Alveolar JE/MCP-1 and endotoxin synergize to provoke lung cytokine upregulation, sequential neutrophil and monocyte influx, and vascular leakage in mice

The C-C chemokine monocyte chemotactic protein 1 (JE/MCP-1) is a key cytoki ne 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 migh t synergize with endotoxin in this compartment to elicit lung inflammatory events. Intratracheal instillation of JE/MCP-1 into BALB/c mice did not pro voke increased bronchoalveolar lavage tumor necrosis factor alpha (TNF-alph a), interleukin 6 (IL-6), and macrophage inflammatory protein 2 (MIP-2) lev els, but elicited monocyte recruitment into this compartment. Intratracheal Escherichia coli endotoxin provoked elevated lavage TNF-alpha, IL-6, and M IP-2 levels, peaking after 6 h in parallel with increased alveolar neutroph il numbers, in the absence of vascular leakage. Mice receiving both endotox in and JE/ MCP-1 showed drastically increased lavage TNF-alpha, IL-6, and M IP-2 levels, 22-fold higher lavage neutrophil numbers, and lung vascular le akage. Moreover, an 8-fold increased alveolar accumulation of monocytes, pe aking at 48 h together with expansion of the resident alveolar macrophage p ool, was noted. Intraperitoneal instead of alveolar deposition of MCPA or e ndotoxin failed to reproduce the synergistic response, and the same was tru e for employment of RANTES instead of MCP-1. Blockade of neutrophil recruit ment by anti-CD18 did not affect the intra-alveolar cytokine response to MC PA plus endotoxin. Together, JE/MCP-1 and endotoxin, when coappearing in th e alveolar compartment at low dosage, elicit an early phase of lung inflamm atory injury with increased cytokine synthesis and neutrophil recruitment, and a late phase of enhanced monocyte traffic and expansion of the alveolar macrophage pool.