THE ANTIINFLAMMATORY AGENT ALPHA-TRINOSITOL EXERTS ITS EDEMA-PREVENTING EFFECT THROUGH MODULATION OF BETA(1) INTEGRIN FUNCTION

Edema formation in acute inflammation can be induced through lowering of interstitial fluid pressure (P-if) and seems to involve dynamic bet a(1) integrin-mediated interactions between dermal cells and extracell ular matrix fibers. The present experiments investigate the role of be ta(1) integrins in the control of P-if. The anti-inflammatory drug alp ha-trinositol (1,2,6-D-myo-inositol trisphosphate) stabilizes P-if in acute inflammation. Pretreatment with 5 mg IV alpha-trinositol in pent obarbital-anesthetized rats inhibited the lowering in P-if and the ede ma formation induced by subdermal injection of anti-beta(1) integrin I gG. This stabilization of the beta(1) integrin function in vivo was pa ralleled by effects of alpha-trinositol on contraction of fibroblast-p opulated three-dimensional collagen lattices in vitro. alpha-Trinosito l was additive to the known stimulatory effect of platelet-derived gro wth factor-BB on the final gel size in the collagen gel contraction as say. Furthermore, alpha-trinositol counteracted the inhibitory effect of anti-beta(1) integrin Fab fragments on collagen gel contraction. Fi nally, subdermal injection of dibutyryl-cAMP (db-cAMP) induced increas ed negativity of P-if 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-trinos itol. The data demonstrate that alpha-trinositol modulates beta(1) int egrin function and may do so via intracellular pathways in turn affect ing the function and/or cell surface expression of beta(1) integrins a nd suggest that alpha-trinositol can serve as a tool to study integrin function. Furthermore, the data indicate that the collagen contractio n assays may provide important information of the control of P-if in v ivo.