Macrophages are necessary for maximal nuclear factor-kappa B activation in response to endotoxin.

Koay MA, Gao X, Washington MK, Parman KS, Sadikot RT, Blackwell TS, Christman JW
Am J Respir Cell Mol Biol. 2002 26 (5): 572-8

PMID: 11970909 · DOI:10.1165/ajrcmb.26.5.4748

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 (i.t.) and/or intravenous (i.v.) routes. Clodronate reduced the number of macrophages in lung lavage 48 h after either i.t. or i.v. administration, but combined i.t. + i.v. clodronate achieved the most profound depletion (90%). Although i.t. clodronate alone had little effect on the evolution of lung inflammation, combined i.t. + i.v. 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)-kappa B and lower concentrations of tumor necrosis factor (TNF)-alpha in lung lavage fluid. Combined i.t. + i.v. clodronate markedly reduced lung NF-kappa B activation and the intensity of neutrophilic alveolitis after intraperitoneal (i.p.) LPS; however, i.v. clodronate alone had no effect on NF-kappa B activation in either liver or lung tissue or the development of neutrophilic alveolitis. We conclude that generalized macrophage depletion reduces NF-kappa B 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-kappa B-dependent innate immune response.

MeSH Terms (20)

Administration, Inhalation Animals Bronchoalveolar Lavage Fluid Cell Count Clodronic Acid Cytokines Disease Models, Animal Endotoxins Injections, Intraperitoneal Injections, Intravenous Instillation, Drug Intubation, Intratracheal Lipopolysaccharides Lung Macrophages, Alveolar Mice Mice, Inbred C57BL Neutrophils NF-kappa B Pneumonia

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