Am. J. Respir. Cell Mol. Biol., Volume 26, Number 5, May, 2002 572-578

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

M. Audrey Koay, Xiang Gao, Mary Kay Washington, Kelly S. Parman, Ruxana T. Sadikot, Timothy S. Blackwell, and John W. Christman

Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, and Department of Pathology, Vanderbilt University School of Medicine, Nashville; and Department of Veterans Affairs, Nashville, Tennessee

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)-B and lower concentrations of tumor necrosis factor (TNF)- in lung lavage fluid. Combined IT+IV clodronate markedly reduced lung NF-B activation and the intensity of neutrophilic alveolitis after intraperitoneal (IP) LPS; however, IV clodronate alone had no effect on NF-B activation in either liver or lung tissue or the development of neutrophilic alveolitis. We conclude that generalized macrophage depletion reduces NF-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-B-dependent innate immune response.

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