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Effect of CD14 blockade on endotoxin-induced acute lung injury in mice
Sadatomo Tasaka1, Akitoshi Ishizaka, Wakako Yamada
1Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
Abstract:
CD14 functions as a cell surface receptor for endotoxin (lipopolysaccharide [LPS]) and is thought to have an essential role in innate immune responses to infection. Previous studies have revealed attenuation of the systemic response after sepsis by blocking CD14. In this study, we tested the hypothesis that CD14 blockade protects against inflammatory responses associated with LPS pneumonia. We examined the effect of an anti-murine CD14 monoclonal antibody (4C1) on the development of acute lung injury induced by intratracheal LPS in mice. We also measured the production of cytokines (tumor necrosis factor-alpha, interleukin-6, and macrophage inflammatory protein-2) and nitric oxide by murine peritoneal macrophages exposed to LPS in vitro. Nuclear factor (NF)-kappa B translocation was evaluated in nuclear extracts from lung homogenates. 4C1 significantly attenuated pulmonary edema and neutrophil emigration after LPS administration. The production of cytokines and nitric oxide by LPS-stimulated macrophages was significantly decreased by 4C1 treatment. NF-kappa B translocation induced by LPS instillation was also suppressed by 4C1. These results suggest that blockade of CD14 might attenuate acute lung injury after intratracheal instillation of LPS through the suppression of NF-kappa B translocation. The inhibitory effect of CD14 blockade on cytokine production and nitric oxide release of macrophages might contribute to the attenuation of lung injury.
Insights
Blocking CD14 receptor reduces inflammation and lung injury caused by lipopolysaccharide (LPS) pneumonia in mice. This targeted approach suppresses key inflammatory pathways, offering potential therapeutic benefits for acute lung injury.
Area of Science:
- Immunology
- Infectious Disease
- Pulmonary Medicine
Background:
- CD14 is a cell surface receptor crucial for innate immunity, recognizing lipopolysaccharide (LPS).
- Previous research indicates CD14 blockade can mitigate systemic responses during sepsis.
- The role of CD14 in LPS-induced pneumonia and associated acute lung injury requires further investigation.
Purpose of the Study:
- To test if CD14 blockade protects against inflammatory responses in LPS-induced pneumonia.
- To evaluate the efficacy of an anti-murine CD14 monoclonal antibody (4C1) in a mouse model of acute lung injury.
Main Methods:
- Intratracheal LPS instillation in mice to induce acute lung injury.
- Administration of anti-murine CD14 monoclonal antibody (4C1).
- Measurement of pulmonary edema, neutrophil emigration, cytokine production (TNF-α, IL-6, MIP-2), nitric oxide, and NF-κB translocation.
Main Results:
- CD14 blockade with 4C1 significantly reduced pulmonary edema and neutrophil infiltration.
- 4C1 treatment markedly decreased the production of pro-inflammatory cytokines and nitric oxide by LPS-stimulated macrophages.
- NF-κB translocation, a key inflammatory signaling pathway, was suppressed by 4C1 in response to LPS.
Conclusions:
- CD14 blockade attenuates acute lung injury induced by LPS pneumonia.
- Suppression of NF-κB translocation is a likely mechanism underlying CD14's protective effect.
- Inhibiting CD14 reduces macrophage inflammatory mediator release, contributing to lung injury mitigation.