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Pharmacologic reduction in tumor necrosis factor activity of pulmonary alveolar macrophages
S K Leeper-Woodford1, B J Fisher, H J Sugerman
1Department of Medicine, Virginia Commonwealth University/Medical College of Virginia, Richmond.
Abstract:
Tumor necrosis factor-alpha (TNF), an inflammatory cytokine released by macrophages, may be a mediator of lung injury during septicemia. We previously reported that the cyclooxygenase inhibitor ibuprofen and histamine receptor antagonists cimetidine (H2 antagonist) and diphenhydramine (H1 antagonist) attenuate lung injury and reduce circulating TNF surges during porcine sepsis. Since pulmonary alveolar macrophages (PAM) may participate in early sepsis by producing TNF, we hypothesized that the TNF activity of PAM is reduced by ibuprofen, cimetidine, and diphenhydramine. To test this, we examined changes in PAM-derived TNF bioactivity and cell viability of freshly isolated porcine PAM during exposure to bacterial endotoxin (LPS), ibuprofen, cimetidine, and diphenhydramine. The TNF activity (% L929 cytotoxicity of PAM conditioned medium) was elevated in LPS-stimulated PAM cultures (15 to 25% increase at 1 to 6 h and 40 to 43% increase at 6 to 48 h, compared with non-LPS-stimulated cultures), and ibuprofen (150 micrograms/ml) added with LPS decreased the TNF activity for 24 h (20 to 28% reduction at 1 to 24 h). Ibuprofen added 1 h after LPS was less effective in reducing the PAM-derived TNF activity (20 to 22% reduction at 2 to 6 h). Cimetidine (112 micrograms/ml) reduced the TNF activity of LPS-stimulated PAM cultures during the first 4 h of LPS exposure (15 to 24% decrease at 1 to 4 h). Diphenhydramine (150 micrograms/ml) attenuated the PAM-derived TNF activity but also decreased viability of PAM, indicating a toxic effect of this agent on PAM.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Ibuprofen and cimetidine reduce tumor necrosis factor-alpha (TNF) produced by lung macrophages during sepsis. Diphenhydramine also reduced TNF but harmed cell viability, suggesting targeted anti-TNF therapies for sepsis-induced lung injury.
Area of Science:
- Immunology
- Pharmacology
- Critical Care Medicine
Background:
- Sepsis can cause lung injury, with tumor necrosis factor-alpha (TNF) implicated as a key mediator.
- Previous studies showed ibuprofen and histamine antagonists reduced lung injury and TNF during porcine sepsis.
- Pulmonary alveolar macrophages (PAM) are potential early producers of TNF in sepsis.
Purpose of the Study:
- To investigate whether ibuprofen, cimetidine, and diphenhydramine reduce TNF activity produced by PAM.
- To assess the effects of these agents on PAM viability.
Main Methods:
- Porcine PAM were isolated and exposed to lipopolysaccharide (LPS) with or without ibuprofen, cimetidine, or diphenhydramine.
- PAM-derived TNF bioactivity was measured by L929 cytotoxicity assay.
- PAM viability was assessed after drug exposure.
Main Results:
- LPS stimulation significantly increased PAM-derived TNF activity.
- Ibuprofen, when added with LPS, reduced TNF activity for 24 hours; delayed addition was less effective.
- Cimetidine reduced TNF activity during the initial 4 hours of LPS exposure.
- Diphenhydramine reduced TNF activity but also decreased PAM viability.
Conclusions:
- Ibuprofen and cimetidine demonstrate potential in mitigating sepsis-induced PAM-derived TNF.
- Diphenhydramine's toxicity to PAM limits its therapeutic potential.
- Targeting PAM-derived TNF may be a viable strategy for treating sepsis-related lung injury.