Role of tumor necrosis factor-alpha in endotoxin-induced lung parenchymal hyporesponsiveness in mice

Although changes in airway responsiveness in pulmonary inflammation are com monly related to the action of infiltrated leukocytes, our previous report suggested a direct role of inflammatory cytokines in LPS-induced lung hypor esponsiveness. The aim of this study was to define if cytokines detected in the BALF (bronchoalveolar lavage fluid) of intratracheal LPS-treated mice could be, at least in part, responsible for 5-HT (5-hydroxytryptamine) lung hyporeactivity. Our results show that intratracheal instillation of LPS in duced a time-dependent increase in IL-(interleukin-)1 beta, IL-6, and TNF ( tumor necrosis factor)alpha in the BALF. Cytokine production was paralleled by 5-HT lung hyporesponsiveness, and intratracheal administration of TNF a lpha proved to be very efficient in inhibiting 5-HT responsiveness. In addi tion, systemic treatment with rolipram, an inhibitor of TNF alpha productio n, was paralleled by a significant recovery of lung responsiveness. On the contrary, IL-1 beta and IL-6 were not demonstrated to play a relevant role in 5-HT hyporesponsiveness. It is concluded that TNF alpha could be a cruci al mediator of LPS-induced lung hyporesponsiveness. (C) 2001 Elsevier Scien ce Inc. All rights reserved.