HIGH-DOSE TUMOR-NECROSIS-FACTOR-ALPHA PRODUCES AN IMPAIRMENT OF HAMSTER DIAPHRAGM CONTRACTILITY - ATTENUATION WITH A PROSTAGLANDIN INHIBITOR

We have investigated the influence of the cytokine tumor necrosis fact or alpha (TNF alpha), an important mediator of sepsis, on in vitro ham ster diaphragm contractility. Costal diaphragm strips were excised and mounted on an experimental apparatus consisting of a force transducer and servomotor. Preparations were randomized to incubation in one of the following solutions: (1) indomethacin 10(-6) M (n = 5); (2) TNF al pha (0.1 ng/ml) (n = 5); (3) TNF alpha (500 ng/ml) (n = 5); and (4) TN F alpha (500 ng/ml) plus indomethacin (10(-6)) (n = 5). Baseline contr actile parameters measured at optimal length included twitch and tetan ic tension, half relaxation time, time to peak tension, force frequenc y response (10-80 Hz), and fatigability in response to repetitive stim ulation. After 90-min incubation in one of the solutions, an identical stimulation protocol was repeated. Initial twitch and tetanus paramet ers were similar between groups. Maximal twitch tension and tetanic te nsion decreased significantly, as did tetanic stimulations at 10-80 Hz in the TNF group (500 ng/ml) (p < 0.05). Coincubation with indomethac in decreased but did not completely abolish the changes in diaphragm f unction caused by the higher dose of TNF. There were no significant ch anges in twitch or tetanus parameters, or in response to repetitive st imulation after incubation in the lower dose TNF group (0.1 ng/ml). We conclude that TNF causes impairment of in vitro diaphragm contractili ty at high incubation concentrations of TNF and that this effect can b e partially blocked by prostaglandin synthetase inhibition. No signifi cant deleterious effect on in vitro contractility was detected at conc entrations of TNF similar to serum levels in human sepsis.