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R Blum

Publications and source records attributed to R Blum.

83 records · Page 5Linked to original sources
PubMedDate not supplied

Effects in humans of intravenously administered endotoxin on soluble cell-adhesion molecule and inflammatory markers: a model of human diseases.

1. Endotoxin, a component of the cell wall of Gram-negative bacteria, could be a predisposing mediator of many pathological disorders. The present study was undertaken to determine the effects and time-course of acute endotoxin challenge on inflammatory and cell-adhesion molecule markers shedding in the plasma as potential surrogates. 2. Six normal male subjects per group (age range 21-35 years) were injected with 4 ng/kg, i.v., reference standard Escherichia coli (0113:h10:k) endotoxin or physiological saline. 3. Plasma inflammatory markers (tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and TNF-receptor I (RI)) and cell-adhesion molecule markers (soluble L-selectin, soluble P-selectin, soluble vascular cell adhesion molecule (VCAM)-1) were determined using sensitive and specific ELISA. 4. Tumour necrosis factor-alpha increased from a basal level of 2.8 pg/mL to approximately 800 pg/mL at 90 min after endotoxin. Similarly, IL-6 peaked 2-3 h after endotoxin injection, with a rapid decline by 6-8 h, and levels returned to basal values by 24 h. 5. In contrast, TNF-RI peaked at 2 h (increasing from basal levels of 900-3300 pg/mL) with a much slower decline and without return to basal levels at 24 h (1400 pg/mL). 6. Endotoxin resulted in a rapid rise in soluble L-selectin within 1 h, which increased from a basal of 150-425 ng/mL. This rapid rise in soluble L-selectin was sustained for up to 2.5 h and then rapidly declined to basal levels by 3.5 h. 7. In contrast, plasma soluble P-selectin levels showed a delayed and progressive increase up to 8 h (increasing from a basal level of 50-95 ng/mL), with a partial decline at 24 h (80 ng/mL). 8. Similarly, soluble VCAM-1 levels showed a progressive rise up to 24 h (increasing from basal values of 600-1000 ng/mL). 9. This acute human model of endotoxin exposure demonstrated an upregulation of inflammatory stimuli leading to a short-term hyperactivation of leucocytes and a more sustained activation of platelets and endothelium. 10. This model provides a non-invasive method for studying the complex effects of endotoxin-like pathogens on different cellular events using soluble plasma surrogate markers.

Adult↗
PubMedDate not supplied

Eosinophils and major basic protein damage but do not detach human amniotic epithelial cells.

Damage and detachment of epithelial cells is thought to contribute to the pathologenesis of asthma. Both eosinophils and neutrophils are found in asthmatic airways and several studies have suggested that eosinophils may be responsible for the epithelial cell detachment of asthma. To compare the capacity of purified human eosinophils and neutrophils to mediate epithelial cell detachment, we utilized a human amniotic epithelial cell-basement membrane model that we have recently described. Activated eosinophils induced little detachment at 4 h (less than 10% detachment), which contrasted with that seen with equivalent numbers of identically handled neutrophils (29 +/- 6% detachment, p less than .05). In contrast, eosinophils did induce damage to epithelial cells to an extent similar to neutrophils when assessed using a 51Cr release assay (17 +/- 6% and 18 +/- 9% release of 51Cr, respectively). When purified preparations of the major eosinophil-derived protein major basic protein (MBP) were studied, similar effects on epithelial cells were observed, i.e., damage (77 +/- 13% release of 51Cr) without detachment (less than 5% cell detachment). These data suggest that neutrophils are more effective in inducing detachment of human epithelial cells, whereas both eosinophils and neutrophils damage human epithelial cells.

Amnion↗
PubMedDate not supplied

Mannan mucin-1 peptide immunization: influence of cyclophosphamide and the route of injection.

The mucin MUC1 is greatly increased in breast cancer and is a potential target for immunotherapy. In mice, MUCI conjugated to oxidized mannan (MUC1-mannan fusion protein [M-FP]) targets the mannose receptor and induces a high frequency of cytotoxic T lymphocytes and anti-tumor responses. On this basis, three phase I trials were performed in patients with adenocarcinoma to evaluate the toxicity and the immunologic responses to mannan MUCI. Forty-one patients with metastatic or locally advanced carcinoma of the breast (trial 1), colon (trial 2), and various adenocarcinomas (trial 3) received increasing doses of M-FP (1 to 300 microg). The immunizations were given at weekly intervals (weeks 1 to 3) and repeated in weeks 7 to 9. Cyclophosphamide (to increase cellular immunity) was given on weeks 1 and 4. M-FP was given intramuscularly in trial 1 and intraperitoneally in trial 2. No toxic effects occurred, and delayed-type hypersensitivity responses were present only as a microscopic lymphocytic infiltration. Overall, approximately 60% of the patients had high-titer MUC1 immunoglobulin G1 antibody responses, with the intraperitoneal route yielding approximately 10-fold higher responses. Cellular responses (proliferation, cytotoxic T cells, or CD8 T cells secreting tumor necrosis factor-alpha alphand interferon-gamma in response to MUC1 stimulation in vitro) were found in 28% of the patients, which was similar to that seen without cyclophosphamide. In most patients, disease progressed, but in five it remained stable. In addition, there were no objective responses. M-FP is not toxic and induces immune responses that were amplified by the intraperitoneal route of immunization. Cyclophosphamide was of no benefit.

Adenocarcinoma↗