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In vitro tumor necrosis factor-alpha secretion by monocytes from patients with cystic fibrosis
J S Elborn1, D Norman, F M Delamere
1Respiratory Medicine Unit, University of Nottingham, City Hospital, United Kingdom.
Abstract:
Immunoreactive tumor necrosis factor-alpha (TNF-alpha) concentration is increased in plasma from patients with cystic fibrosis and chronic Pseudomonas aeruginosa pulmonary infection. To determine if circulating monocytes could be the source of plasma TNF-alpha, we determined in vitro basal and endotoxin-stimulated TNF-alpha secretion by monocytes. In 10 adult patients studied at the time of a symptomatic respiratory exacerbation, basal secretion of TNF-alpha was significantly less than that for 10 matched healthy controls (median 265 pg/micrograms DNA, nonparametric 95% confidence interval 193 to 463 pg/micrograms DNA versus 575, 298 to 923 pg/micrograms DNA; P less than 0.006), although both groups responded equally effectively to added Escherichia coli endotoxin at greater than or equal to 25 ng/ml. In six patients and six matched controls, monocyte culture was repeated after completion of 2 wk anti-pseudomonal antibiotic treatment in the patients. The reduced basal TNF-alpha secretion in the patients had reversed and was not significantly different to that of controls. This effect mirrored a significant reduction in plasma immunoreactive TNF-alpha in these patients (mean +/- SD, 258 +/- 59.3 pg/ml pretreatment versus 133 +/- 47.8 pg/ml post-treatment; P less than 0.05). These findings suggest that a reversible downregulation of TNF-alpha secretion occurred at the time of a symptomatic respiratory deterioration in the presence of chronic P. aeruginosa infection. This may represent a physiologic regulatory mechanism to maintain a local inflammatory response to chronic pulmonary infection in cystic fibrosis.
Insights
In cystic fibrosis patients with Pseudomonas aeruginosa infection, monocyte tumor necrosis factor-alpha (TNF-alpha) secretion is reduced during exacerbations but normalizes after antibiotic treatment, suggesting a reversible regulatory mechanism.
Area of Science:
- Immunology
- Pulmonology
- Infectious Diseases
Background:
- Elevated tumor necrosis factor-alpha (TNF-alpha) in cystic fibrosis (CF) patients with chronic Pseudomonas aeruginosa infection.
- Investigating circulating monocytes as a potential source of plasma TNF-alpha.
Purpose of the Study:
- To assess basal and stimulated TNF-alpha secretion by monocytes in CF patients during respiratory exacerbations.
- To determine if monocyte TNF-alpha secretion changes after antibiotic treatment and if it correlates with plasma levels.
Main Methods:
- Monocyte cultures from 10 CF patients and 10 controls to measure basal and endotoxin-stimulated TNF-alpha secretion.
- Repeat cultures after 2 weeks of anti-pseudomonal antibiotic treatment in patients.
- Measured plasma TNF-alpha levels before and after antibiotic therapy.
Main Results:
- Basal TNF-alpha secretion was significantly lower in CF patients during exacerbations compared to controls.
- Both groups showed similar responses to Escherichia coli endotoxin stimulation.
- Following antibiotic treatment, reduced basal TNF-alpha secretion in CF patients reversed.
- Plasma TNF-alpha levels significantly decreased after antibiotic treatment in CF patients.
Conclusions:
- A reversible downregulation of monocyte TNF-alpha secretion occurs during symptomatic respiratory deterioration in CF with P. aeruginosa infection.
- This downregulation may be a physiological mechanism to regulate local inflammation in chronic pulmonary infections.
- Monocytes are a source of TNF-alpha, and their secretory function is altered during CF exacerbations.