Role of Free Radicals in Lung Injury

doi:10.1378/chest.89.6.859

Chest

Volume 89, Issue 6, June 1986, Pages 859-863

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Free radicals (and other toxic metabolites of oxygen) are generated in most cells as a consequence of normal metabolic processes, but cells are protected from injury by antioxidant mechanisms. Several forms of lung injury appear to result from generation of toxic metabolites of oxygen in quantitites which exceed the antioxidant capacity of lung cells. Several manipulations which prevent free radical production or accumulation or enhance antioxidant capacity of lung tissue may prove to be useful therapeutically in acute and chronic diseases of the lungs.

Section snippets

Acute Lung Injury (Adult Respiratory Distress Syndrome [ARDS])

A remarkable array of clinical settings is associated with noncardiogenic pulmonary edema and respiratory failure, described as ARDS. Because the pathophysiology and pathology are similar regardless of etiology, it is tempting to infer that the pathogenesis is similar as well. Such inferences have led investigators to search for common pathogenetic events with the hope that a single intervention might be effective, regardless of the clinical setting. Toxic metabolites of oxygen appear to be

Emphysema

A less direct role for free radicals in lung injury is typified by current notions about the pathogenesis of pulmonary emphysema. The discovery that patients deficient in alpha-1 proteinase inhibitor are especially susceptible to development of emphysema led to the theory that emphysema may result from an imbalance of proteolytic and antiproteolytic activities in the lungs.³⁰ Activated neutrophils release proteinases and especially neutrophil elastase may injure lung tissue. Alpha-1 proteinase

Free Radicals as a General Mechanism of Tissue Injury

In recent years, free radicals have been implicated in several forms of tissue injury. For example, when the gut is reperfused after a period of ischemia, there is severe tissue injury, and such injury can be prevented by agents which either scavenge free radicals or prevent their generation.³³ Similar data are available for ischemic injury to the kidneys.³⁴ McCord³⁵ has postulated that ischemic injury of the myocardium may occur by a similar mechanism.

The source of free radicals in

Therapeutic Implications

If endogenous generation of free radicals is the pathogenetic common denominator for lung injury, it is possible that pharmacologic therapies could be developed which would be broadly applicable. Several such therapies are under investigation.

Understanding the cellular biochemistry of free radical generation would permit interventions which prevent free radical generation. An example of such an approach is the protection from ischemia-reperfusion injury by the xanthine oxidase inhibitor,

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ROS and RNS act on NF-kB activation (nuclear kappa factor B) and AP-1 (activating protein 1) promoting cell proliferation and survival [49,50] and they are related to stabilization of HIF-1α (hypoxia induced factor 1 alpha), culminating in transcription of several genes involved in metabolism, survival and cell death, angiogenesis, invasion and metastasis [51] and in regulation of activated protein kinase by AMP serine/threonine (AMPK), which contributes to energy metabolism [52]. In conditions of increased inflammatory response, as those that occur in ALI, neutrophils and macrophages are the main cells for producing ROS [53,54]. However, there is also increased ROS production in endothelial and epithelial cells from the lung tissue [8,55].
Acute pulmonary injury, or acute respiratory distress syndrome, has a high incidence in elderly individuals and high mortality in its most severe degree, becoming a challenge to public health due to pathophysiological complications and increased economic burden. Acute pulmonary injury can develop from sepsis, septic shock, and pancreatitis causing reduction of alveolar airspace due to hyperinflammatory response. Oxidative stress acts directly on the maintenance of inflammation, resulting in tissue injury, as well as inducing DNA damages. Once the DNA is damaged, enzymatic DNA repair mechanisms act on lesions in order to maintain genomic stability and, consequently, contribute to cell viability and homeostasis. Although palliative treatment based on mechanical ventilation and antibiotic using have a kind of efficacy, therapies based on modulation of DNA repair and genomic stability could be effective for improving repair and recovery of lung tissue in patients with acute pulmonary injury.
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The increase in oxygen (O2) consumption during exercise induces the formation of reactive oxygen species (ROS) [4]. High levels of ROS are responsible for biomolecular damage such as peroxidation of membrane lipids [5], the formation of protein carbonyls, and even damage to intracellular DNA [6], which ultimately interferes with and changes intracellular metabolism and may even cause cell death [7]. Several studies have observed a correlation of increased ROS production with the onset of muscle fatigue [8,9] and acute muscle injury [10].
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Apart from these deleterious effects, arsenic trioxide (As2O3) also has been shown to have substantial efficacy in treating humans with relapsed or refractory acute promyelocytic leukemia (Zhang et al., 2010). As2O3-induced lung injury may be closely associated with reactive oxygen species (ROS) generation (Brigham, 1986; Bhattacharya and Haldar, 2012)Arsenic can induce ROS generation (Bhattacharya and Haldar, 2012), excessive generation of ROS has a direct toxic effect on lung endothelial cells, and may contribute to subsequent necrotic cell death (Brigham, 1986). Thus, synthetic scavengers of ROS and antioxidative agents could provide possible approaches to reduce the toxicity induced by chronic arsenic exposure.
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: This work was supported by Grant No. HL 19153 (SCOR in Pulmonary Vascular Diseases) from the National Heart, Lung and Blood Institute and grants from the John W. Cooke, Jr., and Laura W. Cooke Fund for Lung Research; The Hugh J. Morgan Fund for Cardiology donated by the Martha Washington Straus−Harry H. Straus Foundation, Inc.; the Upjohn Company and the Bernard Werthan, Sr. Fund for Pulmonary Research.

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