benign splenic lesions (n = 11) and normal healthy dogs (n = 17) by ELISA. Serum big ET-1 levels in dogs with HSA were significantly (P 0.01) higher than in other dogs. High sensitivity (100%, 95% confidence interval 86-100%) and specificity (95%, 95% confidence interval 86-95%) for HSA diagnosis were obtained using a cut-off of 17 pg/mL according to receiver operating characteristic (ROC) curves (area under ROC curve 0.93). PPET1, ETA, VEGF and Hif1-α mRNA expression, measured by real-time PCR, were elevated in HSA compared with normal tissues. These findings suggest that elevated serum big ET-1 could be used as a diagnostic marker for canine HSA.

We performed a randomized, prospective animal study to investigate whether inhibiting the renin-angiotensin system with a (pro)renin receptor blocker (PRRB) prevents acute lung injury (ALI) in a rodent model.We used Thirty-six male Sprague-Dawley rats. We administered lipopolysaccharide (LPS; 2 mg/kg) intratracheally with or without PRRB pretreatment (1 mg/kg/d).We performed bronchoalveolar lavage (BAL) and lung removal at 4 h after LPS administration and measured levels of inflammatory cytokines, high mobility group box 1 (HMGB-1) protein, and total protein in bronchoalveolar lavage fluid (BALF). Myeloperoxidase (MPO) activity was detected in lung tissue homogenates using a sensitive ELISA. We performed hematoxylin and eosin staining and immunohistochemical staining for nonproteolytically activated prorenin in the left lung.The PRRB decreased leukocyte counts and total protein, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-2, IL-6, and IL-10 levels in the BALF and MPO activity in lung tissue. The PRRB reduced interstitial edema, hemorrhage, and the neutrophil count in the lung tissues. Consistent with the reduction in lung tissue damage, immunohistochemical staining showed that the PRRB decreased the amount of nonproteolytically activated prorenin.The PRRB blocked LPS-induced inflammatory response in the lung and protected against ALI. Therefore, it is a potential therapeutic agent for preventing ALI.

Background High-mobility group box 1 (HMGB1) has recently been identified as an important mediator of various kinds of acute and chronic inflammation. The protein encoded by the box-A domain of the HMGB1 gene is known to act as a competitive inhibitor of HMGB1. In this study, we investigated whether box-A gene transfer results in box-A protein production in rats and assessed therapeutic efficacy in vivo using an acute liver failure (ALF) model. Materials and methods Three types of adenovirus vectors were constructed—a wild type and two mutants—and a mutant vector was then selected based on the secretion from HeLa cells. The secreted protein was subjected to a tumor necrosis factor (TNF) production inhibition test in vitro . The vector was injected via the portal vein in healthy Wistar rats to confirm box-A protein production in the liver. The vector was then injected via the portal vein in rats with ALF. Results Western blot analysis showed enhanced expression of box-A protein in HeLa cells transfected with one of the mutant vectors. The culture supernatant from HeLa cells transfected with the vector inhibited TNF-α production from macrophages. Expression of box-A protein was confirmed in the transfected liver at 72 h after transfection. Transfected rats showed decreased hepatic enzymes, plasma HMGB1, and hepatic TNF-α messenger RNA levels, and histologic findings and survival were significantly improved. Conclusions HMGB1 box-A gene transfer results in box-A protein production in the liver and appears to have a beneficial effect on ALF in rats.

Esophagectomy for esophageal cancer is one of the most invasive operative procedures. Surgical stress induces the release of proinflammatory cytokines, and overproduction induces a systemic inflammatory response syndrome, which may lead to acute lung injury and multiple organ dysfunction syndrome. In addition, surgical stress may cause immunosuppression, which may affect not only perioperative mortality but also long-term survival. Between 2006 and 2013, levels of perioperative serum cytokines were evaluated in 90 patients who underwent esophagectomy for esophageal carcinoma. The serum interleukin (IL)-6, IL-8, and IL-10 levels were measured by enzyme-linked immunosorbent assays. We reviewed and assessed medical records, including cytokine profiles, and determined the factors affecting postoperative serum cytokine levels. These cytokine levels peaked on postoperative day 1 and decreased gradually. Of the clinicopathologic factors, a thoracoscopic approach was a significant factor in attenuating IL-6 and IL-8 levels on postoperative day 1 in multivariate analysis, and a longer operative time was a significant factor in increasing these levels. During postoperative days 3–7, the thoracoscopic approach and early enteral nutrition were significant factors in attenuating serum cytokine changes in multivariate analysis, and postoperative infectious complications were significant factors in increasing these levels. The thoracoscopic approach and early enteral nutrition could attenuate the cytokine change after esophagectomy, and a longer operative time and postoperative infectious complication could increase it. We should undertake strategies to minimize the surgical stress to reduce potential short-term and long-term consequences for patients.

OBJECTIVE The perfusion index (PI) derived from plethysmographic signals provides a noninvasive indication of peripheral perfusion. This study aimed to investigate changes in PI and other hemodynamic variables in pigs subjected to endotoxemia. DESIGN Prospective experimental study. SETTING University teaching hospital. ANIMALS Twelve healthy pigs weighing a mean (± standard deviation [SD]) of 31.7 ± 2.0 kg. INTERVENTIONS Pigs were divided into control and endotoxin groups (n = 6 each). Endotoxemia was induced by IV infusion of lipopolysaccharide. Heart rate, mean arterial pressure, cardiac index (CI), central venous pressure, systemic vascular resistance index (SVRI), extravascular lung water index (ELWI), Global end-diastolic volume (GEDV) index, and pulmonary permeability index were measured using a transpulmonary thermodilution monitor in all pigs. PI was measured using a pulse oximeter probe attached to the tail. Pao2 , Paco2 , and plasma lactate concentration were measured by blood gas analysis. Measurements were taken at baseline (T0 ). Saline or lipopolysaccharide was then administered for 30 min to all pigs (control or endotoxemia group, respectively), and each parameter was measured every 30 min up to 270 min. Data were analyzed by analysis of variance and Student's t-tests. MEASUREMENTS AND MAIN RESULTS There were no significant changes in any variables in the control group, but CI, SVRI, PI, ELWI, blood lactate concentration, and Pao2 changed significantly from baseline in the endotoxin group (P < 0.001, P = 0.0048, P < 0.001, P = 0.0064, P < 0.001, and P = 0.0220, respectively). In the endotoxin group, mean (± SD) %PI increased from T0 to 154 ± 34% at T60 (P = .001) and 135 ± 50% at T90 (P =0 .004), which mirrored significant changes in %CI and %SVRI. CONCLUSION The PI may be useful to detect changes in CI and SVRI.

A male Thoroughbred fetus was aborted on day 251 of pregnancy. Gross and histological examinations detected systemic granulomatous lesions in many superficial and visceral lymph nodes and organs including the liver, tonsils, lungs, thymus, spleen, right thyroid gland and gastrointestinal tract, and suppurative placentitis, pyogranulomatous amnionitis and intralesional acid-fast bacilli were also detected. An examination of the DNA base sequence of the β subunit of RNA polymerase demonstrated that Mycobacterium avium strain 104 had infected several organs. To the best of our knowledge, this is the first report of equine fetal mycobacterial infection in Japan.

【Aims】 Many studies of human subjects have demonstrated the utility of assessing serum levels of endothelin-1 (ET-1) and big ET-1 as clinical biomarkers in cardiopulmonary and neoplastic diseases. In this study we explored the feasibility of using serum big ET-1 as a reliable veterinary marker in dogs with various cardiopulmonary and neoplastic diseases. 【Main methods】 Serum big ET-1 levels were measured by ELISA in dogs with cardiopulmonary (n = 21) and neoplastic diseases (n = 57). Dogs exhibiting cardiopulmonary disease were divided into two groups based on the velocity of tricuspid valve regurgitation (3.0 > m/s) measured by ultrasound: without and with pulmonary hypertension. Big ET-1 levels for the dogs with the diseases were compared with levels in normal healthy dogs (n = 17). 【Key findings】 Dogs with cardiopulmonary disease (4.6 ± 4.6 pmol/l) showed a significantly (P < 0.01) higher level of big ET-1 than healthy control dogs (1.1 ± 0.53 pmol/l). Serum levels in the dogs with pulmonary hypertension (6.2 ± 5.3 pmol/l) were significantly (P < 0.01) higher than those without pulmonary hypertension (2.0 ± 0.6 pmol/l). Dogs with hemangiosarcoma (5.6 ± 2.2 pmol/l), adenocarcinoma (2.0 ± 1.8 pmol/l), histiocytic sarcoma (3.3 ± 1.9 pmol/l), chondrosarcoma or osteosarcoma (3.0 ± 1.6 pmol/l) and hepatocellular carcinoma (2.7 ± 1.8 pmol/l) showed significantly (P < 0.05) higher levels than healthy control dogs. 【Significance】These findings point to the potential of serum big ET-1 as a clinical marker for cardiopulmonary and neoplastic diseases in dogs.

Inflammation occurs along with infection during sepsis. 15-Epi-lipoxin A4 has protective and resolving effects in experimental models of infection. In this study, we examined the effects of 15-epi-lipoxin A4 combined with antibiotics on Escherichia coli-induced peritonitis.Prospective experimental study.University research laboratory.Male C57BL/6 mice.Mice were injected with E. coli to induce peritonitis and were given either 15-epi-lipoxin A4 (1 μg/mouse) or placebo (saline) with antibiotics (ceftazidime). The effects of 15-epi-lipoxin A4 on peritoneal cell populations, bacterial burden, and cytokine production were assessed. Survival rates were observed for up to 7 days. In addition, we examined the effects of 15-epi-lipoxin A4 on peritoneal macrophages stimulated with lipopolysaccharide, CpG DNA, or live E. coli.Treatment with 15-epi-lipoxin A4 significantly reduced the number of neutrophils in the peritoneum, inhibited production of cytokines and chemokines, and decreased bacterial load in the serum. Combined treatment of 15-epi-lipoxin A4 with antibiotics significantly improved survival in E. coli-infected mice. 15-Epi-lipoxin A4 also attenuated the production of interleukin-6 and tumor necrosis factor-α by lipopolysaccharide- or CpG DNA-stimulated peritoneal macrophages. Furthermore, 15-epi-lipoxin A4 combined with antibiotics synergistically reduced the production of interleukin-6 and tumor necrosis factor-α by peritoneal macrophages stimulated with live E. coli.15-Epi-lipoxin A4 combined with antibiotics attenuated systemic inflammation, inhibited bacteria dissemination, and improved survival in E. coli-infected mice. The reduced production of interleukin-6 and tumor necrosis factor-α by peritoneal macrophages suggested that 15-epi-lipoxin A4 blocked the initial proinflammatory response. Taken together, these data suggested that 15-epi-lipoxin A4 combined with antibiotics was beneficial in regulating the proinflammatory response in sepsis without exacerbating infection.

This study investigated the effects of direct hemoperfusion with polymyxin B-immobilized fibers (PMX-DHP) on respiratory impairment in endotoxemic pigs.Thirteen anesthetized, mechanically ventilated pigs were divided into PMX-DHP (n=7) and control (n=6) groups. All pigs were hemodynamically monitored with the pulse index contour cardiac output (PiCCO) system (Pulsion Medical Systems, Munich, Germany) and infused intravenously with live Escherichia coli (LD50). In the PMX-DHP group, an arteriovenous extracorporeal circuit with a PMX column was applied for 30 to 150 minutes after endotoxin injection. We analyzed the laboratory data, arterial blood gas levels, and PiCCO variables (extravascular lung water [EVLW] and pulmonary vascular permeability index [PVPI]). Furthermore, we performed computed tomography of the chest in all pigs. The data were statistically analyzed with Student's t-test, the chi-square test, and the Mann-Whitney U-test.With PMX-DHP endotoxemia significantly decreased and blood pressure increased 150 minutes after endotoxin injection. PiCCO revealed more cases of decreased EVLW in the PMX-DHP group. PVPI increased after endotoxin infusion in both groups. Computed tomography showed improvements in the PMX-DHP group. The survival rate was greater in the PMX-DHP group (100%) than in the control group (71%).PMX-DHP is effective for treating respiratory impairment and contributes to the decreased mortality rate in the endotoxemic pigs.

Background The renin-angiotensin system (RAS) affects inflammatory responses during sepsis. Nonproteolytic activation of prorenin by the (pro)renin receptor has recently been shown to stimulate the tissue RAS. In the present study, the effect of (pro)renin receptor blocker (PRRB) pretreatment on sepsis in a rat cecal ligation and puncture (CLP) model was investigated. Materials and methods Male Sprague-Dawley rats underwent CLP and were randomly divided into two groups: PRRB-treated group and control peptide–treated group. Survival was analyzed for 7 d after CLP. The serum concentrations of cytokines and high-mobility group box chromosomal protein 1 (HMGB1) were measured at three time points (0, 3, and 6 h after CLP). Hematoxylin-eosin staining and immunohistochemical staining for nonproteolytically activated prorenin and HMGB1 were performed on the cecum to assess pathologic changes found 6 h after CLP. Results Treatment with PRRB improved the survival rate of the post-CLP septic rats (P = 0.023). PRRB also significantly reduced serum tumor necrosis factor-α, interleukin-1β, and HMGB1 levels 6 h after CLP. In CLP rats that were treated with control peptide, the expression of activated prorenin was elevated in peritoneal foam cells. Moreover, expression of HMGB1 was increased in peritoneal inflammatory cells. In contrast, both were markedly suppressed in CLP rats that were treated with PRRB. Conclusions PRRB significantly improved the survival rate of rats with clinically relevant sepsis, possibly by attenuating a sepsis-induced systemic inflammatory response. We propose that overactivation of the RAS by activation of prorenin in foam cells may be a significant contributor to sepsis.

CXCL-8, known as proinflammatory cytokine interleukin (IL)-8, and its receptor, CXCR-2, are expressed in various cancer cells. CXCL-8/CXCR-2 network is believed to be involved in angiogenesis, growth, and invasion of tumor cells. To date, the clinical significance of CXCL-8/CXCR-2 network in esophageal squamous cell carcinoma (ESCC) remains unclear. Here, we investigated the role of CXCL- 8/CXCR-2 network in ESCC.The subjects included 78 patients with primary ESCC. We examined CXCL-8 and CXCR-2 expression in surgically resected specimens using immunohistochemistry. The association between CXCL-8/CXCR-2 expression and level of preoperative serum cytokines, C-reactive protein (CRP), coagulation factors, clinicopathologic background factors, and survival of ESCC patients was assessed.Thirty-seven (47%) and 36 (46%) patients were positive for CXCL-8 and CXCR-2 expression, respectively. Both CXCL-8 and CXCR-2 were expressed in 26 patients (33%). We compared the results of these 26 patients [CXCL-8(+)/CXCR-2(+) group] with those of the other group (n = 52). The depth of invasion (pT factor; P.001), lymph node metastasis (pN factor; P = .001), pathologic stage (P .001), lymphatic invasion (P = .010), and venous invasion (P = .001) were significantly more advanced in the CXCL-8(+)/CXCR-2(+) group compared with the other group. Preoperative IL-6, IL-8, CRP, fibrin/fibrinogen degradation product, and fibrinogen levels in the CXCL-8(+)/CXCR-2(+) group were also significantly higher than those in the other group (P = .046, .009, .029, .010, and.001, respectively). The CXCL-8(+)/CXCR-2(+) group also showed a significantly lower recurrence-free survival (RFS; P.001) and disease-specific survival (P = .008). As per Cox's hazards model, CXCL-8/CXCR-2 expression (hazard ratio, 2.89; P = .008) was independent predictive factor for RFS.Increased expression of both CXCL-8 and CXCR-2 correlated with tumor progression, metastasis, higher preoperative levels of proinflammatory cytokines, CRP, activation of exogenous coagulation factors, and poor prognosis in ESCC patients. These results indicate that overexpression of both CXCL-8 and CXCR-2 may be a useful marker for predicting the outcome in ESCC patients, and more important, has potential in becoming a critical diagnostic marker for selection of appropriate treatments.

Reproductive toxicities and endocrine disruptions caused by chemicals in adult males are still poorly understood. It is our objectives to understand further details of the initial adverse effects leading severe testicular toxicities of a pharmaceutical endocrine disruptor, diethylstilbestrol (DES). Downregulations of both testicular regulatory proteins, such as the steroidogenic acute regulatory protein (StAR) and the peripheral benzodiazepine receptor (PBR), which play important roles in the transport of cholesterol into the mitochondria, and cytochrome P450 mediating the cholesterol side chain cleavage reaction (P450scc), were observed in the rat orally administered DES (340 μg/kg/2 days) for 2 weeks. We found that after only 1 week treatment with DES, the blood and testicular testosterone (TS) levels were drastically decreased without abnormalities of the StAR and PBR; however, the protein and mRNA levels of P450scc were diminished. Decrease in the conversion rate of cholesterol to pregnenolone was delayed in the in vitro assay using the testicular mitochondrial fraction from the rat treated with DES for 1 week. When the precursors in TS biosynthesis containing the testis were identified and determined by liquid chromatography-mass spectrometry analysis, decreased levels of all precursors except cholesterol were observed. In conclusion, suppressed cytochrome P450scc expression in adult male rat was identified as an initial target of DES in testicular steroidogenesis disorder leading reproductive toxicities. © 2013 Wiley Periodicals, Inc. Environ Toxicol 29: 1452–1459, 2014.

Background Sivelestat sodium hydrate is a specific neutrophil elastase inhibitor effective in acute lung injury (ALI) associated with systemic inflammatory response syndrome. Bowel ischemia reperfusion injury (IRI) induced by supravisceral aortic clamping is associated with an excessive systemic inflammatory response, resulting in remote organ damage, including ALI. In this study, we investigated whether sivelestat can attenuate neutrophil sequestration in the lung, alleviate ALI, and improve survival in a rat bowel IRI model. Methods Adult male Sprague-Dawley rats underwent bowel IRI induced by supravisceral aortic clamping and were randomly assigned to receive sivelestat or saline (control) and monitored for survival. We randomly assigned other rats to undergo laparotomy alone (sham operation), IRI alone, or IRI and sivelestat treatment. We evaluated blood samples for organ function, cytokine levels, and neutrophil elastase activity after reperfusion. Organs were analyzed histologically. We also determined lung injury in another set of rats. Results Bowel IRI induced a significant increase in serum variables indicative of organ function, cytokine concentrations, neutrophil elastase activity, and lung permeability and edema, which reflected the presence of both systemic inflammatory response syndrome and compensatory anti-inflammatory response syndrome. Treatment with sivelestat significantly improved survival rate, lung permeability and edema, and significantly decreased levels of creatinine, interleukin 6, interleukin 10, and neutrophil elastase activity. Histological studies showed that sivelestat-treated rats had less bowel IRI-induced damage to lung and liver tissue than controls. Conclusion In a rat model, administration of sivelestat attenuated the effects of bowel IRI induced by supravisceral aortic clamping, and improved the survival rate.

Objective To examine the accuracy of plethysmography variability index (PVI) as a noninvasive indicator of fluid responsiveness in hypovolaemic dogs. Study design Prospective experimental study. Animals Six adult healthy sevoflurane-anaesthetized Beagle dogs. Methods Dogs were anaesthetized with 1.3-fold their individual minimum alveolar concentration of sevoflurane. The lungs were mechanically ventilated after neuromuscular blockade with vecuronium bromide. Cardiopulmonary variables including mean arterial blood pressure (MAP), central venous pressure (CVP), transpulmonary thermodilution cardiac output (TPTDCO), stroke volume (SV), perfusion index (PI), pulse pressure variation (PPV), stroke volume variation (SVV) and PVI were determined during six stages of graded venous blood withdrawal (5 mL kg−1 increments) and six stages of graded blood infusion (5 mL kg−1 increments). The cardiopulmonary variables were analysed using paired t test or Wilcoxon signed rank test. Correlations between PPV and SVV or PVI were analysed by linear regression. The accuracy of PPV, SVV and PVI for predicting fluid responsiveness was examined by using receiver operating characteristic curve analysis. A value of p Results Blood withdrawal resulted in significant increases in PPV and PVI and decreases in MAP, CVP, TPTDCO, SV and PI. Blood infusion resulted in significant increases in MAP, CVP, TPTDCO, SV and PI and decreases in PPV and PVI. PPV and PVI showed a relevant correlation (p Conclusions and clinical relevance Noninvasive measurement of PVI predicted fluid responsiveness with moderate accuracy equal to PPV in sevoflurane-anaesthetized mechanically ventilated dogs. Provisional threshold values for identification of fluid responsiveness were PPV ≥ 16% and PVI ≥ 12%. Clinical trials are needed to confirm these threshold values in dogs.

Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is characterized by severe worsening dyspnea of unknown etiology and high mortality without effective treatment. Recently, direct hemoperfusion with polymyxin B (PMX)-immobilized fiber cartridge (PMX-DHP) has been reported to improve pulmonary oxygenation and survival in patients with AE-IPF although its mechanism of action remains unknown. To gain insights into the pathobiology of AE-IPF through the beneficial effects of PMX-DHP, we analyzed the profile of cytokines adsorbed onto PMX-fibers used in 9 AE-IPF patients. In addition, the sera of these AE-IPF patients collected immediately before and after PMX-DHP, 9 stable IPF patients and 8 healthy individuals were also analyzed. The serum levels of cytokines including IL-9, IL-12, IL-17, PDGF and VEGF were significantly decreased immediately after PMX-DHP (P

An animal experiment was performed to demonstrate the anti-inflammatory effects of an alpha-lipoic acid (ALA) derivative, dihydrolipoyl histidinate zinc complex (DHLHZn) for acute lung injury (ALI) and to investigate the mechanism of action. Rats were randomly divided into three experimental groups: control group (n = 17), DHLHZn(−) group (n = 11, ALI model rats), and DHLHZn(+) group (n = 12, ALI model rats treated by DHLHZn). Lipopolysaccharides (LPS, 10 mg/kg) were administered intratracheally in the DHLHZn(−) group and the DHLHZn(+) group. For the DHLHZn(+) group, DHLHZn (100 mg/kg) was administered intraperitoneally 2 h prior to LPS administration. Four hours after LPS administration, bronchoalveolar lavage fluid (BALF) and lung tissue were collected. The findings were analyzed using the Mann–Whitney U test. Total number of cells, number of neutrophils and lymphocytes, levels of various inflammatory cytokines, and NF-kB p65 concentration of BALF were significantly lower in the DHLHZn(+) group than in the DHLHZn(−) group (p

Background High mobility group box chromosomal protein 1 (HMGB1) has recently been shown to be an important late mediator of endotoxic shock and sepsis. The purpose of the present study was to investigate the role of HMGB1 in response to ischemia-reperfusion injury. Methods Ischemia-reperfusion injury was induced in male Wistar rats by clamping the superior mesenteric artery for 60 min. Using this model, the serum concentrations and localization of HMGB1 were investigated. The histologic findings from reperfused intestines and the survival rates were compared between the anti-HMGB1 antibody treatment groups (group A treated with 6.0 mg/kg antibody and group B with 0.6 mg/kg antibody) and the control antibody treatment group (control group). Results Serum HMGB1 concentrations increased early after reperfusion and peaked at 3 h. Immunohistochemistry for HMGB1 revealed a high degree of positive staining in the epithelial cells of the damaged villi. Anti-HMGB1 antibody treatment significantly reduced this damage ( P versus 50% in the controls; P Conclusions These results suggest that HMGB1 plays a key role in small intestinal ischemia-reperfusion injury.

We performed proteomics analysis of the cerebrospinal fluid (CSF) of healthy dogs and dogs with meningoencephalitis of unknown etiology (MUE). By comparing two-dimensional electrophoreses (2DE), an upregulated spot was found in MUE dogs. This protein was identified as a neuron-specific enolase (NSE) by analysis with MALDI-TOF mass spectrometry. In comparing dot blots using an antibody against NSE, the NSE levels in the CSF of MUE dogs was significantly higher than that of the controls. NSE is a diagnostic marker of neuroendocrine tumors, brain injury and spinal cord trauma in humans. It seems that the NSE concentration in the CSF is increased by cellular destruction in canine encephalitis. Though elevation of NSE may not be specific in canine encephalitis because the NSE level was increased in other CNS diseases, further study including measurement with serum is necessary.

Background: Direct hemoperfusion with a polymyxin B-immobilized column (PMX-DHP) is recognized to be effective for the treatment of septic shock and is widely applied in Japan. However, it is still unknown whether the efficacy is limited to cardiovascular dysfunction. Therefore, the purpose of this study was to examine the effects of PMX-DHP on a non-hypotensive sepsis model. Methods: Wistar rats were assigned to either a PMX-DHP group, control group, or sham group (n = 7 in each group). A sepsis model was made by intravenous infusion of live E. coli. (LD50). The change in systemic blood pressure was less than 20% of the initial level in this model. In the PMX-DHP group, an arteriovenous extracorporeal circuit with a PMX column was applied until 3 h after E. coli injection. The same procedure with a dummy column was applied in the control group. Plasma levels of ALT, LDH, BUN, tumor necrosis factor alpha (TNFα), interleukin (IL)-1β, IL-6, and IL-10 were measured. The mesenteric microcirculation was observed at 1 and 3 h after E. coli injection. In another series, survival was calculated up to 18 h (n = 14 in each group). Results: Organ damage markers were lower in the PMX-DHP group. The levels of pro-inflammatory cytokines were significantly lower in the PMX-DHP group than in the control group. Microcirculation was better maintained in the PMX-DHP group. Survival was significantly better in the PMX-DHP group (93%) compared with that in the control group (57%, P = 0.03). Conclusions: PMX-DHP was effective in a non-hypotensive sepsis model.

We report an atypical mycobacterial infection in an Indian flap-shelled turtle, Lissemys punctata punctata, that died in an aquarium in Japan. At necropsy, the turtle showed multiple white nodules on the capsular surface and parenchyma of various organs such as the liver, spleen, intestine, and lung. Histologically, granulomatous inflammation surrounding a central zone of necrosis was observed. Sections stained by the Ziehl-Neelsen method revealed numerous acid-fast bacilli in the cytoplasm of macrophages and in the central area of necrosis. The organisms were identified as a mycobacterial species by PCR and nucleotide sequence analysis and revealed 98-100% homology to M. ulcerans. This is, to our knowledge, the first report of mycobacteriosis due to M. ulcerans in a turtle.

The present study aimed to elucidate the possible role of High Mobility Group Box 1 (HMGB1), which is a candidate prognostic marker in diseases that combine inflammation and tissue injury, in acute encephalopathy. HMGB1 in cerebrospinal fluid (CSF) obtained on admission from eight children with acute encephalopathy, and 16 children with febrile seizure, eight children with bacterial/aseptic meningitis, and eight children with fever without neurological symptoms were analyzed using enzyme-linked immunosorbent assay (ELISA). We found no increase in HMGB1 in CSF from acute encephalopathy or in CSF from febrile seizure or fever without neurological complications at early time points, while marked elevation of HMGB1 was seen in CSF from bacterial and aseptic meningitis. In conclusion, HMGB1 is a poor disease marker for acute encephalopathy.

Background: The mumps virus is frequently the causative agent in aseptic meningitis and mumps has still prevailed in Japan. We compared data obtained from patients with mumps meningitis and patients with aseptic meningitis caused by other viruses in order to identify mumps meningitis-specific cytokine/chemokine alterations in cerebrospinal fluide (CSF). Methods: We elucidated the cytokine/chemokine network based on the cytokine/chemokine profiles in CSF from children with mumps meningitis and meningitis due to other viral infections using multiplex cytokine measurement. Seventeen cytokines/chemokines, namely interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p70), IL-13, IL-17, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, granulocyte colony-stimulating factor (G-CSF), granulocyte monocyte colony-stimulating factor (GM-CSF), monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1β (MIP-1β), were measured simultaneously in CSF supernatants from eight children with mumps meningitis, 11 children with other types of viral meningitis and eight children with fever without neurological complications such as convulsion. Results: We found that IL-8, IL-10, IL-12, IL-13 and IFN-γ showed a statistically significant increase in CSF from mumps meningitis when compared to other types of viral meningitis and fever without neurological complications. Conclusion: Mumps meningitis may induce a distinct immunological response when compared with other types of viral meningitis.

The molecular mechanism of severe adverse effects of the endocrine disruptor diethylstilbestrol (DES) on reproductive organs is not currently understood. The effects of DES on testicular proteins were studied in adult male rats orally treated with 0.35 and 3.5 mg DES/kg every two days for two weeks before the manifestation of morphological toxicities. Two up-regulated proteins (glutamine synthetase and chaperonin containing TCP1), two down-regulated proteins (thioredoxin-like 1 and testis-specific autoantigen) and two proteins with altered isoelectric points (protein disulfide isomerase [PDI a3] and enolase 1) were identified in DES groups. Carbonylation of PDI a3 was detected. A significant decrease in PDI activity and significant increases in caspase-12 and calpain activities were also found in the group. It is suggested that testicular toxicity by DES was initiated by the down-regulation of thioredoxin-like-1 leading to the cellular redox inbalances, and the resultant oxidative modification of several important proteins involved in protein foldings.

High-mobility group box 1 (HMGB1) is a monocyte-derived inflammatory mediator that is released in some conditions including shock, tissue injury, and endotoxin-induced lethality. In this study, we determined the plasma and hepatic tissue levels of HMGB1 in a drug-induced rat acute liver failure (ALF) model and investigated the effect of HMGB1 blockade on ALF. Adult male Sprague-Dawley rats, weighing 250 to 300 g, were used for this study. d-galactosamine was injected into the penile vein to induce ALF. To determine HMGB1 levels, plasma and hepatic tissue samples were serially collected after the d-galactosamine injection. To test the effect of HMGB1 blockade, anti-HMGB1 polyclonal antibodies or control antibodies were injected into the penile vein right after injection of d-galactosamine. Levels of HMGB1 were increased in plasma and decreased in hepatic tissue after induction of ALF. Immunohistochemical examination for HMGB1 showed that liver from animals with ALF had little staining, whereas normal liver had strong staining in the nuclei. Injection of anti-HMGB1 antibodies resulted in significant suppression of plasma HMGB1 and hepatic enzymes, marked suppression of plasma inflammatory cytokines, marked improvement of histological findings, and significant improvement of survival. The decrease of hepatic HMGB1 was also significantly suppressed in the group injected with anti-HMGB1 antibodies. The present study suggests that in ALF, the liver may release HMGB1 into the plasma, and that neutralizing the released HMGB1 has a protective effect against injury.

The amyloid of canine amyloid-producing odontogenic tumor (APOT) was evaluated biochemically and immunohistochemically. The N-terminal amino-acid sequence of purified amyloid protein from a canine APOT was strikingly similar to the sequence in both rat ameloblastin and porcine sheathlin. Immunohistochemically, the amyloid in APOT from 9 dogs was strongly reactive with anti-rat ameloblastin, anti-porcine sheathlin, and anti-canine APOT amyloid and weakly reactive with anti-porcine amelogenin but negative for antibodies to cytokeratins, vimentin, desmin, α-smooth muscle actin, amyloid A, glial fibrillary acidic protein, or S100 protein. The neoplastic epithelial cells of APOT were focally reactive with antibodies to ameloblastin, sheathlin, amelogenin, and canine APOT amyloid. The similarity in amino-acid sequence of the amyloid protein of canine APOT to that of enamel proteins, such as ameloblastin, sheathlin, and amelogenin, and the expression of these antigens in both APOT amyloid and in the neoplastic cells suggest that the amyloid of canine APOT is derived from enamel proteins secreted by ameloblasts.

Sivelestat sodium hydrate is a selective inhibitor of neutrophil elastase, which is effective in acute lung injury associated with systemic inflammatory response syndrome. However, the effectiveness of sivelestat in sepsis has not been fully examined. In the present study, the effect of sivelestat on severe sepsis in a rat cecal ligation and puncture (CLP) model was investigated. Adult male Sprague-Dawley rats underwent CLP and were randomly divided into two groups: sivelestat-treated group and saline-treated controls. The serum concentrations of several inflammatory mediators were measured. Hematoxylin-eosin staining, and immunohistochemical staining for high-mobility group box chromosomal protein 1 (HMGB1), IL-8, and CD68 were performed on the lungs to assess pathological changes found 12 h after the CLP procedure. Treatment with sivelestat significantly improved the survival rate of the post-CLP septic animals (P = 0.030). Sivelestat also induced a significant reduction in serum IL-1beta (P = 0.038) and IL-10 (P = 0.008) levels in these CLP rats. Serum HMGB1 levels had no significant difference between the sivelestat-treated and the control group. The lungs from sivelestat-treated rats exhibited less severe pathological changes and decreased the numbers of HMGB1, IL-8, and CD68-positive cells (P < 0.001). Sivelestat significantly improved survival rate of rats with clinically relevant sepsis, possibly by attenuating sepsis-induced systemic inflammatory response and lung injury. This may explain the implicated health benefits of sivelestat in reducing morbidity and mortality from sepsis.

We identify possible differences in the cytokine/chemokine profiles in cerebrospinal fluid (CSF) from children with encephalopathy and febrile seizure. Interleukin (IL)-1β, 2, 4, 5, 6, 7, 8, 10, 12, 13, 17, interferon-γ, tumour necrosis factor-α, granulocyte colony-stimulating factor, granulocyte monocyte colony-stimulating factor, monocyte chemoattractant protein-1 and macrophage inflammatory protein-1β were measured simultaneously in CSF supernatants from children with encephalopathy (n = 8), febrile seizure (n = 16) and fever without neurological complications (n = 8). IL-8 in CSF from children with encephalopathy was significantly elevated compared to that in CSF from children with febrile seizure and fever without neurological complications. IL-8 in CSF was also higher than serum IL-8, suggesting that increased IL-8 was generated from glia cells or astrocytes, not by leakage from serum. Increased IL-8 in CSF in encephalopathy may protect against severe brain damage.

Background Lung resection after induction chemotherapy and/or radiotherapy for down-staging of locally advanced lung cancer can be complicated with lethal interstitial pneumonia. We studied the effects of pneumonectomy on bleomycin-induced lung injury and fibrosis in mice. Methods The mice underwent left pneumonectomy or a sham thoracotomy after intratracheal administration of saline or bleomycin. Lung permeability index, wet-to-dry weight ratio, histological changes, collagen contents, and concentrations of inflammatory mediators and cell counts in broncho-alveolar lavage (BAL) fluid were assessed in the residual right lung 7 d after surgery. Results The index of capillary permeability, lung water content, and inflammatory cell counts in BAL fluid were significantly increased by pneumonectomy. These measurements were highest in the mice with both pneumonectomy and intratracheal administration of bleomycin. Similarly, fibrotic change in lung pathology, as well as an increase in lung collagen content, was most prominent in the mice exposed to both interventions. The BAL fluid concentrations of interleukin-1β, interleukin-6, RANTES, and high mobility group box 1 were significantly increased by pneumonectomy and enhanced by the additional administration of bleomycin. Conclusions The results of this study indicate that pneumonectomy alone causes noncritical lung injury, which amplifies the inflammatory response to bleomycin and promotes lung fibrosis. Several inflammatory mediators appear to be involved in the exacerbation of bleomycin-induced lung injury and fibrosis.