Lung oxidative damage by hypoxia

Abstract

One of the most important functions of lungs is to maintain an adequate oxygenation in the organism. This organ can be affected by hypoxia facing both physiological and pathological situations. Exposure to this condition favors the increase of reactive oxygen species from mitochondria, as from NADPH oxidase, xanthine oxidase/reductase, and nitric oxide synthase enzymes, as well as establishing an inflammatory process. In lungs, hypoxia also modifies the levels of antioxidant substances causing pulmonary oxidative damage. Imbalance of redox state in lungs induced by hypoxia has been suggested as a participant in the changes observed in lung function in the hypoxic context, such as hypoxic vasoconstriction and pulmonary edema, in addition to vascular remodeling and chronic pulmonary hypertension. In this work, experimental evidence that shows the implied mechanisms in pulmonary redox state by hypoxia is reviewed. Herein, studies of cultures of different lung cells and complete isolated lung and tests conducted in vivo in the different forms of hypoxia, conducted in both animal models and humans, are described.

Figure 1

Proposed mechanisms (and effects) for the ROS generation in lungs exposed to hypoxia.

Figure 2

Inhibitors for ROS generation and antioxidants used to study the pulmonary oxidative damage by hypoxia. NOX inhibitors: diphenyleneiodonium (DPI) [, –73, 91, 207]; peroxisome proliferator-activated receptor (PPARγ) [79]; 4-(2-Aminoethyl) benzenesulfonyl fluoride (AEBSF) [74]; apocynin [42, 207]. NOS inhibitors: N^G-monomethyl-L-arginine (L-NMMA): inhibitor of the three isoforms [31]; N-(3-(aminomethyl)benzyl) acetamidine (1400 W) and S-methylisothiourea sulfate (SMT): inhibitors of iNOS [31, 59]; L-NG-nitroarginine (L-NNA): inhibitor of eNOS and nNOS [59, 182]. Mitochondrial inhibitors: complex I: rotenone [38, 40]; diphenyleneiodonium (DPI) [, –73, 91], 1-methyl-4-phenylpyridinium (MPP⁺) [75]. Complex II: 3-nitropropionic acid thenoyltrifluoroacetone: (3-NPA) [208]. Complex III: antimycin A [38, 40, 208]; myxothiazol [40, 42]. Complex IV: cyanide [40]. Enzymatic antioxidants: Catalase [40, 45, 51, 91, 209]; SOD [37, 49, 91]; Ec-SOD [90]; glutathione peroxidase [49]. Nonenzymatic antioxidants: N-acetylcysteine (NAC) [89, 209]; vitamin E [4]; flavonoids [186]; nitro blue tetrazolium (NBT) [–32]; pyrrolidine dithiocarbamate (PDTC) [42, 209]; U74389G [91]. XO/XD inhibitors: allopurinol [89]; tungsten [85]. Others: clodronate, acts by decreasing the number of macrophages.