NDLI: Inhibition of monocyte chemoattractant protein-1 prevents diaphragmatic inflammation and maintains contractile function during endotoxemia

Content Provider	Springer Nature : BioMed Central
Author	Labbe, Katherine Danialou, Gawiyou Gvozdic, Dusanka Demoule, Alexandre Divangahi, Maziar Boyd, John H Petrof, Basil J
Abstract	Introduction 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.
Related Links	https://ccforum.biomedcentral.com/counter/pdf/10.1186/cc9295.pdf
Ending Page	11
Page Count	11
Starting Page	1
File Format	HTM / HTML
ISSN	13648535
DOI	10.1186/cc9295
Journal	Critical Care
Issue Number	5
Volume Number	14
Language	English
Publisher	BioMed Central
Publisher Date	2010-10-07
Access Restriction	Open
Subject Keyword	Intensive Critical Care Medicine Emergency Medicine Systemic Inflammatory Response Syndrome Extensor Digitorum Longus Skeletal Muscle Cell Extensor Digitorum Longus Muscle Critical Illness Myopathy
Content Type	Text
Resource Type	Article
Subject	Critical Care and Intensive Care Medicine
Journal Impact Factor	8.8/2023
5-Year Journal Impact Factor	10.4/2023

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