Prostaglandin E2 Mediates IL-1β-Related Fibroblast Mitogenic Effects in Acute Lung Injury through Differential Utilization of Prostanoid Receptors

White, Kimberly E.; Ding, Qiang; Moore, Bethany B.; Peters‐Golden, Marc; Ware, Lorraine B.; Matthay, Michael A.; Olman, Mitchell A.

doi:10.4049/jimmunol.180.1.637

Cited by 57 publications

(40 citation statements)

References 70 publications

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“…The implication of this pathway elucidates other possible avenues for dioxin-mediated lung dysfunction-in particular, the possibility that IL-1b, a strong COX-2 activator, as well as marker of TCDD oxidative stress (19,20), acts as a conduit between AhR and COX-2 activation. This mechanism is supported by a recent study that proposes that acute lung injury via IL-1b results from the activation of prostenoids, such as prostaglandin E2 (21), which activate mucin secretion.…”

supporting

confidence: 66%

Arylhydrocarbon Receptor Activation in NCI-H441 Cells and C57BL/6 Mice

Wong

Vogel²,

Kokosinski³

et al. 2010

Am J Respir Cell Mol Biol

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The arylhydrocarbon receptor (AhR) is known for its ability to bind aromatic-containing compounds, which starts a molecular cascade involving the induction of cytochrome P450s and inflammatory cytokines. Our hypothesis is that many inhaled environmental toxicant components activate these inflammatory pathways via an initial binding to the AhR. To test this possibility, we treated Clara cell-derived NCI-H441 cells with the AhR agonist, 2,3,7,8-tetrachlordibenzo-p-dioxin (TCDD), and demonstrated that AhR activation increased the expression of both cytochrome P450 s and inflammatory markers. We also found increased mucin 5AC production with TCDD treatment. Similar results were observed in NCI-H441 cells treated with urban dust particles. Mucin 5AC expression was highly correlated with increased-expression cyclooxygenase-2 and IL-1b, thus implicating these two inflammatory markers as possible conduits for AhR-mediated mucin production. We hypothesize that this increase in mucin 5AC production is a result of inflammation-induced differentiation of our epithelial cell to a mucin-producing cell. This theory is supported by morphological changes observed in the cells, as well as decreased expression of Clara cell secretory protein (CC10). In an in vivo C57BL/6 mouse model, TCDD increased expression of inflammatory cytokines, mucin 5AC, and a number of matrix metalloproteases in whole-lung samples. These changes were not seen in mice in which AhR signaling was repressed. These markers from the whole-lung samples have been correlated to onset of bronchitis, asthma, small airways disease, and fibrosis, and their increased expression further implicates AhR activation in producing the molecular environment for the development of lung injury to occur.

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supporting

confidence: 66%

Arylhydrocarbon Receptor Activation in NCI-H441 Cells and C57BL/6 Mice

Wong

Vogel²,

Kokosinski³

et al. 2010

Am J Respir Cell Mol Biol

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“…Indeed, the EP 3 receptor mediates contraction of human pulmonary artery (Maddox et al, 1985;Haye-Legrand et al, 1987;Norel et al, 1991;Qian et al, 1994;Walch et al, 1999) and may modulate relaxant IP receptor function (Jones et al, 1997;Chan and Jones, 2004). In addition, EP 3 receptor signaling is profibrotic (White et al, 2008;Bozyk and Moore, 2011;Harding and LaPointe, 2011) and may limit the beneficial effects of treprostinil in PAH.…”

Section: Discussionmentioning

confidence: 99%

Differential Effects of Selexipag and Prostacyclin Analogs in Rat Pulmonary Artery

Morrison

Studer

Ernst

et al. 2012

J Pharmacol Exp Ther

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{4-[(5,6-Diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid (ACT-333679) is the main metabolite of the selective prostacyclin (PGI 2 ) receptor (IP receptor) agonist selexipag. The goal of this study was to determine the influence of IP receptor selectivity on the vasorelaxant efficacy of ACT-333679 and the PGI 2 analog treprostinil in pulmonary artery under conditions associated with pulmonary arterial hypertension (PAH). Selexipag and ACT-333679 evoked full relaxation of pulmonary artery from control and monocrotaline (MCT)-PAH rats, and ACT-333679 relaxed normal pulmonary artery contracted with either endothelin-1 (ET-1) or phenylephrine. In contrast, treprostinil evoked weaker relaxation than ACT-333679 of control pulmonary artery and failed to induce relaxation of pulmonary artery from MCT-PAH rats. Treprostinil did not evoke relaxation of normal pulmonary artery contracted with either ET-1 or phenylephrine. Expression of prostaglandin E 3 (EP 3 ) receptor mRNA was increased in pulmonary artery from MCT-PAH rats.In contraction experiments, the selective EP 3 receptor agonist sulprostone evoked significantly greater contraction of pulmonary artery from MCT-PAH rats compared with control rats. The presence of a threshold concentration of ET-1 significantly augmented the contractile response to sulprostone in normal pulmonary artery. ACT-333679 did not evoke direct contraction of rat pulmonary artery, whereas treprostinil evoked concentration-dependent contraction that was inhibited by the EP 3 receptor antagonist (2E)-3-(3Ј,4Ј-dichlorobiphenyl-2-yl)-N-(2-thienylsulfonyl)acrylamide. Antagonism of EP 3 receptors also revealed a relaxant response to treprostinil in normal pulmonary artery contracted with ET-1. These data demonstrate that the relaxant efficacy of the selective IP receptor agonist selexipag and its metabolite ACT-333679 is not modified under conditions associated with PAH, whereas relaxation to treprostinil may be limited in the presence of mediators of disease.

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“…LPS-stimulated LTB 4 from primary human monocytes/macrophages (U937 macrophages did not secrete LTB 4 ) was only weakly inhibited by the ginger extract. The double inhibition of prostanoid secretion and IL-1b by ginger phenylpropanoids is interesting because IL-1b is known to reinforce PGE 2 synthesis (70), which plays multiple roles in inflammatory processes (71,72).…”

Section: Discussionmentioning

confidence: 99%

Ginger Phenylpropanoids Inhibit IL-1β and Prostanoid Secretion and Disrupt Arachidonate-Phospholipid Remodeling by Targeting Phospholipases A2

Nievergelt

Marazzi

Schoop³

et al. 2011

The Journal of Immunology

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The rhizome of ginger (Zingiber officinale) is employed in Asian traditional medicine to treat mild forms of rheumatoid arthritis and fever. We have profiled ginger constituents for robust effects on proinflammatory signaling and cytokine expression in a validated assay using human whole blood. Independent of the stimulus used (LPS, PMA, anti-CD28 Ab, anti-CD3 Ab, and thapsigargin), ginger constituents potently and specifically inhibited IL-1β expression in monocytes/macrophages. Both the calcium-independent phospholipase A2 (iPLA2)-triggered maturation and the cytosolic phospholipase A2 (cPLA2)-dependent secretion of IL-1β from isolated human monocytes were inhibited. In a fluorescence-coupled PLA2 assay, most major ginger phenylpropanoids directly inhibited i/cPLA2 from U937 macrophages, but not hog pancreas secretory phospholipase A2. The effects of the ginger constituents were additive and the potency comparable to the mechanism-based inhibitor bromoenol lactone for iPLA2 and methyl arachidonyl fluorophosphonate for cPLA2, with 10-gingerol/-shogaol being most effective. Furthermore, a ginger extract (2 μg/ml) and 10-shogaol (2 μM) potently inhibited the release of PGE2 and thromboxane B2 (>50%) and partially also leukotriene B4 in LPS-stimulated macrophages. Intriguingly, the total cellular arachidonic acid was increased 2- to 3-fold in U937 cells under all experimental conditions. Our data show that the concurrent inhibition of iPLA2 and prostanoid production causes an accumulation of free intracellular arachidonic acid by disrupting the phospholipid deacylation-reacylation cycle. The inhibition of i/cPLA2, the resulting attenuation of IL-1β secretion, and the simultaneous inhibition of prostanoid production by common ginger phenylpropanoids uncover a new anti-inflammatory molecular mechanism of dietary ginger that may be exploited therapeutically.

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Prostaglandin E2 Mediates IL-1β-Related Fibroblast Mitogenic Effects in Acute Lung Injury through Differential Utilization of Prostanoid Receptors

Cited by 57 publications

References 70 publications

Arylhydrocarbon Receptor Activation in NCI-H441 Cells and C57BL/6 Mice

Arylhydrocarbon Receptor Activation in NCI-H441 Cells and C57BL/6 Mice

Differential Effects of Selexipag and Prostacyclin Analogs in Rat Pulmonary Artery

Ginger Phenylpropanoids Inhibit IL-1β and Prostanoid Secretion and Disrupt Arachidonate-Phospholipid Remodeling by Targeting Phospholipases A2

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