Corneal stimulation of MMP-1, -9 and uPA by platelet-activating factor is mediated by cyclooxygenase-2 metabolites

Ottino, Paulo; Bazán, Haydee E. P.

doi:10.1076/ceyr.23.2.77.5471

Cited by 46 publications

(39 citation statements)

References 15 publications

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“…25,26 Platelet activating factor-induced COX-2 upregulation is believed to be involved in the activation of matrix metalloproteinases MMP-1 and MMP-9, which are responsible for collagenolytic damage and ultimately for ulcer formation. 27,28 Increased expression of COX-2 and MMP-9 has been documented in DE. 4 Thus, testing potential drugs in the currently used model should give valuable insights to their potential clinical use.…”

Section: Discussionmentioning

confidence: 99%

Resolvin E1 Improves Tear Production and Decreases Inflammation in a Dry Eye Mouse Model

Schwartz

et al. 2010

Journal of Ocular Pharmacology and Therapeutics

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115

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Purpose: Dry eye (DE) is a common ocular surface disease, particularly among women and the elderly, with chronic symptoms of eye irritation and, in severe cases, blurred vision. Several studies have shown that there is an inflammatory component in DE, although the pathogenesis is not thoroughly understood. Resolvin E1 (RvE1; RX-10001) is an endogenous mediator derived from the omega-3 polyunsaturated fatty acid eicosapentaenoic acid and is involved in inflammation resolution and tissue protection. Here we investigated the role of RvE1 in a DE mouse model. Methods: Thirteen-to 14-week-old female BALB/C mice were exposed to desiccating conditions. One week after DE exposure, animals were treated topically with drug or vehicle 4 times per day for an additional week. Controls were nontreated animals placed in a normal environment. Schirmer's test was performed before treatment initiation and at days 2 and 4 after treatment. Density of corneal epithelial cells was analyzed in vivo using the Rostock Cornea Module of the Heidelberg Retina Tomograph (HRT-II). Corneas were processed using Western blot analysis and immunofluorescence examination. Results: Schirmer's test showed a significant decrease in tear production in DE compared with controls. There was no change at 2 and 4 days after treatment with the vehicle, but a significant increase was observed at 2 and 4 days in the RvE1-treated group. The density of the superficial epithelial cells showed a significant decrease after DE compared with controls, which increased after 7 days of RvE1 treatment. Western blot analysis showed that asmooth muscle actin and cyclooxygenase-2 (COX-2) expression were strongly upregulated after DE and decreased after 7 days of RvE1 treatment. Immunofluorescence confirmed strong positive staining of a-smooth muscle actin and COX-2 in stroma and/or in epithelia after DE, which decreased with RvE1 treatment. The percentage of infiltrating CD4þ T cells and CD11b þ cells decreased after RvE1 treatment when compared with DE. Conclusion: RvE1 promotes tear production, corneal epithelial integrity, and a decrease in inflammatory inducible COX-2. In the stroma, RvE1 inhibits keratocyte transformation to myofibroblasts and lowers the number of monocytes/macrophages in this DE mouse model. These results suggest that RvE1 and similar resolvin analogs have therapeutic potential in the treatment of DE.

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Section: Discussionmentioning

confidence: 99%

Resolvin E1 Improves Tear Production and Decreases Inflammation in a Dry Eye Mouse Model

Schwartz

et al. 2010

Journal of Ocular Pharmacology and Therapeutics

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115

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“…Several reports have suggested that PAF regulates the activity of various MMPs in different cell types, including stimulation of the MMP-9 expression in corneal myofibroblasts (63), COX-2-mediated transactivation of urokinase plasminogen activator and MMP-1 and -9 in corneal cultures (64), and NFB-dependent expression of MMP-9 in endothelial ECV304 cells (65). Most recently, Axelrad et al (66) showed that PAF induced the transactivation of MT1-MMP and TIMP2 genes and the activation of MMP-2 in human umbilical vein endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

Platelet-activating Factor Mediates MMP-2 Expression and Activation via Phosphorylation of cAMP-response Element-binding Protein and Contributes to Melanoma Metastasis

Melnikova

Mourad-Zeidan

Lev

et al. 2006

Journal of Biological Chemistry

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Overexpression of cAMP-response element (CRE)-binding protein (CREB) and activating transcription factor (ATF) 1 contributes to melanoma progression and metastasis at least in part by promoting tumor cell survival and stimulating matrix metalloproteinase (MMP) 2 expression. However, little is known about the regulation of CREB and ATF-1 activities and their phosphorylation within the tumor microenvironment. We analyzed the effect of platelet-activating factor (PAF), a potent phospholipid mediator of inflammation, for its ability to activate CREB and ATF-1 in eight cultured human melanoma cell lines, and we found that PAF receptor (PAFR) was expressed in all eight lines. In metastatic melanoma cell lines, PAF induced CREB and ATF-1 phosphorylation via a PAFRmediated signal transduction mechanism that required pertussis toxin-insensitive G␣ q protein and adenylate cyclase activity and was antagonized by a cAMP-dependent protein kinase A and p38 MAPK inhibitors. Addition of PAF to metastatic A375SM cells stimulated CRE-dependent transcription, as observed in a luciferase reporter assay, without increasing the CRE DNA binding capacity of CREB. Furthermore, PAF stimulated the gelatinase activity of MMP-2 by activating transcription and MMP-2 expression. MMP-2 activation correlated with the PAF-induced increase in the expression of an MMP-2 activator, membrane type 1 MMP. PAF-induced expression of pro-MMP-2 was causally related to PAF-induced CREB and ATF-1 phosphorylation; it was prevented by PAFR antagonist and inhibitors of p38 MAPK and protein kinase A and was abrogated upon quenching of CREB and ATF-1 activities by forced overexpression of a dominant-negative form of CREB. PAFinduced MMP-2 activation was also down-regulated by p38 MAPK and protein kinase A inhibitors. Finally, PAFR antagonist PCA4248 inhibited the development of A375SM lung metastasis in nude mice. This result indicated that PAF acts as a promoter of melanoma metastasis in vivo. We proposed that metastatic melanoma cells overexpressing CREB/ATF-1 are better equipped than nonmetastatic cells to respond to PAF within the tumor microenvironment. cAMP-response element (CRE)2 -binding protein (CREB), activating transcription factor (ATF) 1, and CRE modulators are members of the large basic region leucine zipper superfamily of transcription factors that regulate gene expression in response to cAMP, intracellular Ca 2ϩ mobilization, and cell stimulation with growth factors (1). The ubiquitously expressed CREB and ATF-1 and the preferentially expressed (in neuroendocrine tissues) CRE modulator bind to complete and partial palindromic CRE DNA consensus sites 5Ј-TGACGTCA-3Ј and 5Ј-CGTCA-3Ј. These transcription factors induce genes involved in cellular metabolism and respiration, gene transcription, cell cycle regulation and cell survival, as well as growth factor and cytokine genes (reviewed in Ref. 1). The transcriptional activity of the DNA-bound CREB protein dimers is regulated by phosphorylation of the serine 133 site in the kinase-inducible domain, wh...

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“…Furthermore, COX-2 induction and prostaglandin synthesis mediate the stimulation of uPA, MMP-1, and MMP-9 activity by PAF in rabbit corneas ( 65 ). Interestingly, the release of AA after cPLA2 stimulation induced by PAF does not increase the synthesis of 12(S)-HETE in rabbit corneal epithelia ( 42,43 ).…”

Section: Lipids In Corneal Pathologiesmentioning

confidence: 94%

“…PGF2 ␣ -isopropyl ester (latanoprost), a derivative of PGF2 ␣ , is commonly used as a potent ocular hypotensive drug in the management of glaucoma ( 62 ); however, glaucomatous patients often need to use these types of drugs for extensive periods, and some adverse effects have been reported. In a rabbit model of acute herpetic keratitis, latanoprost increases the severity and recurrence of this infection ( 63 ) ( 65,66 ).…”

Section: Lipids In Corneal Pathologiesmentioning

confidence: 99%

Significance of lipid mediators in corneal injury and repair

Kenchegowda

Bazán

2010

Journal of Lipid Research

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ers of the cornea function in a synchronized way to ensure this transparency.Corneal tissue has three distinct layers, the epithelial, stroma, and endothelial layers, and two acellular regions, the Bowman's layer, which separates the epithelium from the stroma, and the Descemet's membrane, which is between the stroma and the endothelium ( Fig. 1A ). All three layers have a uniform and consistent arrangement throughout the tissue in order to precisely bend and transmit light, fi rst to the lens and then to the retina.The corneal epithelium is the most outer layer, consisting of fi ve to seven layers of stratifi ed nonkeratinized epithelia. The basal cells have a prominent nucleus, are mitotically active, and adhere to the basement membrane through an adhesion complex that anchors the epithelium to the Bowman's layer. Turnover of epithelial cells occurs every fi ve to seven days by displacement of existing cells, which begin their movement toward the surface to then form two to three layers of wing-shaped cells; the cells then begin terminal differentiation and desquamation. The outer-most layer of the epithelium is in intimate contact with the tear fi lm that keeps the surface moist and free of damage that can result from drying (dry eye). This is The cornea, known as the "window of the eye," has two major functions: to protect the intraocular structures and to refract light. In fact, the cornea accounts for two-thirds of the refractive power of the eye. The most important characteristic of this tissue is its transparency, and the lay-

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Corneal stimulation of MMP-1, -9 and uPA by platelet-activating factor is mediated by cyclooxygenase-2 metabolites

Cited by 46 publications

References 15 publications

Resolvin E1 Improves Tear Production and Decreases Inflammation in a Dry Eye Mouse Model

Resolvin E1 Improves Tear Production and Decreases Inflammation in a Dry Eye Mouse Model

Platelet-activating Factor Mediates MMP-2 Expression and Activation via Phosphorylation of cAMP-response Element-binding Protein and Contributes to Melanoma Metastasis

Significance of lipid mediators in corneal injury and repair

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