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 factor alpha (TNF alpha), an important mediator of sepsis, on in vitro hamster 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 alpha (0.1 ng/ml) (n = 5); (3) TNF alpha (500 ng/ml) (n = 5); and (4) TNF alpha (500 ng/ml) plus indomethacin (10(-6)) (n = 5). Baseline contractile parameters measured at optimal length included twitch and tetanic tension, half relaxation time, time to peak tension, force frequency response (10-80 Hz), and fatigability in response to repetitive stimulation. After 90-min incubation in one of the solutions, an identical stimulation protocol was repeated. Initial twitch and tetanus parameters were similar between groups. Maximal twitch tension and tetanic tension decreased significantly, as did tetanic stimulations at 10-80 Hz in the TNF group (500 ng/ml) (p < 0.05). Coincubation with indomethacin decreased but did not completely abolish the changes in diaphragm function caused by the higher dose of TNF. There were no significant changes in twitch or tetanus parameters, or in response to repetitive stimulation after incubation in the lower dose TNF group (0.1 ng/ml). We conclude that TNF causes impairment of in vitro diaphragm contractility at high incubation concentrations of TNF and that this effect can be partially blocked by prostaglandin synthetase inhibition. No significant deleterious effect on in vitro contractility was detected at concentrations of TNF similar to serum levels in human sepsis.