We have now shown that rG-CSF pretreatment in a nonneutropenic canine model of lethal bacterial peritonitis improves cardiovascular function and survival. These improvements are associated with decreases in circulating endotoxin levels. Although G-CSF accelerates alveolar neutrophil recruitment in this model, pulmonary injury is not worsened. In addition to reductions in circulating endotoxin levels, we have shown that G-CSF pretreatment reduces circulating tumor necrosis factor (TNF) levels as well. In contrast, we have found that G-CSF pretreatment in rats before intrabronchial bacterial challenge is detrimental. This effect is in part related to worsened pulmonary injury. Conflicting results from these studies are difficult to interpret because differences exist between the canine and rat models. The canine model includes volume support and also uses canine specific G-CSF at a relatively low dose (5ug/kg). Volume support is not possible in the rat model. Furthermore, because rat G-CSF is not available, human G-CSF has been used which requires much higher dosages (200ug/kg) for comparable changes in circulating neutrophil numbers. To better assess the potential detrimental or beneficial effects of G-CSF pretreatment in pneumonia, we have now completed studies evaluating the effects of prophylactic canine G-CSF in a canine model w have developed of both lobar and diffuse bacterial pneumonia. In this model we have found that, similar to our rat model, prophylactic G-CSF does worsen lung injury. In contrast to the rat however, and similar to what we saw with peritonitis in the canine, G-CSF does improve survival. In early analysis this survival benefit appears related to improved cardiovascular function. In additional studies with this canine model of pneumonia we plan to assess the effects of G-CSF pretreatment to augment host defense, in combination with MAb's directed against either leukocyte or endothelial adhesion receptors to limit inflammatory lung injury. These studies are being done in collaboration with Dr. Robert Rothlein from Boehringer Ingelheim.
