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P21‐activated Kinase, a Novel Drug Target for the Treatment of Postoperative Ileus
Author(s) -
Uray Karen,
Bhattarai Deepa,
Cox Charles
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.628.11
Subject(s) - knockout mouse , pak1 , wild type , inflammation , gene knockout , medicine , proinflammatory cytokine , kinase , endocrinology , immunology , biology , microbiology and biotechnology , receptor , biochemistry , gene , mutant
Ileus, a common postoperative complication, has a significant impact on patient outcomes; however, there are no safe, effective pharmacological therapies for treating postoperative ileus (POI). We have shown that p21‐activated kinase (PAK1) inhibits myosin light chain phosphorylation in human intestinal smooth muscle cells and PAK1 expression is increased in intestinal smooth muscle in an ileus model. The objective of this study was to determine the feasibility of targeting PAK1 for the treatment of POI. POI was induced via gut manipulation in wildtype and PAK1 knockout mice and basal and agonist‐induced intestinal contractility and markers of inflammation, including a cytokine panel and edema development in intestinal smooth muscle, were determined. Gut manipulation caused a significant decrease in ileal contraction amplitude in wildtype mice but did not affect contraction amplitude in PAK1 knockouts. Carbachol response was increased and EC50 for carbachol was decreased in PAK1 knockout mice after gut manipulation compared to wildtype mice. Edema development was significantly increased after gut manipulation in both wildtype and PAK1 knockout mice. Inflammatory cytokines were differentially regulated in response to gut manipulation in PAK1 knockout mice compared to wildtype. While the inflammatory response appeared to be partially attenuated in PAK1 knockout mice, several markers of inflammation including monocyte chemotactic protein 1 (MCP‐1) and edema were increased in both wildtype and PAK1 knockout mice. Thus, while inflammation still developed in intestinal smooth muscle of PAK1 knockout mice, POI was prevented. We conclude that PAK1 is a feasible target for the treatment of POI.