American journal of physiology. Gastrointestinal and liver physiology
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Am. J. Physiol. Gastrointest. Liver Physiol. · Dec 2010
Lipopolysaccharide binding protein inhibitory peptide protects against acetaminophen-induced hepatotoxicity.
Acetaminophen (APAP)-induced liver injury remains the main cause of acute liver failure in the United States. Our previous work demonstrated that LPS binding protein (LBP) knockout mice are protected from APAP-induced hepatotoxicity. LBP is known to bind avidly to LPS, facilitating cellular activation. ⋯ We found no difference in the glutathione levels and APAP-adduct formation between LBPK95A vs. vehicle control both at baseline and after APAP. In conclusion, our results support the hypothesis that LBP-induced liver injury after APAP is due to its ability to mediate activation by endogenous LPS. Our results suggest that blocking LBP-LPS interactions is a potential therapeutic avenue for the treatment of APAP-induced liver injury.
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Am. J. Physiol. Gastrointest. Liver Physiol. · Dec 2010
Vagal nerve stimulation protects against burn-induced intestinal injury through activation of enteric glia cells.
The enteric nervous system may have an important role in modulating gastrointestinal barrier response to disease through activation of enteric glia cells. In vitro studies have shown that enteric glia activation improves intestinal epithelial barrier function by altering the expression of tight junction proteins. We hypothesized that severe injury would increase expression of glial fibrillary acidic protein (GFAP), a marker of enteric glial activation. ⋯ Intestinal expression of GFAP increases following severe burn injury. Stimulation of the vagus nerve increases enteric glia activation, which is associated with improved intestinal barrier function. The vagus nerve may mediate the signaling that occurs from the central nervous system to the enteric nervous system following gastrointestinal injury.
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Am. J. Physiol. Gastrointest. Liver Physiol. · Oct 2010
HIF-1 mediates pathogenic inflammatory responses to intestinal ischemia-reperfusion injury.
Acute lung injury (ALI) and the development of the multiple organ dysfunction syndrome (MODS) are major causes of death in trauma patients. Gut inflammation and loss of gut barrier function as a consequence of splanchnic ischemia-reperfusion (I/R) have been implicated as the initial triggering events that contribute to the development of the systemic inflammatory response, ALI, and MODS. Since hypoxia-inducible factor (HIF-1) is a key regulator of the physiological and pathophysiological response to hypoxia, we asked whether HIF-1 plays a proximal role in the induction of gut injury and subsequent lung injury. ⋯ Lastly, partial HIF-1α deficiency reduced TNF-α, IL-1β, cyclooxygenase-2, and inducible nitric oxide synthase levels in the ileal mucosa after T/HS whereas IL-1β mRNA levels were reduced in the lung after T/HS. This study indicates that prolonged intestinal HIF-1 activation is a proximal regulator of I/R-induced gut mucosal injury and gut-induced lung injury. Consequently, these results provide unique information on the initiating events in trauma-hemorrhagic shock-induced ALI and MODS as well as potential therapeutic insights.
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Am. J. Physiol. Gastrointest. Liver Physiol. · Sep 2010
Transient receptor potential ion channels V4 and A1 contribute to pancreatitis pain in mice.
The mechanisms of pancreatic pain, a cardinal symptom of pancreatitis, are unknown. Proinflammatory agents that activate transient receptor potential (TRP) channels in nociceptive neurons can cause neurogenic inflammation and pain. We report a major role for TRPV4, which detects osmotic pressure and arachidonic acid metabolites, and TRPA1, which responds to 4-hydroxynonenal and cyclopentenone prostaglandins, in pancreatic inflammation and pain in mice. ⋯ Deletion of trpv4 or trpa1 suppressed c-Fos expression and pain behavior, and deletion of trpa1 attenuated pancreatitis. Thus TRPV4 and TRPA1 contribute to pancreatic pain, and TRPA1 also mediates pancreatic inflammation. Our results provide new information about the contributions of TRPV4 and TRPA1 to inflammatory pain and suggest that channel antagonists are an effective therapy for pancreatitis, when multiple proinflammatory agents are generated that can activate and sensitize these channels.
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Am. J. Physiol. Gastrointest. Liver Physiol. · Apr 2010
Ameliorating effects and mechanisms of electroacupuncture on gastric dysrhythmia, delayed emptying, and impaired accommodation in diabetic rats.
The aim of this study was to investigate the effects and mechanisms of electroacupuncture (EA) on gastric accommodation, gastric dysrhythmia, and gastric emptying (GE) in streptozotocin (STZ)-induced diabetic rats. Five experiments were performed in five groups of STZ-induced diabetic rats to study the effects of EA at ST-36 (Zusanli) on gastric slow-wave dysrhythmia, delayed GE and intestinal transit, impaired gastric accommodation, and the mechanisms of EA involving the autonomic and opioidergic pathways. We found the following: 1) EA improved gastric dysrhythmia in the diabetic rats. ⋯ Gastric accommodation was 0.98 +/- 0.13 ml with sham EA and significantly increased to 1.21 +/- 0.15 ml with EA (P = 0.01), and this effect was blocked by naloxone. 4) EA increased vagal activity assessed by the spectral analysis of the heart rate variability. We concluded that EA at ST-36 improves gastric dysrhythmia, delayed GE and intestinal transit, and impaired accommodation in STZ-induced diabetic rats, and the improvement seems to be mainly mediated via the vagal pathway. EA may have a promising therapeutic potential for diabetic gastroparesis.