PROTECTIVE ROLE OF GLUTATHIONE ON ALPHA-1 PROTEINASE-INHIBITOR INACTIVATION BY THE MYELOPEROXIDASE SYSTEM - HYPOTHETICAL STUDY FOR THERAPEUTIC STRATEGY IN THE MANAGEMENT OF SMOKERS EMPHYSEMA

In smoking subjects with obvious emphysema, the interaction between neutrophil-derived MPO and H2O2 produced by alveolar inflammatory cells (alveolar macrophages (AM) and polymorphonuclear neutrophils (PMN)) has the ability to spontaneously inactivate, in vitro, the alpha(1) proteinase inhibitor (alpha(1)PI). This inactivation can induce a desequilibrium of the protease-antiprotease balance in the lungs. In this study, we investigated the ability of glutathione to protect alpha(1)PI. In a cellular model of alpha(1)PI inactivation mimicking the effects of alveolar inflammatory cells present in the lower respiratory tract of smoking patients with emphysema, we demonstrated that glutathione can protect alpha(1)PI against the oxidative inactivation by these activated cells. This protection has been computed in a cellular experimentation (AM and MPO-system) with a 50% inhibitory concentration of 62 mu M. Moreover, glutathione has an important inhibitory effect directly on H2O2, released by PMA-stimulated AM (IC50 = 30 mu M) or PMA stimulated PMN (IC50 = 70 mu M). The mechanism, which governs glutathione may be a result of a scavenging effect on H2O2 as demonstrated in a free cellular experiment. With this in vitro demonstrated effectiveness, glutathione as a therapeutic antioxidant, via the aerosol, has been proposed, in order to prevent tissue damage, inflicted by an excess of activated phagocytic cells, in some lung diseases such as smoking patients with emphysema.