Biomedical subjects

W A Buurman

Publications and source records attributed to W A Buurman.

At least 19 recordsLinked to original sources

PubMed2006

Redox-active iron released during machine perfusion predicts viability of ischemically injured deceased donor kidneys.

Redox-active iron, catalyzing the generation of reactive oxygen species, has been implicated in experimental renal ischemia-reperfusion injury. However, in clinical transplantation, it is unknown whether redox-active iron is involved in the pathophysiology of ischemic injury of non-heart-beating (NHB) donor kidneys. We measured redox-active iron concentrations in perfusate samples of 231 deceased donor kidneys that were preserved by machine pulsatile perfusion at our institution between May 1998 and November 2002 using the bleomycin detectable iron assay. During machine pulsatile perfusion, redox-active iron was released into the preservation solution. Ischemically injured NHB donor kidneys had significantly higher perfusate redox-active iron concentrations than heart-beating (HB) donor kidneys that were not subjected to warm ischemia (3.9 +/- 1.1 vs. 2.8 +/- 1.0 micromol/L, p = 0.001). Moreover, redox-active iron concentration was an independent predictor of post-transplant graft viability (odds ratio 1.68, p = 0.01) and added predictive value to currently available donor and graft characteristics. This was particularly evident in uncontrolled NHB donor kidneys for which there is the greatest uncertainty about transplant outcomes. Therefore, perfusate redox-active iron concentration shows promise as a novel viability marker of NHB donor kidneys.

Adenosine↗

PubMed2006

Low number of omental preadipocytes with high leptin and low adiponectin secretion is associated with high fasting plasma glucose levels in obese subjects.

OBJECTIVE: This study investigates whether fasting plasma glucose (FPG) levels in obese subjects are associated with the number of preadipocytes and their adipokine-secretion capabilities. DESIGN: Abdominal subcutaneous and omental adipose tissues were obtained from 10 female and four male obese subjects (age 37 +/- 8 years; BMI 48 +/- 13 kgm(2)) with a wide range of FPG (range: 4.3-10.6 mm). Stromal vascular cells (SVC) were isolated and cultured and the number of attached SVC (aSVC) per gram adipose tissue determined. The aSVCs were differentiated in vitro to become adipocytes, and the secretion of the adipokine leptin and adiponectin in the culture media was determined. Spearman rank correlation coefficients were calculated between FPG and preadipocyte number and adipokine secretion. PATIENTS: Subject-inclusion criteria: BMI >40 kg/m(2) and for severe comorbid conditions BMI >35 kg/m(2). Subject-exclusion criteria: severe cardiopulmonary pathology (ASA class 3), history of bariatric surgery, manifest psychopathology, 18 years < age > 60 years and for upper-abdominal surgery, age >50 years. All females in the study had regular menstrual periods. None of participants received glucose-lowering medication. RESULTS: No association was observed between BMI and fasting glucose levels. More than 90 +/- 20% of the cultured aSVC fraction was able to store fat droplets, indicating the presence of preadipocytes. A strong negative association was observed between omental preadipocyte number and FPG. A strong association was observed between adipokine secretion by the omental preadipocytes and FPG. No association was observed between subcutaneous preadipocyte number and adipokine secretion and FPG. CONCLUSIONS: In morbid obese subjects, low number of omental preadipocytes with high-leptin- and low-adiponectin-secretion profiles is associated with high FPG.

Adipocytes↗

PubMed2006

Kidney transplantation using elderly non-heart-beating donors: a single-center experience.

Although acceptable outcomes have been reported in both non-heart-beating (NHB) and elderly donors individually, the large pool of elderly NHB donors has not yet been fully utilized. In 1994, we expanded our transplant protocol to include NHB donors aged over 65 years and this study compares the clinical outcomes with regular NHB transplantations. Up to June 2005, 24 patients were transplanted at our center with kidneys from NHB donors aged 65 years or more, whereas 176 patients received grafts from conventional NHB donors during the same period. Grafts from older donors were associated with inferior glomerular filtration rates (29 vs. 44 mL/min after 1 year, p=0.01) and graft survival (52% vs. 68% after 5 years, p=0.19) compared to younger NHB donor grafts, although the difference in graft survival was not statistically significant. Exclusion of older NHB donor kidneys with severe vascular pathology resulted in similar graft survival of older and younger NHB donor kidneys. We conclude that the use of elderly NHB donors in order to expand the donor pool was associated with unacceptable clinical outcomes and cannot be justified without further refinement in their selection, for example, by histological assessment of pretransplant biopsies.

Adolescent↗

PubMed2005

Physiological levels of pro- and anti-inflammatory mediators in cerebrospinal fluid and plasma: a normative study.

Numerous recent studies have reported a significant inflammatory reaction in the brain and the systemic circulation following traumatic brain injury (TBI), infection, or neoplasm of the brain with a sequential release of pro- and anti-inflammatory mediators. Although there is growing knowledge and understanding of the mechanisms leading to the often poor outcome of these patients, only a limited database exists on the physiological expression of pro- and anti-inflammatory cytokines and molecules in plasma and particularly in cerebrospinal fluid (CSF). Therefore, we analyzed paired plasma/CSF samples of healthy human volunteers for the physiological concentrations of Interleukin (IL)-6, IL-8, IL-10, soluble TNF-receptors (sTNF-R) p55 and p75, soluble ICAM (sICAM), and soluble E-selectin (sE-selectin). A physiological release of IL-6, IL-8, IL-10, and sTNF-R p55 and p75 was detected in plasma and CSF. In contrast, sICAM and sE-selectin were only detectable in plasma. Pro- and anti-inflammatory mediators exhibited different concentration patterns in plasma and CSF, suggesting a pro-inflammatory predisposition in the central nervous system.

Adult↗

PubMed2004

Macrophage inhibitory factor, plasminogen activator inhibitor-1, other acute phase proteins, and inflammatory mediators normalize as a result of weight loss in morbidly obese subjects treated with gastric restrictive surgery.

Obesity is demonstrated to be associated with an enhanced inflammatory state, which is suggested to be a cause for the development of obesity-related morbidity. It was hypothesized that a decrease in body weight in morbid obese subjects would lead to a reduction of the inflammatory state in these subjects. Weight loss was achieved by gastric restrictive surgery in 27 morbidly obese patients. Preoperative as well as 3-, 6-, 12-, and 24-month postoperative plasma concentrations of inflammatory mediators macrophage inhibitory factor, plasminogen activator inhibitor-1, lipopolysaccharide binding protein, alpha-1 acid glycoprotein, C-reactive protein, soluble TNFalpha receptors 55 and 75, and leptin were measured. Macrophage inhibitory factor levels remained low normal for 6 months, during weight loss, after which they significantly increased to normal levels at 24 months postoperatively. The other inflammatory mediators remained elevated up to minimally 3 months postoperatively; thereafter they decreased significantly. Both TNFalpha receptors remained elevated up to at least 12 months postoperatively to decrease significantly at 2 yr postoperatively. This study demonstrates that during weight loss, after gastric restrictive surgery, inflammatory mediators remain elevated for at least 3 months postoperatively, suggesting initially an ongoing inflammatory state. However, 2 yr after surgery, the inflammatory mediators reach near normal values.These findings may be an explanation for the reduced comorbidity seen in morbidly obese patients after gastric restrictive surgery.

Acute-Phase Proteins↗

PubMed2003

Low concentrations of ethanol induce apoptosis in human intestinal cells.

BACKGROUND: Increased systemic levels of endotoxin have been detected in human alcoholics and are thought to be derived from the gut. Although a 'leaky gut' is considered to be a necessary factor for alcohol-induced endotoxemia followed by chronic liver injury, the effects of low concentrations of ethanol on intestinal epithelial cells have not been fully understood. The aim of this study was to evaluate intestinal epithelial cell death induced by acute, low concentrations of ethanol in an in vitro system. METHODS: The human intestinal Caco-2 cell line was incubated with 0%, 5%, 10% ethanol for up to 3 h. Phosphatidylserine (PS) externalization, caspase-mediated cytokeratin 18 (CK18) cleavage, and DNA fragmentation were evaluated using flow cytometry. The caspase inhibitor zVAD-fmk was used to test the role of caspases in ethanol-induced cell death. RESULTS: Treatment with 5% and 10% ethanol for 3 h led to a gradual increase in PS externalization. Caspase-mediated CK18 was significantly enhanced as early as 1 h after 10% ethanol incubation, while DNA fragmentation was detected from 2 h onwards. Not only caspase activation but also both PS externalization and DNA fragmentation were completely prevented by pretreatment with the caspase inhibitor. CONCLUSIONS: Apoptotic cell death in confluent Caco-2 cells was induced by acute and low concentrations of ethanol. These results suggest that clinically achievable doses of ethanol impair intestinal barrier function by induction of apoptosis in intestinal epithelial cells. This impairment of the barrier function would allow endotoxin to enter the circulation and evoke hepatic inflammation.

Adenocarcinoma↗

PubMed2002

Decreased plasma orexin-A levels in obese individuals.

Orexin-A and -B stimulate appetite and food intake in rats. Orexins and orexin receptors are present in the hypothalamus as well as the enteric nervous system, the pancreas and the gut. The presence of orexins in peripheral blood, however, has not yet been reported. To determine whether orexin-A is present in human plasma and is related to body weight, we measured plasma orexin-A and leptin levels in a population with a body mass index (BMI) range from 19.8 to 59 kg/m(2). Plasma orexin-A levels correlated negatively and plasma leptin levels correlated positively with BMI. In obese and morbidly obese individuals, orexin-A levels were significantly lower and leptin levels were significantly higher when compared to normal. Our results support previous data suggesting that orexin-A acts also in a peripheral manner. The fact that lower levels of plasma orexin-A are present in obese individuals suggests that it is involved in the regulation of human energy metabolism.

Body Mass Index↗

PubMed2002

The effect of pegylated recombinant human leptin (PEG-OB) on weight loss and inflammatory status in obese subjects.

OBJECTIVE: To investigate whether weekly subcutaneous administration of 60 mg of long-acting pegylated human leptin (PEG-OB) for 8 weeks was able to influence weight loss, metabolic profile and inflammatory status of obese subjects on a mildly hypoenergetic diet (deficit: 3.2 MJ/day). DESIGN: A prospective, randomized, double-blind and placebo-controlled single-center trial. SUBJECTS: Twenty-eight healthy, obese subjects (16 women, 12 men; age 22-65 y; body mass index 27.7-38.7 kg/m2). MEASUREMENTS: Bodyweight, metabolic profile (including lipids), C-reactive protein (CRP) and soluble TNF alpha-receptor (sTNF-R) 55 and 75 levels. RESULTS: At the end of the study no significant differences in the delta or percentage weight loss between the placebo (n = 14) and PEG-OB (n = 14) groups was observed. Also the changes in metabolic profile, CRP, sTNF-R55 and R75 concentrations between the two groups after 8 weeks of treatment did not differ. CONCLUSION: Weekly injection of 60 mg PEG-OB did not lead to additional weight loss after 8 weeks of treatment. Furthermore, PEG-OB administration did not affect the changes in metabolic profile and the inflammatory status of obese subjects.

Adolescent↗

PubMed2002

Prestorage leucocyte reduction of red cell components prevents release of bactericidal permeability increasing protein and defensins.

BACKGROUND AND OBJECTIVES: In this study we examined whether prestorage leucocyte reduction prevents the accumulation of bioreactive substances in red cell units. MATERIALS AND METHODS: Measurements were performed in the supernatants of buffy-coat-depleted (standard red cells) and leucocyte-reduced (filtered red cells) red cell units. The effect of storage was evaluated by taking repetitive samples up to 35 days after donation. We determined the concentrations of polymorphonuclear neutrophil (PMN)-derived bactericidal permeability increasing protein (BPI), defensins and annexin A5. In addition, leucocyte counts (using nageotte chamber) were performed on days 0 and 35. RESULTS: During storage, the concentrations of BPI, defensins and annexin A5 in standard red cells gradually increased. However, in the filtered red cells BPI and defensins were found in only a few samples, whereas the annexin A5 concentration in these units did not change during storage. Haemolysis data in both types of red cell components were similar at all time-points, except prestorage. Significant correlations were found between the release of BPI, defensins and annexin A5 into red cell units and the loss of leucocytes during storage. CONCLUSIONS: PMNs lose their membrane integrity during cold storage and release their contents into red cell components. Prestorage leucocyte reduction of red cell components prevents the accumulation of BPI, defensins and annexin A5.

Annexin A5↗

PubMed2002

Effect of IGF-rich colostrum on bowel adaptation in neonatal piglets with short bowel syndrome.

BACKGROUND: Insulin-like growth factor 1 (IGF-1), a polypeptide growth factor with mitogenic effects on intestinal epithelial crypt cells occurs naturally in high concentrations in colostrum. The hypothesis for this study was that colostrum rich in IGF-1 could promote small bowel adaptation in neonatal piglets with short bowel syndrome. METHODS: Twenty-four piglets, aged 7 days, underwent 75% small bowel resection and were fed 525 kJ x kg(-1) x d(-1) (125 kcal) of colostrum-based formula (Rs(+)) or placebo formula (Rs(-)). Immunoglobulin G (IgG) accounted for 35% of the protein and was compensated with casein and whey protein in the control feed. The piglets were weighed daily and killed 28 days after surgery. Bowel samples were taken at surgery and at death. RESULTS: Relative body-weight increase did not differ between the Rs(+) and Rs(-) group (84% +/- 9% vs. 90% +/- 12%, P = 0.83). There was a significant relative increase in crypt depth in the Rs - compared with the Rs + group (201% +/- 15% vs. 147% +/- 17%, P = 0.02) and total protein (mg/cm bowel) (482 +/- 51 vs. 278 +/- 46, P = 0.008). Increase in villus length, DNA/RNA content, and mitotic index did not differ between groups. CONCLUSION: Colostrum supplement rich in IGF-1 has no benefits over protein-enriched feed with respect to growth and bowel adaptation in neonatal piglets with short bowel syndrome.

Adaptation, Physiological↗

PubMed2002

Increased hepatosplanchnic inflammation precedes the development of organ dysfunction after elective high-risk surgery.

This study investigated the relationship of the hepatosplanchnic production and uptake of inflammatory mediators, hepatosplanchnic perfusion, and outcome during major abdominal surgery to evaluate the hypothesis that regional production of inflammatory mediators precedes the development of hepatic dysfunction. This retrospective analysis of data and blood samples collected during a randomized controlled clinical trial included high-risk surgical patients undergoing major abdominal surgery in a 24-bed university-afilliated intensive care unit. Patients were divided into a subgroup that developed hepatic dysfunction (HD+) postoperatively and a subgroup without hepatic dysfunction (HD-). Hepatic vein and arterial plasma levels of IL-6, IL-8, s-E-selectin, s-ICAM-1, and the TNF-receptors 55 and 75 were measured, and the flux was calculated by multiplying the difference in hepatic vein minus arterial levels of the mediators by the hepatosplanchnic flow. Systemic (thermodilution) and total hepatosplanchnic blood flow (using indocyanine green [ICG]-dilution method) and gastric intramucosal pH (pHi) were assessed preoperatively, 4, 24, and 36 h postoperatively. Of a total of 26 patients, 6 patients developed hepatic dysfunction after their abdominal surgery (mean 6 days postoperatively). The number of sepsis-related deaths and postoperative days on the ventilator were significantly higher in this group. A higher production of IL-8, TNF-receptor-75 and 55 in the hepatosplanchnic area in the HD+ subgroups was found, which preceded the development of organ dysfunction (P = 0.04, P = 0.02, and P = 0.02, respectively). Moreover, the uptake of s-ICAM-1 was significantly increased in this subgroup. Furthermore, total hepatosplanchnic blood flow was significantly higher and pHi was significantly lower in the HD+ group, whereas global hemodynamic data were similar in the two subgroups. In conclusion, the development of postoperative organ dysfunction is preceded by an increased regional inflammatory response, indicated by an increased soluble TNF-receptor shedding and IL-8 production from the hepatosplanchnic area together with an increased uptake of s-ICAM-1. Moreover, an increased total hepatosplanchnic blood flow with intramucosal acidosis was associated with this regional inflammatory response.

Aged↗

PubMed2002

Long term anti-tumour necrosis factor alpha monotherapy in rheumatoid arthritis: effect on radiological course and prognostic value of markers of cartilage turnover and endothelial activation.

OBJECTIVES: To investigate the effect of prolonged neutralisation of tumour necrosis factor alpha (TNFalpha) on the radiological course in rheumatoid arthritis (RA). To assess whether the radiological course can be predicted by clinical variables or biological markers of cartilage and synovium turnover and of endothelial activation. PATIENTS AND METHODS: Forty seven patients with active RA enrolled at our centre in monotherapy trials with adalimumab (D2E7), a fully human anti-TNFalpha monoclonal antibody, were studied for two years. Radiographs of hands and feet obtained at baseline and after one and two years were scored in chronological order by a single, blinded observer using the modified Sharp method. Radiological course was classified as stable or progressive using the smallest detectable difference as cut off point. The relation between radiological course and serum markers of cartilage and synovium turnover (metalloproteinases (MMP-1 and MMP-3), cartilage oligomeric matrix protein (COMP), human cartilage glycoprotein-39 (HC gp-39)), endothelial activation (soluble E-selectin and intercellular adhesion molecule (ICAM-1)), and integrated measures of disease activity were assessed using univariate and multivariate analysis. RESULTS: Radiological evaluation was performed in 36 patients with paired sets of radiographs at baseline and two years. After two years a total of 15/36 (42%) presented no radiological progression. More patients with stable radiological course were still receiving anti-TNFalpha treatment after two years (13/15 (87%) v 11/21 (52%); p=0.03) and had lower baseline COMP and sICAM-1 levels (p=0.01 and 0.04, respectively) than those in the group with progressive disease. In a logistic regression model the combination of sustained TNF neutralisation and baseline COMP and sICAM-1 levels was predictive for radiological outcome (p=0.03). C reactive protein and disease activity score area under the curve were significantly correlated with changes in radiological scores after two years (r=0.40 and 0.37, p<0.05). Long term TNFalpha neutralisation decreased the levels of COMP, sICAM, MMPs, and HC gp-39, but not sE-selectin. CONCLUSION: The results suggest that long term monotherapy with anti-TNFalpha has a positive effect on radiological outcome and modulates cartilage and synovium turnover as measured by biological markers. Baseline serum sICAM-1 levels and COMP levels may be helpful to identify patients with progressive or non-progressive radiological outcome.

Adalimumab↗

PubMed2001

Antimetastatic effect of CpG DNA mediated by type I IFN.

The mechanisms involved in the antimetastatic effect of CpG-containing DNA were investigated in a mouse model of experimental metastasis. Tumor cell colony formation in lungs or livers of mice after i.v. inoculation with syngeneic fibrosarcoma or thymoma cells was determined. The i.v. injection of plasmid DNA or synthetic oligodeoxynucleotides (ODNs) containing unmethylated CpG motifs before tumor cell application strongly inhibited metastasis. Because synthetic CpG-ODN was not directly tumor cytotoxic, the target cells for this CpG-ODN effect were determined. The cytotoxic activity on standard natural killer (NK) targets as well as on fibrosarcoma cells of splenic NK cells and NKT cell-containing liver mononuclear cells derived from CpG-ODN-treated mice was strongly enhanced. Participation of NK/NKT cells in the CpG-induced antimetastatic effect was demonstrated by reduction of the antimetastatic effect in mice depleted of NK/NKT cells and beta2-microglobulin-deficient mice. Neutralization of interleukin 12, interleukin 18, or IFN-gamma did not interfere with the CpG-induced antimetastatic effect. However, in sera of CpG-ODN-treated mice, high levels of IFN-alpha were detected, and in IFN-alpha/beta receptor-deficient mice, the CpG-ODN-induced antimetastatic effect was strongly reduced. These data indicate that CpG-ODNs activate NK/NKT cells for antimetastatic activity indirectly via IFN-alpha/beta receptor activation. The exploitation of the stimulatory activity of CpG-ODN for the innate immune system might be a useful strategy for antimetastatic therapy.

Animals↗

PubMed2001

Apoptosis and chemokine induction after renal ischemia-reperfusion.

BACKGROUND: One of the earliest prerequisites for the development of inflammation after ischemia-reperfusion (I/R) is local chemokine expression. We recently demonstrated that apoptosis, characterized by intracellular caspase-activation, contributes to the development of inflammation after I/R. METHODS: The contribution of apoptosis was investigated using the pan-caspase inhibitor Z-Val-Ala-Asp(OMe)-CH2F in a murine model of renal I/R. Renal expression of the chemokines macrophage inflammatory protein-2 (MIP-2) and KC was studied using RT-PCR and immunohistology. Measuring myeloperoxidase activity and serum ureum and creatinine levels assessed neutrophil influx and kidney dysfunction. RESULTS: We demonstrate renal up-regulation of KC and MIP-2 after 1 to 16 hr of reperfusion. Treatment with the caspase inhibitor Z-Val-Ala-Asp(OMe)-CH2F effectively prevented I/R-induced renal apoptosis, KC, and MIP-2 up-regulation after 2 hr of reperfusion as well as neutrophil influx and functional impairment after 24 hr of reperfusion. CONCLUSIONS: These data for the first time show that chemokine induction following I/R is dependent on caspase activation.

Amino Acid Chloromethyl Ketones↗

PubMed2001

Activated caspase-1 is not a central mediator of inflammation in the course of ischemia-reperfusion.

BACKGROUND: Upon transplantation, donor organs subjected to prolonged ischemia suffer from reperfusion injury. Recent observations suggest that caspase activation is involved in inducing the deleterious inflammatory reaction that mediates reperfusion injury. Release of cytokines like interleukin (IL)-1 and IL-18 may occur during apoptosis through activation of caspase-1/IL-1beta-converting enzyme. We hypothesized that caspase-1 activation is a key event in apoptosis/ caspase-dependent inflammation during the development of renal reperfusion injury. METHODS: Caspase-1-/-, caspase-1+/+ as well as Swiss mice were subjected to 45 min of renal ischemia and 24 hr of reperfusion. Animals were administered agents capable of neutralizing the pro-inflammatory activation products of caspase-1 (IL-1 receptor antagonist, anti-IL-1 receptor antibody, and anti-IL-18 antibody). The extent of renal functional deterioration, inflammation, and apoptosis were compared. RESULTS: No improvement in renal function as reflected by serum ureum and creatinine were found in caspase-1-/- mice as compared to wild type controls. Caspase-1-/- mice showed slightly attenuated renal inflammation as indicated by decreased renal neutrophil influx, but failed to show changes in intrarenal tumor necrosis factor-alpha production. Moreover, caspase-1-/- mice clearly exhibited reperfusion-induced apoptosis as reflected by renal terminal deoxynucleotidyltransferase histology and internucleosomal DNA cleavage. Treatment with IL-1 receptor antagonist, anti-IL-1 receptor antibody, or anti-IL-18 antibody minimally reduced renal functional deterioration, inflammation, and apoptosis. CONCLUSIONS: These findings suggest that activated caspase-1 and its inflammatory products are involved in, but not crucial to, the induction of inflammation after renal ischemia-reperfusion. Hence, apart from caspase-1, other (combinations of) activated caspases are likely to be more prominently involved in renal reperfusion injury.

Animals↗

PubMed2001

Increased leptin concentrations correlate with increased concentrations of inflammatory markers in morbidly obese individuals.

OBJECTIVE: To study whether an increase of plasma leptin concentrations, as observed in the case of increased body weight, is associated with an inflammatory state. SUBJECTS: Sixty-three healthy subjects with body mass index (BMI) ranging from 20 to 61 kg/m2. MEASUREMENTS: Plasma concentrations of leptin, the inflammatory parameter soluble TNF-alpha receptors (TNFR55 and TNFR75), the acute phase proteins lipopolysaccharide binding protein (LBP), serum amyloid A (SAA), alpha-acid glycoprotein (AGP), C-reactive protein (CRP), plasminogen activator inhibitor-1 (PAI-1) and the anti-inflammatory soluble Interleukin-1 decoy receptor (sIL-1RII) were measured. RESULTS: As expected, BMI correlated significantly with leptin (r=0.823, P<0.001), but also with all acute phase proteins, both soluble TNF receptors and PAI concentrations. After correction for BMI and sex, no significant correlation between leptin and the acute phase proteins was seen. Interestingly, however, leptin strongly correlated with both TNF receptors (r=0.523, P<0.001 for TNFR55 and r=0.438, P<0.001 for TNFR75). CONCLUSIONS: This study shows the development of a pro-inflammatory state with increasing body weight. The BMI independent relationship between leptin and both soluble TNF-receptors is consistent with a regulatory role for leptin in the inflammatory state in morbidly obese subjects.

Acute-Phase Proteins↗

PubMed2001

Systemic anti-inflammatory mediators in COPD: increase in soluble interleukin 1 receptor II during treatment of exacerbations.

BACKGROUND: The aim of this study was to test the hypothesis that the chronic inflammatory process present in chronic obstructive pulmonary disease (COPD) is due to a defective endogenous anti-inflammatory mechanism. METHODS: Systemic levels of the anti-inflammatory mediators soluble interleukin 1 receptor II (sIL-1RII), soluble tumour necrosis factor receptor p55 (sTNF-R55) and sTNF-R75, and of C reactive protein (CRP) and lipopolysaccharide binding protein (LBP) were analysed in 55 patients with stable COPD (median forced expiratory volume in one second (FEV(1)) 34% predicted (range 15-78)) and compared with levels in 23 control subjects. In addition, changes in these mediators were studied in 13 patients with COPD (median FEV(1) 34% predicted (range 19-51)) during the first 7 days in hospital with an exacerbation of the disease. RESULTS: Patients with stable COPD were characterised by a systemic inflammatory process indicated by an increased leucocyte count (7.2 (4.7-16.4) v 4.8 (3.5-8.3) x 10(9)/l), raised levels of CRP (11.8 (1.1-75.0) v 4.1 (0.6-75.0) microg/ml) and LBP (45.6 (8.1-200.0) v 27.9 (14.1-71.5) microg/ml), and moderate increases in both sTNF-Rs. In contrast, the sIL-1RII level did not differ between patients and controls (4.53 (2.09-7.60) v 4.63 (3.80-5.93) ng/ml). During treatment of disease exacerbations, systemic levels of both CRP (at day 3) and LBP (at day 7) were significantly reduced compared with day 1, whereas sIL-1RII levels increased. CONCLUSIONS: These data suggest an imbalance in systemic levels of pro- and anti-inflammatory mediators in patients with stable COPD. The increase in the anti-inflammatory mediator sIL-1RII during treatment of exacerbations may contribute to the clinical improvement.

Adult↗

PubMed2001

Intratracheal instillation of lipopolysaccharide in mice induces apoptosis in bronchial epithelial cells: no role for tumor necrosis factor-alpha and infiltrating neutrophils.

This study investigated apoptosis in lungs after local exposure to lipopolysaccharide (LPS). Mice were instilled intratracheally with 5 microg LPS, which corresponds to the amount acquired by smoking approximately 25 cigarettes, and killed at different time points after exposure. Our data demonstrate that local LPS exposure resulted in apoptosis in lungs from 2 h and peaked at 24 h, as detected by ligation-mediated polymerase chain reaction. Morphologic examination and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end label staining demonstrated apoptosis in bronchial epithelial cells early after intratracheal (IT) LPS challenge, whereas infiltrating neutrophils displayed positive staining at 24 and 72 h after exposure. Apoptosis in lungs clearly preceded pulmonary neutrophil infiltration, confirming that neutrophils did not contribute to pulmonary apoptosis at early time points. Further, using three experimental approaches--namely, anti-tumor necrosis factor (TNF)-alpha treatment, IT TNF-alpha instillation, and TNF/lymphotoxin-alpha knockout mice--we demonstrate that TNF-alpha, which was elevated in lungs at both messenger RNA and protein levels after IT LPS challenge, was no primary mediator in LPS-induced apoptosis at early time points. Thus, local LPS exposure in mice resulted in early apoptosis of bronchial epithelial cells independent of infiltrating neutrophils and TNF-alpha, which suggests that apoptosis of bronchial epithelium may be involved in airway injury during exposure to LPS.

Animals↗