Am. J. Respir. Crit. Care Med., Volume 164, Number 3, August 2001, 406-411

Alveolar JE/MCP-1 and Endotoxin Synergize to Provoke Lung Cytokine Upregulation, Sequential Neutrophil and Monocyte Influx, and Vascular Leakage in Mice

ULRICH MAUS, JULIA HUWE, REGINA MAUS, WERNER SEEGER, and JÜRGEN LOHMEYER

Department of Internal Medicine, Justus-Liebig-University, Giessen, Germany

The C-C chemokine monocyte chemotactic protein 1 (JE/MCP-1) is a key cytokine for lung monocyte recruitment, and may be detected in high levels in the alveolar space in lung injury. We hypothesized that alveolar JE/MCP-1 might synergize with endotoxin in this compartment to elicit lung inflammatory events. Intratracheal instillation of JE/MCP-1 into BALB/c mice did not provoke increased bronchoalveolar lavage tumor necrosis factor  (TNF-), interleukin 6 (IL-6), and macrophage inflammatory protein 2 (MIP-2) levels, but elicited monocyte recruitment into this compartment. Intratracheal Escherichia coli endotoxin provoked elevated lavage TNF-, IL-6, and MIP-2 levels, peaking after 6 h in parallel with increased alveolar neutrophil numbers, in the absence of vascular leakage. Mice receiving both endotoxin and JE/ MCP-1 showed drastically increased lavage TNF-, IL-6, and MIP-2 levels, 22-fold higher lavage neutrophil numbers, and lung vascular leakage. Moreover, an 8-fold increased alveolar accumulation of monocytes, peaking at 48 h together with expansion of the resident alveolar macrophage pool, was noted. Intraperitoneal instead of alveolar deposition of MCP-1 or endotoxin failed to reproduce the synergistic response, and the same was true for employment of RANTES instead of MCP-1. Blockade of neutrophil recruitment by anti-CD18 did not affect the intra-alveolar cytokine response to MCP-1 plus endotoxin. Together, JE/MCP-1 and endotoxin, when coappearing in the alveolar compartment at low dosage, elicit an early phase of lung inflammatory injury with increased cytokine synthesis and neutrophil recruitment, and a late phase of enhanced monocyte traffic and expansion of the alveolar macrophage pool.

Keywords: lung; cytokine; alveolar monocyte; inflammation

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