Tumor necrosis factor-a suppresses the ventilatory hypoxic response via nitric oxide dependent pathways

Abstract

TNF-α is a major inflammatory cytokine produced during an acute phase of the immune response to infection and inflammation. It had been shown that the level of TNF-α and IL-1β increases in hypoxia, load on the respiratory system and many respiratory diseases. Recently we demonstrated that elevated TNF-α level in blood reduces the sensitivity of the hypoxic chemoreception, thereby worsening the compensatory capabilities of the respiratory system. The mechanisms by which TNF-α impairs respiratory chemoreflex are still not clear, and may involve multiple inflammatory molecules. The aim of this study were to examine the hypothesis that the ability of TNF-α to reduce the hypoxic ventilatory response may be mediated by NO-dependent ways. The experiments were performed on tracheostomized anaesthetized rats. We studied the effects of intravenous administration of TNF-α during inhibition of NO-synthase. In order to we used L-NAME NO-synthase nonspecific inhibitor that was injected in the tail vein for 10 minutes before the administration of TNF-α. The ventilatory hypoxic response was measured by using rebreathing techniques before and after injections of L-NAME and TNF-α. During the hypoxic rebreathing experiments, was found that the increase of TNF-α in blood weakens the respiratory response to hypoxia. The ventilatory, tidal volume and mean inspiratory flow responses decreased by 27%, 40% and 27% respectively. The maximum effect was observed at 40 minutes of the cytokines action. L-NAME pretreatment eliminated these respiratory effects of TNF-α. Thus the data indicate that the ability of TNF-α to reduce the ventilatory hypoxic response is mediated by the NO-dependent pathway.