Abstract
Sepsis is associated with bacterial translocation (BT) and changes in colonic paracellular permeability (CPP), but the link between these effects is unknown. The present study aimed to identify whether changes in CPP after lipopolysaccharide (LPS) administration triggers BT, colonic inflammation, visceral pain, and sickness behavior and to evaluate the role of myosin light chain kinase (MLCK) in colonocyte cytoskeleton contraction. Rats received the MLCK inhibitor ML-7 alone or combined with LPS. CPP was measured for 6 hours after administration. Visceral pain, food intake, BT, electron microscopy of tight junctions of colonocytes, cytokine levels, and Western blotting of phosphorylated MLC from colonic mucosa were assessed in a time range of 0 to 3 hours after treatment. Sepsis increased CPP at 0 to 6 hours after LPS and associated with tight junction morphological changes, increased MLC phosphorylation, and mucosal release of proinflammatory cytokines. Massive BT, visceral hyperalgesia, and reduced food intake were also observed. Addition of ML-7 prevented all LPS-induced effects, except for changes in food intake. In conclusion, LPS-mediated effects on CPP include gut inflammation, BT, and visceral hyperalgesia. Inhibition of MLCK-dependent colonocyte cytoskeleton contraction by ML-7 prevents the LPS-induced alterations of CPP and its subsequent effects.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Azepines / pharmacology
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Bacterial Translocation / drug effects*
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Blotting, Western
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Cell Membrane Permeability / drug effects
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Colon / cytology
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Colon / drug effects*
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Colon / ultrastructure
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Diarrhea / chemically induced
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Eating / drug effects
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Electromyography
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Enzyme Inhibitors / pharmacology
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Inflammation / etiology
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Inflammation / pathology
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Injections, Intraperitoneal
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Interferon-gamma / analysis
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Interferon-gamma / metabolism
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Interleukin-1 / analysis
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Interleukin-1 / metabolism
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Interleukin-6 / analysis
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Interleukin-6 / metabolism
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Intestinal Mucosa / drug effects*
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Intestinal Mucosa / enzymology
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Intestinal Mucosa / pathology
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Intestinal Mucosa / ultrastructure
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Kinetics
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Lipopolysaccharides / administration & dosage
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Lipopolysaccharides / pharmacology*
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Male
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Muscle Contraction
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Muscle, Skeletal / physiology
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Myosin-Light-Chain Kinase / metabolism*
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Naphthalenes / pharmacology
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Pain Measurement
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Phosphorylation
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Proteins / analysis
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Proteins / metabolism
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Rats
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Rats, Wistar
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Tight Junctions / drug effects*
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Tight Junctions / ultrastructure
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Tumor Necrosis Factor-alpha / analysis
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Azepines
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Enzyme Inhibitors
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Interleukin-1
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Interleukin-6
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Lipopolysaccharides
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Naphthalenes
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Proteins
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Tumor Necrosis Factor-alpha
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ML 7
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Interferon-gamma
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Myosin-Light-Chain Kinase