PHARMACOKINETICS AND CATABOLISM OF TUMOR-NECROSIS-FACTOR-ALPHA IN RATLUNGS

The role of the lungs in the catabolism of tumor necrosis factor alpha (TNF-alpha) either in normal rats, or in rats subjected to an acute c igarette smoking episode has been evaluated by using isolated and perf used lung preparations. After administration of TNF-alpha into the lun g perfusion medium, there was no clearance of the cytokine in both con trol and smoker rat lungs and only 0.2 +/- 0.1% of the administered do se was recovered in the bronchoalveolar lavage fluid. When TNF-alpha w as instilled into the bronchoalveolar tree, concentrations of the cyto kine in the perfusate increased progressively so that after 3 h up to 68.8 +/- 8% and 52.7 +/- 11.4% of the administered dose had been trans ferred from the bronchial lumen to the perfusion medium of either cont rol or smoker rat lungs, respectively, the latter values being signifi cantly lower (p less than or equal to 0.05) than those obtained in con trol lungs. Moreover, total recoveries of TNF-alpha evaluated in smoke r rat lungs (65.5 +/- 10.2%) were also significantly lower than those observed in control rat lungs (82.8 +/- 7.1%). In conclusion, it appea rs that transfer of TNF-alpha is almost exclusively unidirectional, fr om the alveolar space to the plasma pool with partial degradation duri ng the transalveolar passage. These results may be useful when attempt ing to deliver TNF-alpha by aerosol.