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-Kit W-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-Kit W-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.
Highlights
Platelet activating factor (1-alkyl-2-acetyl glycerophosphocholine, PAF) is a bioactive lipid molecule produced by both enzymatic and non-enzymatic mechanisms [1]
CPAF is topically active and results in a dose-dependent transient increase in ear thickness that is dependent on mast cells
In a previous study [7] and in Fig 1A, we show that a single topical application of increasing doses of the non-hydrolyzable PAF-R agonist, CPAF, results in a dose-dependent increase in ear thickness at two hours after application
Summary
Platelet activating factor (1-alkyl-2-acetyl glycerophosphocholine, PAF) is a bioactive lipid molecule produced by both enzymatic and non-enzymatic mechanisms [1]. PAF is perhaps best known for its pro-inflammatory effects that mediate the systemic reaction to shock, allergic reactions, and anaphylaxis [1] In this role, PAF’s actions are thought to be mediated by its ability to stimulate vasodilation and vascular permeability, platelet aggregation, bronchoconstriction, and alterations in leukocyte function [1]. PAF’s actions are thought to be mediated by its ability to stimulate vasodilation and vascular permeability, platelet aggregation, bronchoconstriction, and alterations in leukocyte function [1] These effects on leukocytes include the ability of PAF to stimulate mast cell activation and migration [8,9,10], mononuclear and neutrophilic phagocytosis [11,12,13], and M2 polarization of macrophages [14]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
