Title:Oxidative and Nitrosative Stress in the Pathogenesis of Obstructive Lung Diseases of Increasing Severity
Volume: 27
Issue: 42
Author(s): Antonino Di Stefano*, Mauro Maniscalco, Bruno Balbi and Fabio L.M. Ricciardolo
Affiliation:
- Divisione di Pneumologia e Laboratorio di Immunopatologia dell’Apparato Cardio Respiratorio, Istituti Clinici Scientifici Maugeri SpA, Societa Benefit, IRCCS, Veruno,Italy
Keywords:
Oxidative stress, asthma, COPD, inflammation, nitrosative stress, pathogenesis.
Abstract: The imbalance between increased oxidative agents and antioxidant defence mechanisms
is central in the pathogenesis of obstructive lung diseases such as asthma and COPD. In
these patients, there are increased levels of reactive oxygen species. Superoxide anions (O2
-),
Hydrogen Peroxide (H2O2) and hydroxyl radicals (•OH) are critical for the formation of further
cytotoxic radicals in the bronchi and lung parenchyma. Chronic inflammation, partly induced
by oxidative stress, can further increase the oxidant burden through activated phagocytic
cells (neutrophils, eosinophils, macrophages), particularly in severer disease states. Antioxidants
and anti-inflammatory genes are, in fact, frequently downregulated in diseased patients.
Nrf2, which activates the Antioxidant Response Element (ARE) leading to upregulation
of GPx, thiol metabolism-associated detoxifying enzymes (GSTs) and stressresponse
genes (HO-1) are all downregulated in animal models and patients with asthma and
COPD. An exaggerated production of Nitric Oxide (NO) in the presence of oxidative stress
can promote the formation of oxidizing reactive nitrogen species, such as peroxynitrite
(ONO2
-), leading to nitration and DNA damage, inhibition of mitochondrial respiration, protein
dysfunction, and cell damage in the biological systems. Protein nitration also occurs by
activation of myeloperoxidase and H2O2, promoting oxidation of nitrite (NO2
-). There is increased
nitrotyrosine and myeloperoxidase in the bronchi of COPD patients, particularly in
severe disease. The decreased peroxynitrite inhibitory activity found in induced sputum of
COPD patients correlates with pulmonary function. Markers of protein nitration - 3-
nitrotyrosine, 3-bromotyrosine, and 3-chlorotyrosine - are increased in the bronchoalveolar
lavage of severe asthmatics. Targeting the oxidative, nitrosative stress and associated lung inflammation
through the use of either denitration mechanisms or new drug delivery strategies
for antioxidant administration could improve the treatment of these chronic disabling obstructive
lung diseases.
