INDUCTION OF HYPERRESPONSIVENESS IN HUMAN AIRWAY TISSUE BY NEUTROPHILS - MECHANISM OF ACTION

Background The two main features of asthma are bronchial hyperresponsi veness and inflammation. The inflammatory response in asthma consists of infiltration and activation of a variety of inflammatory cells incl uding neutrophils. Our previous studies have shown that stimulated neu trophil supernatants cause hyperresponsiveness of human bronchial tiss ue in vitro. Objective To investigate the effect of the sensitization status of the tissue and the albumin concentration used to prepare sup ernatants on the response of human bronchial tissue to stimulated neut rophil supernatants. Methods Neutrophil supernatants were prepared fro m human isolated blood in the presence of varying concentrations of al bumin (0%, 0.1% and 4%). Neutrophil supernatants were added to sensiti zed and non-sensitized human isolated bronchial tissue which was stimu lated with electrical field stimulation (EFS) (20 s every 4 min). Rece ptor antagonists specific for the prostaglandin and thromboxane (10(-7 ) M GR32191), platelet activating factor (10(-6) M WEB 2086), leukotri ene D-4 (10(-6) M MK-679) and neurokinin A (10(-7) M SR48968) receptor s were used to identify neutrophil products responsible for the effect s observed in the bronchial tissue. Results In non-sensitized human br onchial tissue, stimulated neutrophil supernatants induced a direct co ntraction in the presence of 0% and 0.1% but not 4% albumin. This cont raction was due to leukotriene D-4 as MK-679 completely inhibited the contraction. In contrast, stimulated neutrophil supernatants increased responsiveness of sensitized human bronchial tissue to EFS. The incre ased responsiveness was observed only in the presence of 0.1% albumin, with the site of modulation likely to be prejunctional on the parasym pathetic nerve. The increased responsiveness was not inhibited by any of the antagonists tested. Conclusion Sensitization status of the tiss ue and albumin concentration effect the responsiveness of human bronch ial tissue to stimulated neutrophil supernatant. Our results suggest a possible role for neutrophils in hyperresponsiveness.