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 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 alpha (TNF-alpha), 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-alpha, 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-alpha, 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.
Maus
U
U
Department of Internal Medicine, Justus-Liebig-University, Giessen, Germany. Ulrich.A.Maus@med.uni-giessen.de
Huwe
J
J
Maus
R
R
Seeger
W
W
Lohmeyer
J
J
D000818:Animals; D002465:Cell Movement; D018932:Chemokine CCL2 / Q000494:pharmacology*; D016207:Cytokines / Q000494:pharmacology*; D004731:Endotoxins / Q000494:pharmacology*; D005260:Female; D007249:Inflammation; D008168:Lung / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000276:immunology; D018375:Neutrophil Activation; D015854:Up-Regulation
D018932:Chemokine CCL2; D016207:Cytokines; D004731:Endotoxins