Changes In Tumor Necrosis Factor-alpha Research Articles

Efficacy and safety of mesenchymal stem cell therapy for acute respiratory distress syndrome-a systematic review and meta-analysis.

Mesenchymal stem cells (MSC) therapy for acute respiratory distress syndrome (ARDS) represents a burgeoning treatment approach, supported by numerous preclinical studies confirming its efficacy. Our study aims to provide a comprehensive evaluation of both the safety and effectiveness of MSC. We conducted searches across three databases (PubMed, Embase, Cochrane) for randomized controlled studies up to June 23, 2024. A meta-analysis was performed on variables including adverse events, mortality, changes in the PaO2/FiO2 ratio, intensive care unit (ICU), length of stay, ventilation-free days, and changes in pro-inflammatory and anti-inflammatory cytokines. Relative risk (RR) values were employed for dichotomous variables, while mean difference (MD) and standard mean difference (SMD) were used for continuous variables. Risk bias was assessed using risk of bias 2 (ROB2). The meta-analysis encompassed 17 experiments involving 796 patients, with 410 undergoing MSC treatment and 386 in the control group. Primary outcomes indicated that MSC treatment did not escalate adverse events [RR =1.04; 95% confidence interval (CI): 0.90, 1.19; P=0.59; I2=0%]. On the contrary, it significantly diminishes the mortality (RR =0.79; 95% CI: 0.64, 0.97; P=0.02; I2=0%). Regarding secondary outcomes, MSCs led to a significant improvement in the PaO2/FiO2 ratio for ARDS patients (SMD =0.53; 95% CI: 0.15, 0.92; P=0.007; I2=0%). However, there were no significant differences in ICU length of stay (MD =-1.77; 95% CI: -6.97, 3.43; P=0.50; I2=63%) and ventilation-free days (MD =-1.29; 95% CI: -4.09, 1.51; P=0.37; I2=0%). MSCs significantly lowered C-reactive protein (CRP) (SMD =-0.65; 95% CI: -1.18, -0.13; P=0.01; I2=56%) and interleukin-6 (IL-6) levels compared to the control group (SMD =-0.76; 95% CI: -1.34, -0.17; P=0.01; I2=74%). However, changes in interleukin-10 (AIL-10) (SMD =-0.46; 95% CI: -1.51, 0.58; P=0.38; I2=77%), and changes in tumor necrosis factor-alpha (ATNF-α) (SMD =-1.5; 95% CI: -3.39, 0.40; P=0.12; I2=92%) levels showed no significant changes. MSC therapy demonstrates reliable safety, with a significant impact on reducing mortality and improving certain clinical symptoms. Moreover, in certain aspects, it may alleviate the inflammatory response in ARDS. Nonetheless, these findings necessitate validation through additional high-quality randomized controlled trials.

Comparison of the Effect of Amaranth Oil vs. Rapeseed Oil on Selected Atherosclerosis Markers in Overweight and Obese Subjects: A Randomized Double-Blind Cross-Over Trial.

It is well known that rapeseed oil improves lipid profile and has antiatherosclerotic properties. Recently, amaranth oil has also become popular due to its potential health benefits. However, the effect of this oil on atherosclerosis markers in humans is not clear. Therefore, this study aimed to compare the effect of amaranth and rapeseed oils on selected atherosclerosis-related parameters in overweight and obese subjects. In this randomized cross-over study, 44 subjects were instructed to consume 20 mL of amaranth oil and rapeseed oil during two consecutive three-week intervention periods separated by a washout period of the same duration as the intervention. The outcome variables included changes in tumor necrosis factor-alpha, adiponectin, oxidized low-density lipoprotein, apolipoproteins (Apo) A1, B and E as well as glucose and insulin homeostasis markers. Compared to rapeseed oil, amaranth oil had a slight positive effect on adiponectin levels (mean (95% confidence interval): 0.55 (0.22–0.89) vs. -0.29 (−0.75–0.16), p = 0.0002) but negatively affected ApoB concentrations (0.05 (−0.01–0.11) vs. 0.03 (−0.07–0.00), p = 0.0004) and ApoB/A1 ratio (0.01 (−0.03–0.05) vs. −0.02 (−0.04–0.00), p = 0.0113). No differences between the other analyzed parameters were observed. In conclusion, amaranth oil does not have a greater beneficial effect on atherosclerosis markers than rapeseed oil. However, further studies with a longer intervention period are needed. The study was retrospectively registered with the German Clinical Trials Register within the number: DRKS00014046, date of registration: 3 May 2018.

The effect of four-week intermittent fasting from dawn to sunset on circulating brain-derived neurotrophic factor levels in subjects with metabolic syndrome and healthy subjects

BackgroundBrain-derived neurotrophic factor (BDNF) is a key neurotrophin that regulates food intake and energy hemostasis. BDNF also promotes neurogenesis, neuroplasticity, and neuroprotection. There are conflicting reports regarding how intermittent fasting affects circulating BDNF levels. We tested the hypothesis that 4-week intermittent fasting from dawn to sunset (4-week-IF) would decrease circulating BDNF levels in subjects with metabolic syndrome and healthy subjects. MethodsWe conducted pilot studies in subjects with metabolic syndrome and healthy subjects who fasted from dawn to sunset for more than 14 h for four consecutive weeks. We measured serum BDNF levels and metabolic parameters before 4-week-IF, at the end of 4th week during 4-week-IF, and one week after 4-week-IF. ResultsWe enrolled 28 subjects, 14 with metabolic syndrome (women/men:6/8) with a mean age of 59 years and 14 healthy subjects (women/men:1/13) with a mean age of 32 years. Overall, BDNF levels decreased at the end of 4th week during 4-week-IF compared with the levels before 4-week-IF (mean paired difference = −98.5 ng/ml, P = 0.0006). When subjects with metabolic syndrome were compared with healthy subjects, subjects with metabolic syndrome had a lower mean paired reduction in BDNF levels at the end of 4th week during 4-week-IF compared with the levels before 4-week-IF (BDNF mean paired difference = −27.6 ng/ml vs. −169.5 ng/ml, P = 0.003). Multivariate linear regression analysis showed a positive correlation between the change in tumor necrosis factor-alpha and change in BDNF levels at the end of 4th week during 4-week-IF compared with the levels before 4-week-IF in subjects with metabolic syndrome (P = 0.040) and healthy subjects (P = 0.007). The change in weight and body mass index independently predicted the change in BDNF levels 1 week after 4-week-IF compared with the levels before 4-week-IF in subjects with metabolic syndrome. ConclusionFour-week-IF resulted in a reduction in the BDNF levels at the end of 4th week during 4-week-IF. Higher BDNF levels and a lower reduction in BDNF levels at the end of 4th week during 4-week-IF compared with the levels before 4-week-IF in subjects with metabolic syndrome than healthy subjects suggest a potential BDNF resistance similar to insulin and leptin resistance in metabolic syndrome. A positive correlation between the change in BDNF and change in tumor necrosis factor-alpha levels at the end of 4th week during 4-week-IF compared with the levels before 4-week-IF suggests that BDNF is a biomarker of inflammation and endothelial dysfunction in addition to its neurotrophic and anorexigenic features.

Intravenous parecoxib for early postoperative cognitive dysfunction in elderly patients: evidence from a meta-analysis

ABSTRACT Background Inflammation plays a key role in the etiology and pathology of postoperative cognitive dysfunction (POCD). Cyclooxygenase (COX)-2 inhibitor parecoxib is used for the treatment of acute pain due to its potent anti-inflammatory and analgesic effects. Herein, we evaluated the efficacy and safety of parecoxib on early POCD in geriatric patients. Objective This study was performed to evaluate the efficacy and safety of parecoxib for early postoperative cognitive dysfunction (POCD) in elderly patients. Methods Comprehensive literature search based on six electronic databases was applied to retrieve all related randomized controlled trials (RCTs). Two independent reviewers screened each article for eligibility according to the predetermined inclusion criteria. The Cochrane’s Tool was applied to evaluate the methodological quality of included studies. RevMan 5.3 was used to conduct meta-analysis. Results Eight RCTs comprising a total of 1106 subjects prepared for orthopedic surgical operation were selected. All the identified RCTs were conducted in China. The methodological qualities of included studies were judged to be medium to high. The integrated data showed that perioperative intravenous parecoxib could remarkably reduce the incidence of POCD with improved Mini-Mental State Examination (MMSE) score. Parecoxib could significantly reduce the concentrations of interleukin-6, but results regarding the changes in tumor necrosis factor-alpha, C-reactive protein, and S100β levels remained inconsistent. Conclusion Perioperative parecoxib administration is effective in reducing the incidence of POCD and improving the MMSE score compared with control. However, the beneficial effect of parecoxib has been tested only in the Chinese population. Future RCTs in western countries with larger-scale and more comprehensive neurological tests are needed.

Dioscin attenuates Bleomycin-Induced acute lung injury via inhibiting the inflammatory response in mice

Aim: Acute lung injury (ALI), a critical illness syndrome with high morbidity and mortality, is characterized by a severe inflammatory response. Dioscin exerts protective effects against crystalline silica-induced pulmonary inflammation and fibrosis in mice. Bleomycin (BLM) is widely used to induce ALI and fibrosis in animal models. This study aims to investigate the effects of dioscin on BLM-induced ALI in mice. Methods: C57BL/6 mice were intratracheally injected with BLM to induce ALI. Lungs and bronchoalveolar lavage fluids were then harvested on day 7 for evaluation. Changes in tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), and interleukin-10 (IL-10) expression level were measured by RT-qPCR and ELISA. Protein expressions of nuclear factor-kappa B (NF-κB), cyclooxygenase-2 (COX-2), and high-mobility group box 1 (HMGB1) were measured by western blot. Results: Dioscin protects against BLM-induced ALI by decreasing the numbers of total and inflammatory cells, lung edema, myeloperoxidase activity, and malondialdehyde content. Moreover, dioscin significantly inhibited TNF-α, IL-1β, NF-κB, COX-2, and HMGB1 levels, and upregulated IL-10 levels. Conclusion: Our data indicate that dioscin attenuates oxidative stress, the lung inflammatory response, and acute lung injury in BLM-challenged mice.

Effects of External Focused Ultrasound on Inflammatory Markers in Neuropathic Pain Caused by Common Peroneal Nerve Injury

Abstract INTRODUCTION Various rodent models have long been employed to study treatments for chronic pain. However, these studies have resulted in unsuccessful phase-I and II human trials that have failed to result in viable options for patients. Though limitations of animal models are no doubt one issue, lack of objective markers corresponding with pain relief play a role. Our lab has shown significant pain relief in a common peroneal nerve injury (CPNI) rat model following administration of external pulsed low-intensity focused ultrasound (liFUS), thus, establishing external liFUS as a promising technique for treatment of neuropathic pain. Current knowledge of liFUS effects are limited to observable behavioral changes, and little is known of the mechanism of action. To successfully translate this device into the clinic, we examine molecular changes in the inflammatory cascade. METHODS Male rats underwent CPNI to induce neuropathic pain. External liFUS treatment was performed on the L5 dorsal root ganglion (DRG) in the neuropathic model, which was determined from responses to Von Frey fibers (VFF). 24 h post liFUS treatment, L5 DRGs were obtained from 4 distinct cohorts: rats that underwent CPNI with liFUS, CPNI with sham liFUS, sham CPNI with liFUS, and sham CPNI sham liFUS (n = 4 for each group). Using a membrane-based sandwich immunoassay (Proteome Profiler Rat Cytokine Array Kit from R&D System), we assessed relative abundances of 6 anti-inflammatory cytokines and 16 pro-inflammatory cytokines. RESULTS CPNI resulted in an 82.5% decrease of tumor necrosis factor alpha (TNFa) and a 61.8% increase of macrophage inflammatory protein 1-alpha (MIP-1a). liFUS led to a 60% decrease in MIP-1a and a 40% increase in TNFa. Other changes in cytokines were not affected by CPNI or liFUS. CONCLUSION liFUS resulted in similar changes in TNFa and MIP-1a, as compared to spinal cord stimulation and other medical treatments for pain syndromes. Further work will examine inflammatory responses over time and in female rats.

Acute effect of a resistance exercise session on markers of cartilage breakdown and inflammation in women with rheumatoid arthritis.

To assess the acute effect of resistance exercise (RE) on circulating biomarkers of cartilage breakdown and inflammation in women with rheumatoid arthritis (RA). Thirty-four volunteers (17 with and 17 without RA), participated in a 25 min RE session (knee extension, knee flexion, hip abduction and hip adduction) with one set of 12 repetitions at 50% of one repetition maximum (1RM) and one set of eight repetitions at 75% of 1RM. Blood samples were collected 30 and 5 min before, immediately after and 1, 2 and 24 h after the session. We used analysis of variance for repeated-measures with Bonferroni adjustments to assess differences between groups over time. In both groups we found significant changes in interleukin (IL)-1 beta (P = 0.045), IL-1 receptor antagonist (IL-1ra) (P < 0.001), IL-10 (P = 0.004), IL-6 (P < 0.001) and cartilage oligomeric matrix protein (COMP) P < 0.001) in response to exercise, but no changes in tumor necrosis factor-alpha and C-reactive protein levels. We found no differences in the responses of the two groups to the session, except for COMP levels, which are more sensitive to exercise and rest effects in RA patients. Women with and without RA have similar changes in response to a RE session in levels of inflammation biomarkers, but not of cartilage breakdown. IL-10 and IL-1ra increased after the RE session, indicating that RE may have an acute anti-inflammatory effect. Additional studies are necessary to clarify if repeated RE sessions can have long-term anti-inflammatory effects and the possible clinical repercussions of this cartilage breakdown characteristic in response to exercise in RA patients.

The predictive value of somatic and cognitive depressive symptoms for cytokine changes in patients with major depression.

ContextElevated concentrations of proinflammatory cytokines have been hypothesized as an important factor in the pathophysiology of depression. Depression itself is considered to be a heterogeneous disorder. Current findings suggest that “cognitive” and “somatic” symptom dimensions are related to immune function in different ways. So far, little research has been done on the longitudinal aspects of inflammation in patients with major depression, especially with respect to different symptom dimensions of depression. Therefore, we investigated which aspects of depression may predict changes in tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6 over 4 weeks.MethodsForty-one patients with major depression diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), and 45 healthy controls were enrolled. Serum measurements of TNF-alpha and IL-6 were conducted at baseline and 4 weeks later. Psychometric measures included the assessment of cognitive-affective depressive symptoms and somatic symptoms during the last 7 days as well as somatic symptoms during the last 2 years.ResultsPatients with depression showed increased levels of TNF-alpha (P<0.05) compared to healthy controls. Hierarchical regression analyses indicated that neither depressive nor somatic symptoms predict changes in proinflammatory cytokines in the whole sample of depressed patients. Moderation analyses and subsequent sex-stratified regression analyses indicated that higher somatoform symptoms during the last 2 years significantly predict an increase in TNF-alpha in women with major depression (P<0.05) but not in men. Exploratory analyses indicated that the stability of TNF-alpha and IL-6 (as indicated by intraclass correlation coefficients) over 4 weeks was high for TNF-alpha but lower for IL-6.ConclusionThe present study demonstrated that a history of somatoform symptoms may be important for predicting future changes in TNF-alpha in women with major depression.

Suppression of dextran sulfate sodium-induced colitis in mice by radon inhalation.

The enhanced release of reactive oxygen species from activated neutrophils plays important role in the pathogenesis of inflammatory bowel disease. We previously reported that radon inhalation activates antioxidative functions in various organs of mice. In this study, we examined the protective effects of radon inhalation on dextran sulfate sodium- (DSS) induced colitis in mice which were subjected to DSS for 7 days. Mice were continuously treated with air only (sham) or radon at a concentration of 2000 Bq/m3 from a day before DSS administration to the end of colitis induction. In the results, radon inhalation suppressed the elevation of the disease activity index score and histological damage score induced by DSS. Based on the changes in tumor necrosis factor-alpha in plasma and myeloperoxidase activity in the colon, it was shown that radon inhalation suppressed DSS-induced colonic inflammation. Moreover, radon inhalation suppressed lipid peroxidation of the colon induced by DSS. The antioxidant level (superoxide dismutase and total glutathione) in the colon after DSS administration was significantly higher in mice treated with radon than with the sham. These results suggested that radon inhalation suppressed DSS-induced colitis through the enhancement of antioxidative functions in the colon.

Effects of Tongmai Huoxue Yin ( ) on Tumor Necrosis Factor-alpha in the Acute Cerebral Ischemia Model Rat

To observe the interfering action of Tongmai Huoxue Yin (see text) on the acute cerebral ischemia model rat. Total 60 SD rats, 30 females and 30 males, were randomly divided into 4 groups, sham-operation group, model group, Nimodipine group and Tongmai Huoxue Yin group, 15 rats in each group. The acute cerebral ischemia rat model was duplicated, the middle cerebral artery (MCA) were ligated and the thread was inserted for the rats in the model group, Nimodipine group and Tongmai Huoxue Yin group, for the rats in the sham-operation group, the arteries were separated without ligature and the thread was not inserted. After the modeling has succeed, the water-decocted concentrated solution of 20-fold Tongmai Huoxue Yin clinical dosage was intragastrically administrated in a dose of 3 mL/100 g d divided into twice, 1.5 mL/100 g once. Distilled water 3 mL/100 g x d was intragastrically administrated, 1.5 mL/100 g once, for the rat in the model group, Nimodipne suspension 3 mL/100 g x d (0.6 mg / 100 g) for the Nimodipine group and 3 mL/100 g x d (5.4 g/100 g) for the Tongmai Huoxue Yin group, no drugs for the sham-operation group. And changes of tumor necrosis factor-alpha (TNF-alpha) contents in the serum and brain tissue were investigated. Compared with the model group, compared with the sham-operation group, serum TNF-alpha content at 5 h of focal cerebral ischemic ischemia in the model group started to increase and reached to the high peak at 12 h, but in both the Tongmai Huoxue Yin group and the Nimodipine group decreased in varying degrees at the same time; compared with the sham-operation group, brain TNF-alpha content at 6 h of focal cerebral ischemic ischemia in the model group started to increase and reached to the high peak at 12 h, but in both the Tongmai Huoxue Yin group and the Nimodipine group decreased in varying degrees, with the most obviously decreased at 24 h of ischemia.Tongmai Huoxue Yin could significantly decrease TNF-alpha content in the brain tissue. Tongmai Huoxue Yin has a protective action on acute cerebral ischemia injury in the rat.

Effect of weight loss on adipokine levels in obese patients

Background:Adipose tissue functions as an endocrine organ by releasing adipokines which have important roles in the regulation of inflammation and insulin sensitivity. Although there is evidence of improvement in circulating levels of adipokines with weight loss, few studies relate such changes to specific diets. We investigated the effects of weight loss achieved by two different diets on circulating adipokine levels in obese individuals.Methods:A total of 120 obese patients (body mass index ≥ 35 kg/m2) underwent a three-month screening period on a low-fat, reduced-calorie diet. Patients failing to achieve a 5% weight loss using this approach were randomly allocated to either a low carbohydrate/high protein diet (n = 17) or to a commercial very low calorie diet (LighterLife®, n = 14) for a period of nine months.Results:At nine months, a significant weight loss was only maintained for Lighter-Life® (−32.3 ± 22.7 kg, P < 0.0001) but not on the low carbohydrate/high protein diet. Changes in adiponectin (15.8 ± 17.1 ng/mL versus −0.8 ± 6.2 ng/mL, P = 0.003) and leptin (−17.6 ± 24.3 ng/mL versus −3.0 ± 9.2 ng/mL, P = 0.049) at nine months were significantly greater for LighterLife® than for the low carbohydrate/high protein diet, which may reflect greater weight loss and decrease in fat mass. Changes in tumor necrosis factor-alpha, interleukin-6, and plasminogen activator inhibitor type 1 did not differ significantly between the dietary interventions at nine months.Conclusion:A significant weight loss of 23.8% from baseline weight was observed using a very low calorie diet and resulted in significant improvements in circulating levels of leptin, plasminogen activator inhibitor type 1, and adiponectin, which are likely to be due to weight loss and not macronutrient intake.

Clinical significance of measuring levels of tumor necrosis factor-alpha and soluble interleukin-2 receptor in nasopharyngeal carcinoma

Conclusion: Changes in tumor necrosis factor-alpha (TNF-α) and soluble interleukin-2 (sIL-2R) levels appear to be closely related to tumor progression and prognosis in nasopharyngeal carcinoma (NPC). Further investigation is suggested. Objectives: The study examined whether changes in TNF-α and sIL-2R in NPC can be used to predict tumor progression and prognosis. Patients and methods: The study was carried out in 58 patients with NPC newly diagnosed from December 2003 to December 2006 at a single institution and 60 control subjects of comparable age. Blood levels of TNF-α and sIL-2R were monitored before, during, and 3 months and 1 year after treatment. Results: Differences in TNF-α level between patients with NPC in all four stages and healthy controls and in sIL-2R level between patients with advanced stage NPC and healthy controls were significant (p <0.05). Furthermore, 1 year after completing radiotherapy, levels of TNF-α and sIL-2R in patients with recurrent tumors were significantly different from those in patients without recurrence and healthy control subjects.

Spatiotemporal quantification of tumor necrosis factor-alpha and interleukin-10 after crush injury in rat sciatic nerve utilizing immunohistochemistry

The purpose of this study was to investigate quantitatively the longitudinal temporal, spatial changes of the tumor necrosis factor-alpha (TNF) and interleukin-10 (IL-10) immunopositive cells during Wallerian degeneration and the following regeneration after crush injury in rat sciatic nerve using immunohistochemistry and enzyme linked immunosorbent assay (ELISA). The number of TNF-immunopositive cells reached its peak and increased significantly in all the segments distal to the crush site 3 days after injury. On Day 7, TNF-immunopositive cells decreased in all the segments distal to the crush site, and a significant decrease was observed 14 days after injury. From Day 21 to Day 56, there were no significant differences in the numbers of TNF-immunopositive cells. The average size of TNF immunopossitive cells became significantly larger with degeneration. The number of IL-10-immunopositive cells decreases significantly 1 day after crush injury. IL-10-immunopositive cells increased on Day 3, returning to control levels. Seven days after injury, a significant increase in the number of IL-10-immunopositive cells was observed. There was also no significant difference in the number of IL-10-immunopositive cells beyond Day 14 except for a part of distal segments. The number of IL-10-immunopositive cells showed no significant differences in all the segments on Day 56. The protein levels of IL-10 measured by ELISA were similar to the result of immunohistochemistry. These results suggest that the significant change in IL-10 occurred prior to the significant change in TNF and that IL-10 may be the key to the change in TNF.

A mechanism of hyperthermia‐induced apoptosis in ras‐transformed lung cells

Lung cancer, the leading cause of cancer-related deaths in both men and women, is the consequence of disordered apoptosis, induction of which may have therapeutic utility. Hyperthermia has been identified as a stimulus for apoptosis. We investigated the mechanism of hyperthermia-induced cell death in ras-transformed lung cells. Effect of hyperthermia (43 degrees C for 180 min) was compared between two cell lines, an immortalized (sv-40) normal human bronchial epithelial (BEAS2-B) and its malignant transformed (H-ras transfected) counterpart (BZR-T33). Survival after hyperthermia: 7-d growth culture BEAS2-B, 1.03 +/- 0.007 and BZR-T33, 0.39 +/- 0.008 (P < 0.05); clonogenic assays BEAS2-B, 0.76 +/- 0.003 and BZR-T33, 0.41 +/- 0.004 (P < 0.05). Hoechst positive (apoptotic) cells: BEAS2-B, 11 +/- 3% and BZR-T33, 78 +/- 5% (P < 0.05). TUNEL, DNA fragmentation, and Annexin-V all corroborate this result. Western blot comparing the effect of hyperthermia in BZR-T33 cells to BEAS2-B cells revealed: TRAIL and FAS-L displayed significant increases (threefold and twofold, respectively); caspase-3 showed a decrease in uncleaved form and an increase in cleaved form, and a 50-fold increase in activity effectively blocked with the caspase-3 inhibitor DEVD-fmk; caspase-9 showed near depletion of uncleaved; poly (ADP-ribose) polymerase (PARP) degradation was clearly visible during heating. After hyperthermia, gene expression demonstrates a 5.7-fold increase in TRAIL and insignificant changes in tumor necrosis factor-alpha (TNF-alpha), FAS-L, and caspases 3, 8, 9 in transformed cells. Data demonstrated that hyperthermia induces apoptosis in transformed cells, and that apoptosis is mediated by caspase-3 as a result of activation of cell-death membrane receptors of the tumor-necrosis-factor family. In summary, these data suggest that hyperthermia could become an additional modality in the multidisciplinary approach to the treatment of lung cancer.

Requisite Role for Complement C5 and the C5a Receptor in Granulomatous Response to Mycobacterial Glycolipid Trehalose 6,6′‐Dimycolate

The development of pulmonary granulomatous lesions during mycobacterial infection is a complex phenomenon, in part caused by responses elicited towards the surface glycolipid trehalose 6,6'-dimycolate (TDM; cord factor). The molecular mechanisms underlying granuloma formation following challenge with TDM are not yet completely understood. The present study defines pathologic differences in acute response to Mycobacterium tuberculosis TDM in C57BL/6 mice and mice lacking the C5a receptor (C5aR-/-). Mice were intravenously injected with TDM prepared in water-in-oil-in-water emulsion and examined for histologic response and changes in proinflammatory cytokines and chemokines in lung tissue. Control C5a receptor-sufficient mice demonstrated a granulomatous response that peaked between days 4 and 7. Increased production of macrophage inflammatory protein-1 alpha (MIP-1alpha), interleukin-1beta (IL-1beta) and CXC chemokine KC (CXCL1) correlated with development of granulomas, along with modest change in tumor necrosis factor-alpha (TNF-alpha). In contrast, the C5aR-/- mice revealed markedly exacerbated inflammatory response. The receptor-deficient mice also demonstrated a lack of coherent granulomatous response, with severe oedema present and instances of lymphocytic cuffing around pulmonary vessels. Lung weight index was increased in the C5aR-/- mice, correlating with increased MIP-1alpha, KC, IL-1beta and TNF-alpha over that identified in the congenic C5aR-sufficient controls. Correlate experiments performed in C5-deficient (B10.D2-H2d H2-T18c Hco/oSnJ) mice revealed similar results, leading to the conclusion that C5 plays a significant role in mediation of chemotactic and activation events that are the basis for maturation of granulomatous responses to TDM.

Changes of tumor necrosis factor-alpha and the effects of ulinastatin injection during cardiopulmonary cerebral resuscitation.

The changes of tumor necrosis factor-alpha (TNF-alpha) and brain ultrastructure during cardiopulmonary resuscitation and the effects of ulinastation injection were observed, and the mechanism was investigated. Twenty-four adult healthy Sprague-Dawley rats were randomly divided into control group (8 rats), resuscitation group (8 rats) and ulinastatin (UTI) group (8 rats). Rats in control group underwent tracheotomy without clipping the trachea to induce circulatory and respiratory standstill. Rats in resuscitation and ulinastatin group were subjected to the procedure of establishing the model of cardiopulmonary cerebral resuscitation (CPCR). Rats in ulinastatin group were given with UTI 104 U/kg once after CPCR. In the control group, the plasma was collected immediate, 30 min, 2 h, 4 h, and 6 h after tracheotomy. In resuscitation group and UTI group, plasma was collected immediate after tracheotomy, 30 min, 2 h, 4 h and 6 h after successful resuscitation. The plasma levels of TNF-alpha were determined by radioimmunoassay (RIA). At the end of the experiment, 2 rats were randomly selected from each group and were decapitated. The cortex of the brain was taken out immediately to observe the ultrastructure changes. In control group, there were no significant differences in the level of TNF-alpha among different time points (P>0.05). In resuscitation group, the level of TNF-alpha was increased obviously after resuscitation (P<0.01) and reached its peak 2 h later after resuscitation. An increasing trend of TNF-alpha showed in UTI group. There were no differences in TNF-alpha among each sample taken after successful resuscitation and that after tracheotomy. The utrastructure of brains showed the injury in UTI group was ameliorated as compared with that in resuscitation group. In early period of CPCR, TNF-alpha was expressed rapidly and kept increasing. It indicated that TNF-alpha might take part in the tissue injury after CPCR. The administration of UTI during CACR could depress TNF-alpha and ameliorate brain injury. By regulating the expression of damaging mediator, UTI might provide a protective effect on the tissue injury after CPCR.

TNF-alpha and TNF-alpha receptor type 1 upregulation in glia and neurons after peripheral nerve injury: studies in murine DRG and spinal cord.

The purpose of the current study was to evaluate changes in tumor necrosis factor-alpha (TNF-alpha ) and TNF-alpha receptor 1 (p55 receptor) using double fluorescent immunohistochemistry in glial and neural cells in the dorsal root ganglion and spinal cord after sciatic nerve injury in mice. SUMMARY OF BACKGROUND DATA.: TNF-alpha is a primary mediator of the inflammatory response and is primarily synthesized and released in the nervous system by macrophages and Schwann cells following peripheral nerve injury. TNF-alpha is also released from astrocytes and microglia in the central nervous system, where it plays a crucial role in the pathophysiology of injury. Sixteen female mice were used. Under anesthesia, the left sciatic nerve was crushed. At 3, 5, and 14 days after surgery, the spinal cord at the level of L5 and the left L5 DRG were removed and processed for immunohistochemistry. Tissue sections were double stained with antibodies to either glial fibrillary acidic protein (GFAP; marker for astrocytes or satellite cells) or NeuN (marker for neurons), and TNF or p55 receptor. RESULTS.: In the dorsal root ganglion, GFAP-immunoreactive (IR) satellite cells became evident after injury and were also immunoreactive for both TNF-alpha and p55 receptor. Dorsal root ganglion neurons expressed p55 receptor after injury. TNF-alpha and GFAP-IR satellite cells surrounded p55-IR neurons. Furthermore, the number of GFAP-IR astrocytes dramatically increased in the spinal cord after nerve injury, and some astrocytes were also TNF-alpha -IR and p55 receptor-IR. TNF-alpha -1R astrocytes were seen around p55 receptor-IR neurons. These data demonstrate that upregulation of glial TNF-alpha is associated with the expression of the p55 receptor on adjacent neurons. This association may have induced the expression of several cytokines and immediate early genes in dorsal root ganglion and spinal cord neurons via the TNF signaling pathway. These findings may be related to the pathogenesis of neuropathic pain.

Effects of glycine on plasma and liver tissue changes of TNF-alpha, ET-1 and nitric oxide contents in rats with obstructive jaundice.

To evaluate the effect of glycine on plasma and liver tissue changes of tumor necrosis factor-alpha (TNF-alpha), endothelin-1 (ET-1) and nitric oxide (NO) contents in rats with obstructive jaundice. Ninety healthy Wistar rats of both sexes weighing 275+/-25 g were randomly divided into sham-operated, bile duct-ligated, and bile duct-ligated plus glycine-treated groups, the latter was performed with 5% glycine solution substituting for tap water drunk ad libium for 5 days before and 6 days after operation. Blood and liver tissue were sampled at the time of sacrifice on the 8th day post operation. Plasma total bilirubin, endotoxin, levels, as well as TNF-alpha, ET-1 and NO contents in liver tissue were determined. Plasma endotoxin and total bilirubin levels were significantly higher in both bile duct-ligated and bile duct-ligated plus glycine-treated rats than in sham-operated animals (P=0.000613, 0.00921 and 0.00737, 0.00841 respectively), whereas they did not display any statistically significant difference between the former groups (P=0.417 and 0.374 respectively). Likewise, TNF-alpha, ET-1 and NO contents in both plasma and liver tissue were significantly increased in both bile duct-ligated and bile duct-ligated plus glycine-treated rats compared with sham-operated animals(P=0.00813, 0.00793, 0.00671, 0.00804, 0.00872, and 0.00947 in plasma and 0.00531, 0.00785, 0.00912, 0.00981 and 0.00635 in liver tissue respectively). However, these inflammatory mediators in both plasma and liver tissue were significantly reduced in bile duct-ligated rats fed on 5% glycine solution compared with that without (P=0.00953, 0.00891, 0.0795, 0.00867, 0.0697 and 0.00907 in plasma and liver tissue respectively). Reduction of TNF-alpha, ET-1 and NO contents in plasma and liver tissue of rats fed on glycine may be helpful to alleviate pathological lesions in obstructive jaundice.

The mRNA expression patterns of tumor necrosis factor-alpha and TNFR-I in some vital organs after thermal injury.

To investigate changes of tumor necrosis factor-alpha (TNF-alpha) and TNFR-I expression in vital organs and their significance in the pathogenesis of multiple organ damage associated with endogenous endotoxin following major burns. Wistar rats subjected to a 35 % full-thickness scald injury were sacrificed at 12 h, 24 h, 48 h, and 72 h postburn, respectively. Meanwhile, eight rats were taken as normal controls. Tissue samples from liver, spleen, kidney, lung and intestine were collected to assay tissue endotoxin levels and measure TNF-alpha and TNFR-I expression. In addition, blood samples were obtained for the determination of organ function parameters. Endotoxin levels in liver, spleen and lung increased markedly after thermal injury, with the highest level in liver. The gene expression of TNF-alpha in liver, lung and kidney was up-regulated after thermal injury, while the TNFR-I mRNA expression in liver, lung, kidney and intestine was shown decreased throughout the observation period. Thus, the mRNA expression ratio of TNF-alpha to TNFR-I was significantly increased postburn, particularly in pulmonary tissue (67-fold). In addition, the significant correlations between the expression of TNFR-I or the expression ratio of TNF-alpha/TNFR mRNA in liver tissue and serum aspartate aminotransferase levels were noted (P<0.05-0.01). Similar results were also obtained between pulmonary TNF-alpha mRNA expression and myeloperoxidase activities (P<0.01), whereas there was a highly negative correlation between levels of renal TNFR-I mRNA expression and serum creatinine. Burn injury could result in the translocation of gut-derived endotoxin that was mainly distributed in the liver, spleen and lung. The translocated endotoxin then made the expression of TNF-alpha and TNFR-I mRNA up-regulated and down-regulated respectively in various organs, which might be involved in the pathogenesis of multiple organ damage following burns.

Mast cells modulate the inflammatory but not the proliferative response in healing wounds.

Upon stimulation, mast cells release a heterogeneous group of factors that promote inflammation and influence cell proliferation. Mast cells accumulate at sites of injury, further suggesting a critical role in wound healing. To assess the importance of mast cells in tissue repair, we compared wound healing in mast cell-deficient WBB6F1/J-KitW/KitW-v (KitW/KitW-v) and wild type WBB6F1/++ (WT) mice. During the inflammatory phase, neutrophil infiltration into wounds of the KitW/KitW-v mice was significantly less than that of WT mice (84.6 +/- 10.3 vs. 218 +/- 26.0 cells/10 high-power fields at day 3, p < 0.001), while wound macrophage and T cell infiltration were similar in both strains. The decrease in neutrophils could not be explained by changes in tumor necrosis factor-alpha or macrophage inflammatory protein-2 levels, because the amounts of these two neutrophil chemoattractants were similar in both KitW/KitW-v and WT mice. Surprisingly, the absence of mast cells had no effect on the proliferative aspects of wound healing, including reepithelialization, collagen synthesis, and angiogenesis. Although mast cells are known to release proangiogenic mediators, vascular endothelial growth factor levels were similar in WT and KitW/KitW-v mice. Moreover, levels of fibroblast growth factor-2 were increased in KitW/KitW-v mice (4206 +/- 107 vs. 1865 +/- 249 pg/ml, p < 0.01). These results suggest that mast cells modulate the recruitment of neutrophils into sites of injury, yet indicate that mast cells are unlikely to exert a major influence on the proliferative response within healing wounds.