PHARMACOLOGICAL REDUCTION IN TUMOR-NECROSIS-FACTOR ACTIVITY OF PULMONARY ALVEOLAR MACROPHAGES

Tumor necrosis factor-alpha (TNF), an inflammatory cytokine released b y macrophages, may be a mediator of lung injury during septicemia. We previously reported that the cyclooxygenase inhibitor ibuprofen and hi stamine receptor antagonists cimetidine (H-2 antagonist) and diphenhyd ramine (H-1 antagonist) attenuate lung injury and reduce circulating T NF surges during porcine sepsis. Since pulmonary alveolar macrophages (PAM) may participate in early sepsis by producing TNF, we hypothesize d that the TNF activity of PAM is reduced by ibuprofen, cimetidine, an d diphenhydramine. To test this, we examined changes in PAM-derived TN F bioactivity and cell viability of freshly isolated porcine PAM durin g exposure to bacterial endotoxin (LPS), ibuprofen, cimetidine, and di phenhydramine. The TNF activity (% L929 cytotoxicity of PAM conditione d medium) was elevated in LPS-stimulated PAM cultures (15 to 25% incre ase at 1 to 6 h and 40 to 43 % increase at 6 to 48 h, compared with no n-LPS-stimulated cultures), and ibuprofen (150 mug/ml) added with LPS decreased the TNF activity for 24 h (20 to 28% reduction at 1 to 24 h) . Ibuprofen added 1 h after LPS was less effective in reducing the PAM -derived TNF activity (20 to 22% reduction at 2 to 6 h). Cimetidine (I 12 mug/ml) reduced the TNF activity of LPS-stimulated PAM cultures du ring the first 4 h of LPS exposure (15 to 24 % decrease at 1 to 4 h). Diphenhydramine (150 mug/ml) attenuated the PAM-derived TNF activity b ut also decreased viability of PAM, indicating a toxic effect of this agent on PAM. These findings suggest that ibuprofen and cimetidine att enuate the TNF bioactivity of PAM and that the cytotoxicity of agents that reduce TNF activity must be noted concurrently with studies exami ning attenuation of cellular TNF activity.