Inhibition of monocyte chemoattractant protein-1 prevents diaphragmatic inflammation and maintains contractile function during endotoxemia.
BACKGROUND
Respiratory muscle weakness is common in sepsis patients. Proinflammatory mediators produced during sepsis have been implicated in diaphragmatic contractile dysfunction, but the role of chemokines has not been explored. This study addressed the role of monocyte chemoattractant protein-1 (MCP-1, also known as CCL2), in the pathogenesis of diaphragmatic inflammation and weakness during endotoxemia.


METHODS
Mice were treated as follows (n = 6 per group): (a) saline, (b) endotoxin (25 μg/g IP), (c) endotoxin + anti-MCP-1 antibody, and (d) endotoxin + isotype control antibody. Muscles were also exposed to recombinant MCP-1 in vivo and in vitro. Measurements were made of diaphragmatic force generation, leukocyte infiltration, and proinflammatory mediator (MCP-1, IL-1α, IL-1β, IL-6, NF-κB) expression/activity.


RESULTS
In vivo, endotoxin-treated mice showed a large decrease in diaphragmatic force, together with upregulation of MCP-1 and other cytokines, but without an increase in intramuscular leukocytes. Antibody neutralization of MCP-1 prevented the endotoxin-induced force loss and reduced expression of MCP-1, IL-1α, IL-1β, and IL-6 in the diaphragm. MCP-1 treatment of nonseptic muscles also led to contractile weakness, and MCP-1 stimulated its own transcription independent of NF-κB activation in vitro.


CONCLUSIONS
These results suggest that MCP-1 plays an important role in the pathogenesis of diaphragmatic weakness during sepsis by both direct and indirect mechanisms. We speculate that its immunomodulatory properties and ability to modify skeletal muscle function make MCP-1 a potential therapeutic target in critically ill patients with sepsis and associated respiratory muscle weakness.
Meakins-Christie Laboratories, McGill University, 3626 Saint Urbain, Montreal, Quebec, Canada. katherine.labbe@mail.mcgill.ca
Katherine
K
Labbe
Gawiyou
G
Danialou
Dusanka
D
Gvozdic
Alexandre
A
Demoule
Maziar
M
Divangahi
John H
JH
Boyd
Basil J
BJ
Petrof
D000818:Animals; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors* / Q000502:physiology; D003964:Diaphragm / Q000473:pathology* / Q000503:physiopathology; D019446:Endotoxemia / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009119:Muscle Contraction / Q000502:physiology; D018908:Muscle Weakness / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control
D018932:Chemokine CCL2; D018836:Inflammation Mediators