ROLE OF TUMOR-NECROSIS-FACTOR-ALPHA ON AI RWAY SMOOTH-MUSCLE CELLS

Asthma is a disease characterized by a bronchial hyperresponsiveness ( BHR). Although the underlying mechanisms that induce this increase in bronchial reactivity remain unknown, evidence suggests that the inflam matory process present in the airways could play an important role in the development of BHR. This latter may result from alterations in the intrinsic properties of airway smooth muscle induced by inflammatory mediators. Tumor necrosis factor alpha :(TNF alpha), a pro-inflammator y cytokine, appears to be an interesting candidate considering on one hand that it is able to induce, in human and in animals, a BHR to diff erent inhaled pharmacological agents and on the other hand that high l evels of TNF alpha were found in asthmatic airways. Our studies show t hat TNF alpha induces in a direct manner somes modifications of the br onchial smooth muscle which can underly an increased muscle contractil ity. These modifications include an alteration of the intracellular ca lcium homeostasis and an increase in the mitogen capacity of the human airway smooth muscle cells. Using antibodies directed against the two existing receptor type of TNF alpha (TNFRp55 and TNFRp75) and TNF alp ha-analogs obtained by directed mutagenesis, we showed that these modi fications result from the activation of TNFRp55. The implication of th is receptor in the other pathophysiologic characteristics of asthma is also discussed in this review.