OXIDANT-PROTEASE INTERACTION IN THE LUNG - PROSPECTS FOR ANTIOXIDANT THERAPY

In inflammatory lung disorders, oxidants and proteases complement each other in their potential to destroy lung parenchyma. It is therefore rational to combine therapeutic strategies aimed at augmenting the ant iproteolytic defenses of the lung in diseases such as emphysema with a ntioxidant strategies. In the healthy lung, the oxidant burden is bala nced by the local antioxidant defenses. However, both an increased oxi dant burden and/or decreased antioxidant defenses may reverse the phys iologic oxidant-antioxidant balance in favor of oxidants, leading to l ung injury. This concept points to an obvious therapeutic strategy: au gmentation of the antioxidant screen of the lung to prevent oxidant-me diated tissue damage. Studies using reduced glutathione (GSH), the maj or pulmonary antioxidant, as a model therapeutic agent demonstrated th at GSH can be administered directly to the respiratory epithelial surf ace by aerosol and is fully functional as an antioxidant both in vitro and in vivo. In pulmonary diseases such as idiopathic pulmonary fibro sis or following HN infection, GSH aerosol therapy not only normalized deficient pretherapy GSH levels in the lung, but was capable of favor ably influencing cellular events such as oxidant release by pulmonary inflammatory cells, The same was true for oral antioxidant therapy wit h N-acetylcysteine, a glutathione precursor. These results suggest tha t it is possible to use antioxidants to reverse the imbalance between oxidants and antioxidants at the site of oxidant injury to prevent the progressive tissue damage in lung disorders characterized by high oxi dant states, Antioxidants, alone and in combination with antiproteases , merit further long-term studies for clinical therapy.