There have been reports that the administration of TNF produces many of the cardiopulmonary changes seen with endotoxin (LPS). We asked whether all of LPS effects can be mimicked by TNF infusion. The effects of infusion of (human recombinant) TNF (50 micrograms/kg/30 min) and LPS (3 micrograms/kg/30 min) on permeability characteristics of sheep lungs were compared. Thirteen sheep were chronically instrumented for cardiopulmonary studies including lung lymph data. Infusion of LPS and TNF result in an increase of body temperature and lung lymph protein clearance (measured as the product of Lymph Flow and Lymph/Plasma Protein Ratio). The two responses had entirely different time courses. This might be related to the significantly longer period of pulmonary hypertension (MPAP) with LPS, which was only transient with TNF. Similar differences in plasma levels of thromboxane B2 (TxB2) were also noted. There were also differences in leukocyte kinetics, arterial blood gases, and plasma lactate levels. This indicates that although TNF infusion results in an increased pulmonary microvascular permeability, this event occurs without concomitant changes in thromboxane metabolism and exhibits time characteristics somewhat different from endotoxin.