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Endotoxemia induced MCP-1 expression in the intestinal muscularis causes leucocyte infiltration that mediates smooth muscle dysfunction
Critical Care volume 5, Article number: P055 (2001)
Endotoxemia causes a molecular and leukocytic inflammatory response with the intestinal muscularis, which is associated with an inhibition of gastrointestinal motility. The network of resident macrophages seems to play a major role as an initiator of this cascade. We hypothesize that these resident cells evoke the extravasation of immunocompetent leucocytes in the intestinal muscularis through the release of chemotactic cytokines (eg MCP-1).
Endotoxemia was induced in ACI rats by a single intraperitoneal injection of lipopolysaccharide (LPS: 15 mg/kg). Animals were treated with LPS, LPS + non-specific antibody or LPS + MCP-1 antibody and sacrificed 18 hours after LPS for functional and immunohistochemical studies (N = 6 each). Semi-quantitative RT-PCR was also performed to delineate the time course of MCP-1 mRNA expression (0, 1, 3, 6, 24, and 48 hours). MCP-1 mRNA peak expression was confirmed and quantified by SYBR Green two-step real-time RT-PCR. Cellular infiltration (polymorphonuclear neutrohils, monocytes) and MCP-1 protein expression was determined by immunohistochemistry. Spontaneous and bethanechol stimulated circular muscle strip contractility was assessed using a standard organ bath. Statistical analysis was performed using the unpaired Student t-test. Data were considered statistical significant at a P < 0.05.
Endotoxemia caused a significant increase in MCP-1 mRNA expression in the intestinal muscularis, peaking at 3 hours and returned to near control levels after 48 hours. SYBR Green real-time PCR revealed a 280-fold increase in MCP-1 mRNA expression 3 hours after LPS compared to control tissue (relative quantification: ΔΔCT = -8.1 ± 0.25). MCP-1 protein was immunohistochemically located in resident muscularis macrophages. LPS application caused a significant infiltration of leucocytes into the intestinal muscularis and a 51% decrease in muscle contractility, which was significantly blocked by MCP-1 antibody treatment (8% decrease), but not by the non-specific antibody (38% decrease, at bethanechol 300 μM).
The results suggest that locally derived MCP-1 plays a major role in the recruitment of monocytes during endotoxemia from which kinetically active substances contribute to ileus.
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Türler, A., Schwarz, N., Türler, E. et al. Endotoxemia induced MCP-1 expression in the intestinal muscularis causes leucocyte infiltration that mediates smooth muscle dysfunction. Crit Care 5, P055 (2001). https://doi.org/10.1186/cc1123
- Smooth Muscle Dysfunction
- Circular Muscle Strip
- Intestinal Muscularis
- Muscularis Macrophage