Participation of leukotriene D4 and tumor necrosis factor on lipopolysaccharide-induced airway hyperresponsiveness in guinea pigs.

Abstract

In guinea pigs, a marked increase in airway responsiveness to acetylcholine (Ach) was observed at 2 h after lipopolysaccharide (LPS) inhalation. To examine the mediators responsible for the airway hyperresponsiveness, the changes of peptide-leukotrienes (LTs), tumor necrosis factor (TNF), interleukin-1 (IL-1), histamine and 5-hydroxytryptamine (5-HT) levels in bronchoalveolar lavage fluid (BALF) were measured. Airway responsiveness to Ach reached a peak 2 h after LPS inhalation. The influx of neutrophil into BALF increased gradually and reached a peak 24 h after LPS inhalation. After the inhalation of LPS, LTD4 and TNF contents in BALF increased within the first 2 h after LPS inhalation. However, other mediators were not detected or increased 6 h after LPS inhalation. Aeroinhalation of LTD4 and murine recombinant TNF-alpha caused airway hyperresponsiveness in guinea pigs. In addition, a LTD4 antagonist, BAYx7195, and an inhibitor of TNF, pentoxifylline, inhibited the LPS-induced airway hyperresponsiveness. These results suggest that LTs and/or TNF play an important role in the onset of airway hyperresponsiveness in guinea pigs.