Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/75572
Citations | ||
Scopus | Web of Science® | Altmetric |
---|---|---|
?
|
?
|
Type: | Journal article |
Title: | Phosphoinositide 3-Kinase γ inhibition plays a crucial role in early steps of inflammation by blocking neutrophil recruitment |
Other Titles: | Phosphoinositide 3-Kinase gamma inhibition plays a crucial role in early steps of inflammation by blocking neutrophil recruitment |
Author: | Ferrandi, C. Ardissone, V. Ferro, P. Ruckle, T. Zaratin, P. Ammannati, E. Hauben, E. Rommel, C. Cirillo, R. |
Citation: | Journal of Pharmacology and Experimental Therapeutics, 2007; 322(3):923-930 |
Publisher: | Amer Soc Pharmacology Experimental Therapeutics |
Issue Date: | 2007 |
ISSN: | 0022-3565 1521-0103 |
Statement of Responsibility: | Chiara Ferrandi, Vittoria Ardissone, Pamela Ferro, Thomas Rückle, Paola Zaratin, Elena Ammannati, Ehud Hauben, Christian Rommel, and Rocco Cirillo |
Abstract: | Leukocyte trafficking to inflammatory sites is a gradual process, which is dominated in its early phases by chemokine- and cytokine-mediated neutrophil recruitment. The chemokine regulated on activation normal T cell expressed and secreted (RANTES) has been shown to be highly expressed in the joints of patient with rheumatoid arthritis and to promote leukocyte trafficking into the synovial tissue. In this study, we investigated the effect of RANTES in a murine model of peritoneal chemotaxis, and we found that RANTES dose-dependently induces neutrophil recruitment. Then, through morphological and histological analyses, we observed that activated neutrophils represent the major infiltrating population in response to RANTES chemotactic stimulus. Furthermore, we demonstrated that oral administration of either nonisoform-specific phosphoinositide 3-kinase (PI3K) inhibitor LY294002 (morpholin-4-yl-8-phenylchromen-4-one) or selective PI3Kgamma inhibitor AS041164 (5-benzo[1,3]dioxol-5-ylmethylene-thiazolidine-2,4-dione) blocks RANTES-induced chemotaxis and reduces the level of AKT phosphorylation. Because the two compounds showed a similar pharmacokinetic profile in terms of bioavailability and half-life after oral route administration, the selective inhibition of the PI3Kgamma-isoform pathway through AS041164 was three times more potent in reducing neutrophil recruitment. Finally, to confirm the blockade of neutrophil infiltration that occurs in the early phase of the inflammatory response, AS041164 was also tested in a model of carrageenan-induced paw edema in rats. Therefore, the PI3Kgamma pathway plays an important role in controlling neutrophil chemotaxis during early steps of inflammation. |
Keywords: | Peritoneum Neutrophils Animals Mice Inflammation Isoenzymes Enzyme Inhibitors Administration, Oral Chemotaxis Biological Availability Chemokine CCL5 Class Ib Phosphatidylinositol 3-Kinase Phosphoinositide-3 Kinase Inhibitors |
Rights: | Copyright © 2007 by The American Society for Pharmacology and Experimental Therapeutics |
DOI: | 10.1124/jpet.107.123026 |
Published version: | http://dx.doi.org/10.1124/jpet.107.123026 |
Appears in Collections: | Aurora harvest 4 Surgery publications |
Files in This Item:
There are no files associated with this item.
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.