LIGATION OF ENDOTHELIAL ALPHA(V)BETA(3) INTEGRIN INCREASES CAPILLARY HYDRAULIC CONDUCTIVITY OF RAT LUNG

Complement-mediated pulmonary edema results from increases in lung cap illary hydraulic conductivity (Lp), possibly by receptor-mediated mech anisms. We considered the Lp effects of vitronectin and the vitronecti n-containing complement complex SC5b-9, which ligate the integrin alph a,beta(3) Vitronectin, SC5b-9, and SC5b-9-enriched zymosan-activated s erum all rapidly increased Lp, as determined by the split-drop techniq ue in single lung capillaries of rat lung. The Lp increases were inhib ited by a monospecific (LM609) and a polyclonal (R838) antibody agains t the alpha,beta(3), integrin but not by an irrelevant monoclonal anti body isotype matched with LM609, by a monoclonal antibody against the alpha,beta(5) integrin, or by preimmune rabbit serum. Vitronectin mono mers failed to increase Lp. The tyrosine kinase blockers genistein and methyl 2,5-dihydroxycinnamate caused significant concentration-depend ent inhibitions of Lp increases due to vitronectin and zymosan-activat ed serum. By contrast, the protein kinase C blocker calphostin C had n o major effect. We conclude that (1) multivalent ligation of the lumin ally located alpha,beta(3) integrin of lung capillary endothelium incr eases transcapillary liquid flux, and (2) the dominant signal transduc tion pathway for this effect occurs through tyrosine kinase activation .