Macrophages are necessary for maximal nuclear factor-kappa B activation in response to endotoxin.
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.
Koay
M Audrey
MA
Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2650, USA.
Gao
Xiang
X
Washington
Mary Kay
MK
Parman
Kelly S
KS
Sadikot
Ruxana T
RT
Blackwell
Timothy S
TS
Christman
John W
JW
D000280:Administration, Inhalation; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002452:Cell Count; D004002:Clodronic Acid / Q000008:administration & dosage; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004731:Endotoxins / Q000008:administration & dosage*; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007322:Instillation, Drug; D007442:Intubation, Intratracheal; D008070:Lipopolysaccharides / Q000008:administration & dosage*; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016676:Macrophages, Alveolar / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D009504:Neutrophils / Q000473:pathology; D011014:Pneumonia / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
D016207:Cytokines; D004731:Endotoxins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D004002:Clodronic Acid; C044101:endotoxin, Escherichia coli