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MCP-1 causes leukocyte recruitment and subsequently endotoxemic ileus in rat
Andreas Türler1, Nicolas T Schwarz, Esther Türler
1Department of Medicine, Division of Gastroenterology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15261, USA.
Abstract:
Endotoxemia causes an inflammatory response within the intestinal muscularis and gastrointestinal dysmotility. We hypothesize that the resident macrophage-derived chemokine monocyte chemoattractant protein-1 (MCP-1) plays a significant role in the recruitment of leukocytes into the lipopolysaccharide (LPS)-stimulated rat intestinal muscularis. MCP-1 mRNA expression was investigated by RT-PCR. Leukocyte extravasation and MCP-1 protein localization were determined by immunohistochemistry. Contractile activity was assessed by using a standard organ bath in rats that were treated with saline, recombinant MCP-1, LPS, LPS + nonspecific antibody, or LPS + MCP-1 antibody. Endotoxemia caused a significant 280-fold increase in MCP-1 mRNA expression in the muscularis, peaking at 3 h. MCP-1 protein was immunohistochemically located to muscularis macrophages. LPS application caused significant leukocyte recruitment into the muscularis and a 51% decrease in muscle contractility. MCP-1 antibody treatment significantly averted leukocyte recruitment and significantly prevented muscle dysfunction. These parameters were not significantly altered by the nonspecific antibody. Results show that resident muscularis macrophage-derived MCP-1 plays a major role in the recruitment of monocytes during endotoxemia, which then subsequently secrete kinetically active substances that cause ileus.
Insights
Monocyte chemoattractant protein-1 (MCP-1) from intestinal macrophages drives leukocyte recruitment during endotoxemia, leading to gastrointestinal dysmotility. Blocking MCP-1 prevents this inflammatory response and restores normal muscle function.
Area of Science:
- Gastroenterology
- Immunology
- Physiology
Background:
- Endotoxemia induces intestinal inflammation and impaired gastrointestinal motility.
- The role of resident macrophage-derived chemokines in this process is not fully understood.
Purpose of the Study:
- To investigate the role of monocyte chemoattractant protein-1 (MCP-1) in leukocyte recruitment and gastrointestinal dysmotility during endotoxemia in rats.
Main Methods:
- MCP-1 mRNA expression was measured using RT-PCR.
- Leukocyte extravasation and MCP-1 protein localization were assessed via immunohistochemistry.
- Intestinal contractility was evaluated in an organ bath following various treatments.
Main Results:
- Lipopolysaccharide (LPS) significantly increased MCP-1 mRNA and protein in the intestinal muscularis, primarily in macrophages.
- LPS induced substantial leukocyte recruitment and a 51% reduction in muscle contractility.
- Treatment with an MCP-1 antibody significantly inhibited leukocyte infiltration and prevented muscle dysfunction.
Conclusions:
- Resident macrophage-derived MCP-1 is a key mediator of leukocyte recruitment in the endotoxemic intestinal muscularis.
- MCP-1 contributes significantly to the development of endotoxemia-induced gastrointestinal dysmotility (ileus).