title: The anti-inflammatory agent alpha-trinositol exerts its edema-preventing effects through modulation of beta 1 integrin function.
abstract: Edema formation in acute inflammation can be induced through lowering of interstitial fluid pressure (Pif) and seems to involve dynamic beta 1 integrin-mediated interactions between dermal cells and extracellular matrix fibers. The present experiments investigate the role of beta 1 integrins in the control of Pif. The anti-inflammatory drug alpha-trinositol (1,2,6-D-myo-inositol trisphosphate) stabilizes Pif in acute inflammation. Pretreatment with 5 mg IV alpha-trinositol in pentobarbital-anesthetized rats inhibited the lowering in Pif and the edema formation induced by subdermal injection of anti-beta 1 integrin IgG. This stabilization of the beta 1 integrin function in vivo was paralleled by effects of alpha-trinositol on contraction of fibroblast-populated three-dimensional collagen lattices in vitro. alpha-Trinositol was additive to the known stimulatory effect of platelet-derived growth factor-BB on the final gel size in the collagen gel contraction assay. Furthermore, alpha-trinositol counteracted the inhibitory effect of anti-beta 1 integrin Fab fragments on collagen gel contraction. Finally, subdermal injection of dibutyryl-cAMP (db-cAMP) induced increased negativity of Pif to the same extent as did anti-beta 1 integrin antibodies, and in vitro db-cAMP reduced the ability of fibroblasts to contract collagen gels. The latter effect was opposed by alpha-trinositol. The data demonstrate that alpha-trinositol modulates beta 1 integrin function and may do so via intracellular pathways in turn affecting the function and/or cell surface expression of beta 1 integrins and suggest that alpha-trinositol can serve as a tool to study integrin function. Furthermore, the data indicate that the collagen contraction assays may provide important information of the control of Pif in vivo.
authors.affiliation: Department of Physiology, University of Bergen, Norway.
authors.forename: S A
authors.initials: SA
authors.lastname: Rodt
authors.forename: R K
authors.initials: RK
authors.lastname: Reed
authors.forename: M
authors.initials: M
authors.lastname: Ljungström
authors.forename: T O
authors.initials: TO
authors.lastname: Gustafsson
authors.forename: K
authors.initials: K
authors.lastname: Rubin
mesh_terms: D000208:Acute Disease; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000077214:Becaplermin; D002478:Cells, Cultured; D002846:Chromatography, Affinity; D003094:Collagen / Q000378:metabolism; D004487:Edema / Q000503:physiopathology / Q000517:prevention & control*; D005109:Extracellular Matrix / Q000187:drug effects; D005110:Extracellular Space / Q000187:drug effects / Q000502:physiology; D005260:Female; D005782:Gels; D007249:Inflammation / Q000150:complications / Q000503:physiopathology; D007295:Inositol Phosphates / Q000494:pharmacology*; D019012:Integrin beta1; D016023:Integrins / Q000187:drug effects / Q000502:physiology*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011312:Pressure; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D005782:Gels; D007295:Inositol Phosphates; D019012:Integrin beta1; D016023:Integrins; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D011994:Recombinant Proteins; D000077214:Becaplermin; D003094:Collagen; C059368:atrinositol