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 ne utrophil-derived MPO and H2O2 produced by alveolar inflammatory cells (alveolar macrophages (AM) and polymorphonuclear neutrophils (PMN)) ha s the ability to spontaneously inactivate, in vitro, the alpha(1) prot einase inhibitor (alpha(1)PI). This inactivation can induce a desequil ibrium of the protease-antiprotease balance in the lungs. In this stud y, we investigated the ability of glutathione to protect alpha(1)PI. I n 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 activa ted cells. This protection has been computed in a cellular experimenta tion (AM and MPO-system) with a 50% inhibitory concentration of 62 mu M. Moreover, glutathione has an important inhibitory effect directly o n H2O2, released by PMA-stimulated AM (IC50 = 30 mu M) or PMA stimulat ed 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 c ellular experiment. With this in vitro demonstrated effectiveness, glu tathione as a therapeutic antioxidant, via the aerosol, has been propo sed, in order to prevent tissue damage, inflicted by an excess of acti vated phagocytic cells, in some lung diseases such as smoking patients with emphysema.