The Anti - inflammatory Agent a - Trinositol Exerts Its Edema - Preventing Effect Through Modulation of 1 Integrin Function

Edema formation in acute inflammation can be induced through lowering of interstitial fluid pressure (Pif) and seems to involve dynamic t3l integrin-mediated interactions between dermal cells and extracellular matrix fibers. The present experiments investigate the role of I31 integrins in the control of Pif. The anti-inflammatory drug a-trinositol (1,2,6D-myo-inositol trisphosphate) stabilizes Pif in acute inflammation. Pretreatment with 5 mg IV a-trinositol in pentobarbitalanesthetized rats inhibited the lowering in Pif and the edema formation induced by subdermal injection of anti-j81 integrin IgG. This stabilization of the PI integrin function in vivo was paralleled by effects of a-trinositol on contraction of fibroblast-populated three-dimensional collagen lattices in vitro. a-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, a-trinositol counE_ dema can be formed within a few minutes after the onset of acute inflammatory reactions in skin. Since edema occurs in 5 to 10 minutes and while it normally takes 12 to 24 hours to turn over the interstitial fluid volume, the transcapillary fluid flux has to be increased more than 100 times above normal for edema to form under these circumstances.' The increased capillary fluid filtration rate has commonly been ascribed to an increased capillary hydrostatic pressure and/or permeability.2 The capillary filtration rate is the product of the capillary filtration coefficient and net filtration pressure, which is normally 0.5 to 1 mm Hg in skin.3 In acute inflammation, the capillary filtration coefficient increases only by a factor of 2 to 3; therefore, the major part of the increased capillary filtration will have to rely on an increased capillary net filtration pressure. Increased negativity of interstitial fluid pressure (Pif) from -0.5 to -1 mm Hg in the control condition to -5 to -10 mm Hg has been shown to occur concomitant with edema formation in several acute inflammatory reactions and will enhance capillary fluid filtration.4 Thus, the observation of increased negativity Received March 7, 1994; accepted July 19, 1994. From the Department of Physiology (S.A.R., R.K.R.), University of Bergen (Norway); the Department of Medical and Physiological Chemistry (M.L., K.R.), University of Uppsala (Sweden); and Perstorp Pharma (T.O.G.), Lund, Sweden. Presented in part as Proceedings of the XXXII Congress of the International Union of Physiological Sciences, Glasgow, Scotland, August 1993. Correspondence to Prof Rolf K. Reed, Department of Physiology, University of Bergen, Arstadveien 19, N-5009 Bergen, Norway. © 1994 American Heart Association, Inc. teracted the inhibitory effect of anti-,81 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-,31 integrin antibodies, and in vitro db-cAMP reduced the ability of fibroblasts to contract collagen gels. The latter effect was opposed by a-trinositol. The data demonstrate that a-trinositol modulates f, integrin function and may do so via intracellular pathways in turn affecting the function and/or cell surface expression of ,1 integrins and suggest that a-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 Pf in vivo. (Circ Res. 1994;75:942-948.)