CONTROLLED TRIALS OF RG-CSF AND CD11B-DIRECTED MAB DURING HYPEROXIA AND ESCHERICHIA-COLI PNEUMONIA IN RATS

We studied the effects of inhibiting and augmenting neutrophil functio n by using an immunocompetent rat model of infectious and hyperoxic lu ng injury. After intrabronchial Escherichia coli challenge at all frac tional inspired O-2 (FIO2) values studied (FIO2 = 0.21, 0.60, and 0.95 ) and after lethal O-2 exposure alone (FIO2 = 0.90), lung injury, as m easured by histological and physiological changes, was reduced by a CD 11b/CD18-directed monoclonal antibody (MAb, 1B6, P < 0.05 vs. controls ) but was increased by recombinant granulocyte colony-stimulating fact or (rG-CSF; P < 0.05 vs. control; MAb 1B6 vs. rG-CSF, P < 0.004), Pulm onary neutrophil counts were reduced by MAb 1B6 (P < 0.04) and increas ed by rG-CSF (P < 0.0004) compared with control animals. However, desp ite antibiotics, MAb 1B6 and rG-CSF both significantly increased the r elative risk of death, independent of O-2 concentration, during E. col i pneumonia (1.74 x 1.20 and 2.39 x/divided by 1.19, respectively, eac h P < 0.01). During lethal hyperoxia, MAb 1B6 increased the relative r isk of death (1.76 x 1.28, P < 0.16), whereas rG-CSF had no effect on survival (0.97 x 1.28, P = 0.89). Thus inhibition of neutrophil functi on attenuated and enhancement worsened lung injury in response to infe ctious and hyperoxic challenges, supporting a pathophysiological role of the neutrophil in these processes. However, it is problematic that MAb 1B6 therapy, despite preventing lung damage, ultimately worsened h ost defenses and survival. Furthermore, rG-CSF also adversely affected survival during infectious lung injury, demonstrating the inherent ri sks of inhibiting or augmenting neutrophil function in an immunocompet ent host during infection.