REDUCED PHYSEAL AREA AND CHONDROCYTE PROLIFERATION IN PASTEURELLA-MULTOCIDA TOXIN-TREATED RATS

Pasteurella multocida toxin depresses weight gain in rats and pigs. It also affects tissues with rapidly dividing cells. In the present stud y, we investigated the role of this protein toxin on chondrocyte growt h in vivo. Rats were divided into a single- or multiple-dose group and were given, respectively, either a single injection (0.15 or 0.6 mu g /kg toxin subcutaneously) or multiple injections (0.01-0.2 mu g/kg sub cutaneously) of toxin. Bone (humerus) and other selected tissues were stained for bromodeoxyuridine immunoreactivity (BrDU-IR) in order to g auge cell proliferation. Physeal area was measured in rats from the mu ltiple-dose group. Serum from single- and multiple-dose groups were te sted for tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL -6) activity using a bioassay system. Decreased weight gain, feed inta ke, and feed efficiency were observed in single- and multiple-dose gro ups of rats. Decreased BrDU-IR indices were present in the resting and proliferative zone chondrocytes of the humeral physis in rats from th e multiple-dose group, as was decreased physeal area. Increased serum IL-6 bioactivity was present in rats after 24 hours, and no changes in TNF-alpha bioactivity were seen in any group. No alterations in BrDU- IR were seen in rats fed restricted (80% of control) diets. These stud ies show that sublethal doses of toxin decrease weight gain and affect growth of long bones through suppression of chondrocyte proliferation . These effects may be mediated by direct binding of the toxin to targ et cells or IL-6 but are not associated with altered feed intake or TN F-induced cachexia.