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: S A Rodt, R K Reed, M Ljungström, T O Gustafsson, K Rubin
• Journal: Circulation research (Circ Res) Vol. 75 Issue 5 Pg. 942-8 (Nov 1994) ISSN: 0009-7330 [Print] United States
• PMID: 7522989 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Gels
• Inositol Phosphates
• Integrin beta1
• Integrins
• Platelet-Derived Growth Factor
• Proto-Oncogene Proteins c-sis
• Recombinant Proteins
• Becaplermin
• Collagen
• atrinositol

Topics

• Acute Disease
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Becaplermin
• Cells, Cultured
• Chromatography, Affinity
• Collagen (metabolism)
• Edema (physiopathology, prevention & control)
• Extracellular Matrix (drug effects)
• Extracellular Space (drug effects, physiology)
• Female
• Gels
• Inflammation (complications, physiopathology)
• Inositol Phosphates (pharmacology)
• Integrin beta1
• Integrins (drug effects, physiology)
• Platelet-Derived Growth Factor (pharmacology)
• Pressure
• Proto-Oncogene Proteins c-sis
• Rats
• Rats, Wistar
• Recombinant Proteins (pharmacology)