Increased arachidonic acid levels in phospholipids of human colonic mucosa in inflammatory bowel disease

Pacheco, Sergio Vicente Guevara; Hillier, Keith; Smith, Carl C.

doi:10.1042/cs0730361

Cited by 62 publications

(31 citation statements)

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“…Of note, increase in tissue concentrations of PGs has also been observed in patients with ulcerative colitis (144,193). The conversion of arachidonic acid to its metabolites in the mucosa of patients with inflammatory bowel disease was also found to be significantly higher compared with that of healthy subjects (136). Taken together, it appears that the mucosal epithelium may play a significant role in influencing GI motility in inflammation.…”

Section: Gastrointestinal (Gi) Tractmentioning

confidence: 62%

Regulation of Smooth Muscle Contraction by the Epithelium: Role of Prostaglandins

2011

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As an analog to the endothelium situated next to the vascular smooth muscle, the epithelium is emerging as an important regulator of smooth muscle contraction in many vital organs/tissues by interacting with other cell types and releasing epithelium-derived factors, among which prostaglandins have been demonstrated to play a versatile role in governing smooth muscle contraction essential to the physiological and pathophysiological processes in a wide range of organ systems. As widely distributed throughout the body, including the blood vessels, airways, gastrointestinal, urinary, and reproductive tracts, smooth muscles have a variety of critical functions such as controlling blood pressure, respiration, and gastrointestinal peristalsis. Abnormality in smooth muscle contractility results in various disorders and diseases including hypertension, asthma, and dyspepsia (89, 95,179). Therefore, smooth muscle contraction is tightly regulated. Apart from the long-recognized regulation by neurotransmitters released from the innervating nerve endings or hormones from the blood stream nearby (66), smooth muscle contraction has been known, for over three decades, to be regulated by the endothelium lining the blood vessels with nitric oxide (NO) as the most important endothelial-derived factor (51, 121). Over recent decades, evidence has also been accumulated indicating an important role of the epithelium, the cell layer lining the luminal surface of many organs or tracts, such as the trachea/bronchus, stomach, intestine, bladder, and reproductive organs, in the regulation of smooth muscle contraction, with a number of epithelium-derived factors identified. However, the importance of the epithelium in regulating smooth muscle tones has not been adequately appreciated. In this review, we will examine the evidence collected from a number of organ systems and hope to provide a clearer picture as to how the epithelium acts as an indispensable regulator of smooth muscle contraction, with epithelium-derived prostaglandins (PGs) as the key mediators, participating in many vital physiological processes as well as the pathogenesis of many diseases.

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Section: Gastrointestinal (Gi) Tractmentioning

confidence: 62%

Regulation of Smooth Muscle Contraction by the Epithelium: Role of Prostaglandins

2011

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“…Increased levels of AA in the intestinal mucosa and plasma of patients with Crohn's disease have been documented (7,10,11,35,36). The increased levels of AA in the intestinal mucosa of Crohn's patients is accompanied by an increase in phospholipase A 2 (PLA 2 ) levels and activity (26,27,33,34), and there is increased COX-2 expression in the colonic epithelium (46).…”

Section: Discussionmentioning

confidence: 99%

Linoleic acid induces interleukin-8 production by Crohn's human intestinal smooth muscle cells via arachidonic acid metabolites

Alzoghaibi¹,

Walsh²,

Willey³

et al. 2004

American Journal of Physiology-Gastrointestinal and Liver Physi

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Previously we reported that linoleic acid (LA), but not oleic acid, caused a marked increase in the secretion of IL-8 by Crohn's human intestinal smooth muscle (HISM) cells. Antioxidants inhibited this response, implicating a role for oxidative stress and NF-κB, a transcription factor for IL-8 that is activated by oxidative stress. In this study, we examined two mechanisms whereby LA, the dietary precursor for arachidonic acid (AA), could increase the production of IL-8 via activation of AA pathways: 1) by generation of reactive oxygen species by the AA-pathway enzymes to activate NF-κB or 2) by AA metabolites. Normal and Crohn's HISM cells were exposed to LA, oxidizing solution (Ox), or oxidizing solution enriched with LA (OxLA). Exposure of cells to Ox or OxLA induced oxidative stress as determined by thiobarbituric acid reactive substances. In normal cells, Ox but not LA activated NF-κB as determined by transfection experiments and Western blot. In Crohn's cells, NF-κB was spontaneously activated and was not further activated by Ox or LA. In contrast, TNF-α markedly increased activation of NF-κB in both normal and Crohn's cells. These results indicated that LA did not increase IL-8 by activating NF-κB, so we evaluated the second mechanism of an effect of AA metabolites. In normal cells, OxLA, but not LA, markedly stimulated IL-8, whereas in Crohn's cells, both OxLA and LA stimulated IL-8. OxLA, also stimulated production of AA metabolites leukotriene B4(LTB4), PGE2, and thromboxane B2(TXB2) by normal and Crohn's cells. To determine whether AA metabolites mediated the IL-8 response, cells were treated with OxLA plus indomethacin (Indo), a cyclooxygenase inhibitor, and nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor. Both Indo and NDGA blocked the IL-8 response to OxLA. To determine more specifically a role for AA metabolites, AA was used. Similar to OxLA, OxAA stimulated production of IL-8 and AA metabolites. Pinane thromboxane, a selective thromboxane synthase inhibitor and receptor blocker, inhibited OxAA stimulation of TXB2and IL-8 in a dose-response manner. MK886, a selective 5-lipoxygenase inhibitor, inhibited OxAA stimulation of LTB4and IL-8 also in a dose-response manner. Analysis of specific gene products by RT-PCR demonstrated that HISM cells expressed receptors for both thromboxane and LTB4. We conclude that AA metabolites mediated the IL-8 response to LA in HISM cells. Both cyclooxygenase and lipoxygenase pathways were involved. LA did not increase IL-8 by activating NF-κB, but NF-κB appeared to be involved, because LA increased IL-8 only in situations where NF-κB was activated, either spontaneously in Crohn's cells or by Ox in normal cells. We speculate that AA metabolites increased IL-8 production by enhancing NF-κB-dependent transcription of IL-8.

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“…These differences in PC may be associated with changes in various species of PC or in other lipids. Indeed, the fatty acid side chains in the mucosa of patients with inflammatory bowel disease have been shown to be shifted to less essential fatty acids and more arachidonic acid (58).…”

Section: Discussionmentioning

confidence: 99%

Anti-inflammatory Effects of Phosphatidylcholine

Treede

Braun

Sparla

et al. 2007

Journal of Biological Chemistry

248

210

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We recently showed that mucus from patients with ulcerative colitis, a chronic inflammatory disorder of the colon, is characterized by a low level of phosphatidylcholine (PC) while clinical studies reveal that therapeutic addition of PC using slow release preparations is beneficial. The positive role of PC in this disease is still elusive. Here we tested the hypothesis that exogenous application of PC has anti-inflammatory properties using three model systems. First, human Caco-2 cells were treated with tumor necrosis factor-␣ (TNF-␣) to induce a pro-inflammatory response via activation of NF-B. Second, latex bead phagosomes were analyzed for their ability to assemble actin in vitro, a process linked to pro-inflammatory signaling and correlating with the growth versus killing of mycobacteria in macrophages. The third system used was the rapid assembly of plasma membrane actin in macrophages in response to sphingosine 1-phosphate. TNF-␣ induced a pro-inflammatory response in Caco-2 cells, including 1) assembly of plasma membrane actin; 2) activation of both MAPKs ERK and p38; 3) transport of NF-B subunits to the nucleus; and 4) subsequent up-regulation of the synthesis of pro-inflammatory gene products. Exogenous addition of most PCs tested significantly inhibited these processes. Other phospholipids like sphingomyelin or phosphatidylethanolamine showed no effects in these assays. PC also inhibited latex bead phagosome actin assembly, the killing of Mycobacterium tuberculosis in macrophages, and the sphingosine 1-phosphate-induced actin assembly in macrophages. TNF-␣ induces the activation of signaling molecules and the reorganization of the actin cytoskeleton in human intestinal cells. Exogenous application of PC blocks pro-inflammatory signaling in Caco-2 cells, in phagosomes in vitro and facilitates intracellular survival of mycobacteria. We provide further evidence that actin assembly by membranes is part of the pro-inflammatory response. Collectively, these results provide a molecular foundation for the clinical studies showing a beneficial effect of PC therapy in ulcerative colitis.

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Increased arachidonic acid levels in phospholipids of human colonic mucosa in inflammatory bowel disease

Cited by 62 publications

References 0 publications

Regulation of Smooth Muscle Contraction by the Epithelium: Role of Prostaglandins

Regulation of Smooth Muscle Contraction by the Epithelium: Role of Prostaglandins

Linoleic acid induces interleukin-8 production by Crohn's human intestinal smooth muscle cells via arachidonic acid metabolites

Anti-inflammatory Effects of Phosphatidylcholine

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