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Topical application of a platelet activating factor receptor agonist suppresses phorbol ester-induced acute and chronic inflammation and has cancer chemopreventive activity in mouse skin.

Sahu RP, Rezania S, Ocana JA, DaSilva-Arnold SC, Bradish JR, Richey JD, Warren SJ, Rashid B, Travers JB, Konger RL - PLoS ONE (2014)

Bottom Line: Using an ear inflammation model, co-administration of topical CPAF treatment resulted in a paradoxical decrease in both acute ear thickness changes associated with a single PMA application, as well as the sustained inflammation associated with chronic repetitive PMA applications.Moreover, mice treated topically with CPAF also exhibited a significant reduction in chemical carcinogenesis.These data provide additional evidence that PAF-R activation exerts complex immunomodulatory effects in a model of chronic inflammation that is relevant to neoplastic development.

View Article: PubMed Central - PubMed

Affiliation: Departments of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, United States of America.

ABSTRACT
Platelet activating factor (PAF) has long been associated with acute edema and inflammatory responses. PAF acts by binding to a specific G-protein coupled receptor (PAF-R, Ptafr). However, the role of chronic PAF-R activation on sustained inflammatory responses has been largely ignored. We recently demonstrated that mice lacking the PAF-R (Ptafr-/- mice) exhibit increased cutaneous tumorigenesis in response to a two-stage chemical carcinogenesis protocol. Ptafr-/- mice also exhibited increased chronic inflammation in response to phorbol ester application. In this present study, we demonstrate that topical application of the non-hydrolysable PAF mimetic (carbamoyl-PAF (CPAF)), exerts a potent, dose-dependent, and short-lived edema response in WT mice, but not Ptafr -/- mice or mice deficient in c-Kit (c-KitW-sh/W-sh mice). Using an ear inflammation model, co-administration of topical CPAF treatment resulted in a paradoxical decrease in both acute ear thickness changes associated with a single PMA application, as well as the sustained inflammation associated with chronic repetitive PMA applications. Moreover, mice treated topically with CPAF also exhibited a significant reduction in chemical carcinogenesis. The ability of CPAF to suppress acute and chronic inflammatory changes in response to PMA application(s) was PAF-R dependent, as CPAF had no effect on basal or PMA-induced inflammation in Ptafr-/- mice. Moreover, c-Kit appears to be necessary for the anti-inflammatory effects of CPAF, as CPAF had no observable effect in c-KitW-sh/W-sh mice. These data provide additional evidence that PAF-R activation exerts complex immunomodulatory effects in a model of chronic inflammation that is relevant to neoplastic development.

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Following a single application of PMA, Ptafr-/- mice exhibit a reduction in PMA-induced ear thickness while CPAF treatment also induces a paradoxical PAF-R dependent decrease in PMA-induced ear thickness.For all studies in Figs 6, WT and Ptafr-/- mice were treated with VEH, PMA, CPAF (6 nmole) or PMA + CPAF as described in Fig 4A&B. Ear thickness measurements were made just prior to reagent application as well as at the indicated time points up to 48 hrs. 6A. Ptafr-/- mice exhibit a reduction in early and delayed ear thickness increases following a single PMA application. Ear thickness plots for WT and Ptafr-/- mice treated with and without PMA are shown. Statistically significant changes are noted to WT mice treated with PMA relative to Ptafr-/- mice treated with PMA. Results represent the mean and SEM of ear thickness after subtracting the ear thickness at time 0 (n = 4–12 mice per group). *, p<0.05; **, p<0.01; t-test. 6B. Coadministration of topical CPAF blocks PMA-induced increases in ear thickness at all time points (2–48 hrs). PMA-induced ear thickness changes were assessed in WT or Ptafr-/- mice treated with PMA or PMA + CPAF. After subtracting the ear thickness at time 0, the ability of CPAF to suppress PMA-induced ear thickness changes was calculated as a percentage inhibition of PMA-induced ear thickness increases. CPAF treatment resulted in a significant inhibition of PMA-induced ear thickness changes at all time points (p<0.01–0.05; % inhibition significantly different from no inhibition, Wilcoxon Signed Rank Test). CPAF treatment had no significant effect on PMA-induced ear thickness changes in Ptafr-/- mice (One sample analysis, Wilcoxon Signed Rank Test). The percent inhibition of PMA-induced ear thickness changes by CPAF in WT mice was also significantly different than that seen in Ptafr-/- mice (*, p<0.05; **, p<0.01; t-test).
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pone-0111608-g006: Following a single application of PMA, Ptafr-/- mice exhibit a reduction in PMA-induced ear thickness while CPAF treatment also induces a paradoxical PAF-R dependent decrease in PMA-induced ear thickness.For all studies in Figs 6, WT and Ptafr-/- mice were treated with VEH, PMA, CPAF (6 nmole) or PMA + CPAF as described in Fig 4A&B. Ear thickness measurements were made just prior to reagent application as well as at the indicated time points up to 48 hrs. 6A. Ptafr-/- mice exhibit a reduction in early and delayed ear thickness increases following a single PMA application. Ear thickness plots for WT and Ptafr-/- mice treated with and without PMA are shown. Statistically significant changes are noted to WT mice treated with PMA relative to Ptafr-/- mice treated with PMA. Results represent the mean and SEM of ear thickness after subtracting the ear thickness at time 0 (n = 4–12 mice per group). *, p<0.05; **, p<0.01; t-test. 6B. Coadministration of topical CPAF blocks PMA-induced increases in ear thickness at all time points (2–48 hrs). PMA-induced ear thickness changes were assessed in WT or Ptafr-/- mice treated with PMA or PMA + CPAF. After subtracting the ear thickness at time 0, the ability of CPAF to suppress PMA-induced ear thickness changes was calculated as a percentage inhibition of PMA-induced ear thickness increases. CPAF treatment resulted in a significant inhibition of PMA-induced ear thickness changes at all time points (p<0.01–0.05; % inhibition significantly different from no inhibition, Wilcoxon Signed Rank Test). CPAF treatment had no significant effect on PMA-induced ear thickness changes in Ptafr-/- mice (One sample analysis, Wilcoxon Signed Rank Test). The percent inhibition of PMA-induced ear thickness changes by CPAF in WT mice was also significantly different than that seen in Ptafr-/- mice (*, p<0.05; **, p<0.01; t-test).

Mentions: The pro-inflammatory tumor promoter PMA is known to induce a rapid edema reaction in mouse ears [42], [43]. This is followed by a gradual rise in leukocyte infiltration as measured by MPO and/or N-acetylglucosaminidase (NAF) activity that peaks at around 24 hrs [42], [43]. Given that PAF is a potent vasoactive lipid mediator that promotes rapid edema reactions [37], we next examined how CPAF would affect early inflammatory changes following the first PMA application in WT and Ptafr-/- mice. As seen in Fig 6A, PMA treatment induces a rapid increase in ear thickness that was first observed two hours after application. Ear thickness changes peaked at approximately 24 to 48 hrs. In contrast, Ptafr-/- mice exhibited a reduction in the initial ear thickness changes noted at 2 & 8 hrs, suggesting that PMA-induced edema responses were PAF-dependent. It was therefore surprising to find that WT mice treated with CPAF immediately after PMA application also exhibited an approximately 50% loss of PMA-induced early ear thickness changes observed at 2 hrs (Fig 6B). This suggests a complex role for the PAF-R in regulating initial vasoactive edema changes in response to PMA.


Topical application of a platelet activating factor receptor agonist suppresses phorbol ester-induced acute and chronic inflammation and has cancer chemopreventive activity in mouse skin.

Sahu RP, Rezania S, Ocana JA, DaSilva-Arnold SC, Bradish JR, Richey JD, Warren SJ, Rashid B, Travers JB, Konger RL - PLoS ONE (2014)

Following a single application of PMA, Ptafr-/- mice exhibit a reduction in PMA-induced ear thickness while CPAF treatment also induces a paradoxical PAF-R dependent decrease in PMA-induced ear thickness.For all studies in Figs 6, WT and Ptafr-/- mice were treated with VEH, PMA, CPAF (6 nmole) or PMA + CPAF as described in Fig 4A&B. Ear thickness measurements were made just prior to reagent application as well as at the indicated time points up to 48 hrs. 6A. Ptafr-/- mice exhibit a reduction in early and delayed ear thickness increases following a single PMA application. Ear thickness plots for WT and Ptafr-/- mice treated with and without PMA are shown. Statistically significant changes are noted to WT mice treated with PMA relative to Ptafr-/- mice treated with PMA. Results represent the mean and SEM of ear thickness after subtracting the ear thickness at time 0 (n = 4–12 mice per group). *, p<0.05; **, p<0.01; t-test. 6B. Coadministration of topical CPAF blocks PMA-induced increases in ear thickness at all time points (2–48 hrs). PMA-induced ear thickness changes were assessed in WT or Ptafr-/- mice treated with PMA or PMA + CPAF. After subtracting the ear thickness at time 0, the ability of CPAF to suppress PMA-induced ear thickness changes was calculated as a percentage inhibition of PMA-induced ear thickness increases. CPAF treatment resulted in a significant inhibition of PMA-induced ear thickness changes at all time points (p<0.01–0.05; % inhibition significantly different from no inhibition, Wilcoxon Signed Rank Test). CPAF treatment had no significant effect on PMA-induced ear thickness changes in Ptafr-/- mice (One sample analysis, Wilcoxon Signed Rank Test). The percent inhibition of PMA-induced ear thickness changes by CPAF in WT mice was also significantly different than that seen in Ptafr-/- mice (*, p<0.05; **, p<0.01; t-test).
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pone-0111608-g006: Following a single application of PMA, Ptafr-/- mice exhibit a reduction in PMA-induced ear thickness while CPAF treatment also induces a paradoxical PAF-R dependent decrease in PMA-induced ear thickness.For all studies in Figs 6, WT and Ptafr-/- mice were treated with VEH, PMA, CPAF (6 nmole) or PMA + CPAF as described in Fig 4A&B. Ear thickness measurements were made just prior to reagent application as well as at the indicated time points up to 48 hrs. 6A. Ptafr-/- mice exhibit a reduction in early and delayed ear thickness increases following a single PMA application. Ear thickness plots for WT and Ptafr-/- mice treated with and without PMA are shown. Statistically significant changes are noted to WT mice treated with PMA relative to Ptafr-/- mice treated with PMA. Results represent the mean and SEM of ear thickness after subtracting the ear thickness at time 0 (n = 4–12 mice per group). *, p<0.05; **, p<0.01; t-test. 6B. Coadministration of topical CPAF blocks PMA-induced increases in ear thickness at all time points (2–48 hrs). PMA-induced ear thickness changes were assessed in WT or Ptafr-/- mice treated with PMA or PMA + CPAF. After subtracting the ear thickness at time 0, the ability of CPAF to suppress PMA-induced ear thickness changes was calculated as a percentage inhibition of PMA-induced ear thickness increases. CPAF treatment resulted in a significant inhibition of PMA-induced ear thickness changes at all time points (p<0.01–0.05; % inhibition significantly different from no inhibition, Wilcoxon Signed Rank Test). CPAF treatment had no significant effect on PMA-induced ear thickness changes in Ptafr-/- mice (One sample analysis, Wilcoxon Signed Rank Test). The percent inhibition of PMA-induced ear thickness changes by CPAF in WT mice was also significantly different than that seen in Ptafr-/- mice (*, p<0.05; **, p<0.01; t-test).
Mentions: The pro-inflammatory tumor promoter PMA is known to induce a rapid edema reaction in mouse ears [42], [43]. This is followed by a gradual rise in leukocyte infiltration as measured by MPO and/or N-acetylglucosaminidase (NAF) activity that peaks at around 24 hrs [42], [43]. Given that PAF is a potent vasoactive lipid mediator that promotes rapid edema reactions [37], we next examined how CPAF would affect early inflammatory changes following the first PMA application in WT and Ptafr-/- mice. As seen in Fig 6A, PMA treatment induces a rapid increase in ear thickness that was first observed two hours after application. Ear thickness changes peaked at approximately 24 to 48 hrs. In contrast, Ptafr-/- mice exhibited a reduction in the initial ear thickness changes noted at 2 & 8 hrs, suggesting that PMA-induced edema responses were PAF-dependent. It was therefore surprising to find that WT mice treated with CPAF immediately after PMA application also exhibited an approximately 50% loss of PMA-induced early ear thickness changes observed at 2 hrs (Fig 6B). This suggests a complex role for the PAF-R in regulating initial vasoactive edema changes in response to PMA.

Bottom Line: Using an ear inflammation model, co-administration of topical CPAF treatment resulted in a paradoxical decrease in both acute ear thickness changes associated with a single PMA application, as well as the sustained inflammation associated with chronic repetitive PMA applications.Moreover, mice treated topically with CPAF also exhibited a significant reduction in chemical carcinogenesis.These data provide additional evidence that PAF-R activation exerts complex immunomodulatory effects in a model of chronic inflammation that is relevant to neoplastic development.

View Article: PubMed Central - PubMed

Affiliation: Departments of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, United States of America.

ABSTRACT
Platelet activating factor (PAF) has long been associated with acute edema and inflammatory responses. PAF acts by binding to a specific G-protein coupled receptor (PAF-R, Ptafr). However, the role of chronic PAF-R activation on sustained inflammatory responses has been largely ignored. We recently demonstrated that mice lacking the PAF-R (Ptafr-/- mice) exhibit increased cutaneous tumorigenesis in response to a two-stage chemical carcinogenesis protocol. Ptafr-/- mice also exhibited increased chronic inflammation in response to phorbol ester application. In this present study, we demonstrate that topical application of the non-hydrolysable PAF mimetic (carbamoyl-PAF (CPAF)), exerts a potent, dose-dependent, and short-lived edema response in WT mice, but not Ptafr -/- mice or mice deficient in c-Kit (c-KitW-sh/W-sh mice). Using an ear inflammation model, co-administration of topical CPAF treatment resulted in a paradoxical decrease in both acute ear thickness changes associated with a single PMA application, as well as the sustained inflammation associated with chronic repetitive PMA applications. Moreover, mice treated topically with CPAF also exhibited a significant reduction in chemical carcinogenesis. The ability of CPAF to suppress acute and chronic inflammatory changes in response to PMA application(s) was PAF-R dependent, as CPAF had no effect on basal or PMA-induced inflammation in Ptafr-/- mice. Moreover, c-Kit appears to be necessary for the anti-inflammatory effects of CPAF, as CPAF had no observable effect in c-KitW-sh/W-sh mice. These data provide additional evidence that PAF-R activation exerts complex immunomodulatory effects in a model of chronic inflammation that is relevant to neoplastic development.

Show MeSH
Related in: MedlinePlus