Systemic organ endothelial injury and V(O2)-D(O2) relationship alterations occur frequently in the setting of acute lung injury, and they are believed to play an important role in the pathogenesis of the multiple organ dysfunction syndrome (MODS). However, the relationship, if any, between systemic organ endothelial injury and V(O2)-D(O2) relationship alterations remains unknown. We hypothesized that microvascular endothelial injury and attendant interstitial edema would result in increased diffusion distances for oxygen and altered systemic organ V(O2)-D(O2) relationships. To test this hypothesis, we utilized the in situ autoperfused feline ileal preparation to evaluate ileal V(O2)-D(O2) relationships in control animals (n = 5) and in animals with HCl-induced acute lung and systemic organ injury (n = 5). As expected, ileal endothelial protein permeability (CL/CP) was increased in HCl-injured animals compared to control animals (0.187 +/- 0.024 versus 0.097 +/- 0.009; p < 0.01). However, contrary to our original hypothesis and despite marked morphologic and endothelial protein permeability alterations, ileal V(O2)-D(O2) relationships were not altered in the HCl-injured animals. Moreover, V(O2)-D(O2) relationships in the ileum remained unchanged even when ileal venous pressures were increased to 15 mm Hg. Taken together, these findings do not support an important role for oxygen diffusion limitation in the pathogenesis of altered systemic organ V(O2)-D(O2) relationships.