Macrophages Are Necessary for Maximal Nuclear Factor-Kappa B Activation in Response to Endotoxin

Am J Respir Cell Mol Biol. 2002 May;26(5):572-8. doi: 10.1165/ajrcmb.26.5.4748.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Administration, Inhalation
  • Animals
  • Bronchoalveolar Lavage Fluid / cytology
  • Cell Count
  • Clodronic Acid / administration & dosage
  • Cytokines / metabolism
  • Disease Models, Animal
  • Endotoxins / administration & dosage*
  • Injections, Intraperitoneal
  • Injections, Intravenous
  • Instillation, Drug
  • Intubation, Intratracheal
  • Lipopolysaccharides / administration & dosage*
  • Lung / drug effects
  • Lung / metabolism
  • Lung / pathology
  • Macrophages, Alveolar / cytology
  • Macrophages, Alveolar / drug effects
  • Macrophages, Alveolar / immunology
  • Macrophages, Alveolar / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / metabolism*
  • Neutrophils / pathology
  • Pneumonia / chemically induced
  • Pneumonia / immunology
  • Pneumonia / metabolism*
  • Pneumonia / pathology

Substances

  • Cytokines
  • Endotoxins
  • Lipopolysaccharides
  • NF-kappa B
  • Clodronic Acid
  • endotoxin, Escherichia coli