期刊
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
卷 26, 期 5, 页码 572-578出版社
AMER THORACIC SOC
DOI: 10.1165/ajrcmb.26.5.4748
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资金
- NHLBI NIH HHS [HL 61419] Funding Source: Medline
To define the role of macrophages in regulating the lung's response to Escherichia coli endotoxin (lipopolysaccharide [LPS]), depletion of macrophages was accomplished by administration of dichloromethylene diphosphonate (clodronate) delivered via intratracheal (IT) and/or intravenous (IV) routes. Clodronate reduced the number of macrophages in lung lavage 48 h after either IT or IV administration, but combined IT+IV clodronate achieved the most profound depletion (90%). Although IT clodronate alone had little effect on the evolution of lung inflammation, combined IT+IV clodronate treatment decreased neutrophilic alveolitis 4 h after exposure to aerosolized LPS by 80% compared with mice treated with empty liposomes. This decrease was associated with impaired activation of nuclear factor (NF)-kappaB and lower concentrations of tumor necrosis factor (TNF)-alpha in lung lavage fluid. Combined IT+IV clodronate markedly reduced lung NF-kappaB activation and the intensity of neutrophilic alveolitis after intraperitoneal (IP) LPS; however, IV clodronate alone had no effect on NF-kappaB activation in either liver or lung tissue or the development of neutrophilic alveolitis. We conclude that generalized macrophage depletion reduces NF-kappaB activation, generation of cytokines, and neutrophilic lung inflammation in response to gram negative bacterial endotoxin. These findings define the role of the macrophage as a critical component for initiation of the NF-kappaB-dependent innate immune response.
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