Oxidant-Antioxidant Balance in Acute Lung Injury

doi:10.1378/chest.122.6_suppl.314S

Chest

Volume 122, Issue 6, Supplement, December 2002, Pages 314S-320S

https://doi.org/10.1378/chest.122.6_suppl.314S Get rights and content

ARDS is a disease process that is characterized by diffuse inflammation in the lung parenchyma. The involvement of inflammatory mediators in ARDS has been the subject of intense investigation,¹ ² and oxidant-mediated tissue injury is likely to be important in the pathogenesis of ARDS.³ In response to various inflammatory stimuli, lung endothelial cells, alveolar cells, and airway epithelial cells, as well as activated alveolar macrophages, produce both nitric oxide and superoxide, which may react to form peroxynitrite, which can nitrate and oxidize key amino acids in various lung proteins, such as surfactant protein A, and inhibit their functions. The nitration and oxidation of a variety of crucial proteins present in the alveolar space have been shown to be associated with diminished function in vitro and also have been identified ex vivo in proteins sampled from patients with acute lung injury (ALI)/ARDS. Various enzymes and low-molecular-weight scavengers that are present in the lung tissue and alveolar lining fluid decreased the concentration of these toxic species. The purpose of this brief chapter is to review the results from various studies demonstrating increased levels of reactive oxygen-nitrogen intermediates in the alveolar spaces of patients with ALI/ARDS.

Section snippets

Oxidants and Lung Injury

As mentioned before, the generation of oxidants during inflammatory conditions has been well-documented. The unequivocal measurement of ROS in biological systems is very difficult because the biological half-lives of the molecules are in the range of nanoseconds to milliseconds in length, coupled with the fact that the concentrations may vary dramatically within the time course of a particular disease state. However, measurements of stable by-products such as nitrate and nitrite, and modified

Increased Levels of NO in the BALF and Edema Fluid of Patients With ARDS

ARDS is a disease process that is characterized by diffuse inflammation in the lung parenchyma. Concentrations of nitrate and nitrite (NOx), which are the stable breakdown by-products of NO, can be measured in biological fluids using the Greiss reaction. NOx concentrations were significantly higher than normal in the BALF from patients who were at risk for developing ARDS, as well as in the BALF of those with ARDS,¹⁵ and remained elevated throughout the course of ARDS. In all cases, the

Evidence for the Existence of Nitrated Proteins In Vivo

Several studies have provided evidence that nitration reactions occur in vivo during inflammatory processes. 3-Nitrotyrosine residues, which are products of the addition of a nitro-group (NO₂) to the ortho position of the hydroxyl group of tyrosine, are stable end-products of RNS-mediated reactions. Therefore, they serve as footprints of RNS action, which are readily detectable by immunohistochemistry, enzyme-linked immunosorbent assay or high-pressure liquid chromatography (HPLC).³⁸

Oxidant-Antioxidant Balance in ARDS

While the direct measurements of oxidants poses problems, the monitoring of antioxidant concentrations and/or oxidant-antioxidant balance also has been assessed. For instance, selected antioxidants were measured including plasma ascorbate, a major plasma antioxidant, and were significantly decreased in patients with ongoing ARDS when compared to healthy control subjects.⁵² In addition, ubiquinol, a key lipid-soluble antioxidant residing in the membranes of the mitochondria, was significantly

Conclusion

How does the above information translate to the bedside care of the patient who has experienced a lung injury? The data presented herein indicate that stable decomposition products of both NO and intermediates generated by its reaction with ROS are detected in high concentrations in both the BALF and EF of patients who are at risk of developing ARDS or who have established ARDS. Levels of reactive species correlate both with the outcome of the disease and the severity of the injury to the

References (57)

Y Kuroki et al.
Chemical modification of surfactant protein A alters high affinity binding to rat alveolar type II cells and regulation of phospholipid secretion
J Biol Chem
(1988)
JM Fukuto et al.
Conversion of nitroxyl (HNO) to nitric oxide (NO) in biological systems: the role of physiological oxidants and relevance to the biological activity of HNO
Biochem Biophys Res Commun
(1993)
BA Freeman et al.
Hyperoxia increases oxygen radical production in rat lungs and lung mitochondria
J Biol Chem
(1981)
H Ischiropoulos et al.
Peroxynitrite formation from macrophage-derived nitric oxide
Arch Biochem Biophys
(1992)
NW Kooy et al.
Agonist-induced peroxynitrite production from endothelial cells
Arch Biochem Biophys
(1994)
MU Shiloh et al.
Phenotype of mice and macrophages deficient in both phagocyte oxidase and inducible nitric oxide synthase
Immunity
(1999)
A Kobayashi et al.
Expression of inducible nitric oxide synthase and inflammatory cytokines in alveolar macrophages of ARDS following sepsis
Chest
(1998)
JI Sznajder et al.
Increased hydrogen peroxide in the expired breath of patients with acute hypoxemic respiratory failure
Chest
(1989)
C Szabo et al.
Novel roles of nitric oxide in hemorrhagic shock
Shock
(1999)
A van der Vliet et al.
Formation of reactive nitrogen species during peroxidase-catalyzed oxidation of nitrite: a potential additional mechanism of nitric oxide-dependent toxicity
J Biol Chem
(1997)

S Zhu et al.

Nitration of surfactant protein A (SP-A) tyrosine residues results in decreased mannose binding ability

Arch Biochem Biophys

(1996)

ER Pacht et al.

Deficiency of alveolar fluid glutathione in patients with sepsis and the adult respiratory distress syndrome

Chest

(1991)

JA Leff et al.

Serum antioxidants as predictors of adult respiratory distress syndrome in patients with sepsis

Lancet

(1993)

G Johnson et al.

Cardioprotective effects of acidified sodium nitrite in myocardial ischemia with reperfusion

J Pharmacol Exp Ther

(1990)

JC Marshall

Inflammation, coagulopathy, and the pathogenesis of multiple organ dysfunction syndrome

Crit Care Med

(2001)

LB Ware et al.

The acute respiratory distress syndrome

N Engl J Med

(2000)

RG Spragg et al.

Alterations in adenosine triphosphate and energy charge in cultured endothelial and P388D1 cells after oxidant injury

J Clin Invest

(1985)

CG Cochrane et al.

Pathogenesis of the adult respiratory distress syndrome: evidence of oxidant activity in bronchoalveolar lavage fluid

J Clin Invest

(1983)

IY Haddad et al.

Nitric oxide and lung injury

IM Fierro et al.

Induction of NOS in rat blood PMN in vivo and in vitro: modulation by tyrosine kinase and involvement in bactericidal activity

J Leukoc Biol

(1999)

L Kobzik et al.

Nitric oxide synthase in human and rat lung: immunocytochemical and histochemical localization

Am J Respir Cell Mol Biol

(1993)

JM Hickman-Davis et al.

Surfactant protein A mediates mycoplasmacidal activity of alveolar macrophages

Am J Physiol

(1998)

C Sittipunt et al.

Nitric oxide and nitrotyrosine in the lungs of patients with acute respiratory distress syndrome

Am J Respir Crit Care Med

(2001)

WR Tracey et al.

Immunochemical detection of inducible NO synthase in human lung

Am J Physiol Lung Cell Mol Physiol

(1994)

CY Liu et al.

Increased level of exhaled nitric oxide and up-regulation of inducible nitric oxide synthase in patients with primary lung cancer

Br J Cancer

(1998)

YP Moodley et al.

Nitric oxide levels in exhaled air and inducible nitric oxide synthase immunolocalization in pulmonary sarcoidosis

Eur Respir J

(1999)

D Saleh et al.

Increased production of the potent oxidant peroxynitrite in the lungs of patients with idiopathic pulmonary fibrosis

Am J Respir Crit Care Med

(1997)

S Nicholson et al.

Inducible nitric oxide synthase in pulmonary alveolar macrophages from patients with tuberculosis

J Exp Med

(1996)

Cited by (272)

GSTP alleviates acute lung injury by S-glutathionylation of KEAP1 and subsequent activation of NRF2 pathway
2024, Redox Biology
Oxidative stress plays an important role in the pathogenesis of acute lung injury (ALI). As a typical post-translational modification triggered by oxidative stress, protein S-glutathionylation (PSSG) is regulated by redox signaling pathways and plays diverse roles in oxidative stress conditions. In this study, we found that GSTP downregulation exacerbated LPS-induced injury in human lung epithelial cells and in mice ALI models, confirming the protective effect of GSTP against ALI both in vitro and in vivo. Additionally, a positive correlation was observed between total PSSG level and GSTP expression level in cells and mice lung tissues. Further results demonstrated that GSTP inhibited KEAP1-NRF2 interaction by promoting PSSG process of KEAP1. By the integration of protein mass spectrometry, molecular docking, and site-mutation validation assays, we identified C434 in KEAP1 as the key PSSG site catalyzed by GSTP, which promoted the dissociation of KEAP1-NRF2 complex and activated the subsequent anti-oxidant genes. In vivo experiments with AAV-GSTP mice confirmed that GSTP inhibited LPS-induced lung inflammation by promoting PSSG of KEAP1 and activating the NRF2 downstream antioxidant pathways. Collectively, this study revealed the novel regulatory mechanism of GSTP in the anti-inflammatory function of lungs by modulating PSSG of KEAP1 and the subsequent KEAP1/NRF2 pathway. Targeting at manipulation of GSTP level or activity might be a promising therapeutic strategy for oxidative stress-induced ALI progression.
Repurposing methylene blue in the management of COVID-19: Mechanistic aspects and clinical investigations
2021, Biomedicine and Pharmacotherapy
The severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is the most recent coronaviruses, which has infected humans, and caused the disease COVID-19. The World Health Organization has declared COVID-19 as a pandemic in March 2020. The SARS-CoV-2 enters human hosts majorly via the respiratory tract, affecting the lungs first. In few critical cases, the infection progresses to failure of the respiratory system known as acute respiratory distress syndrome acute respiratory distress syndrome may be further associated with multi-organ failure and vasoplegic shock. Currently, the treatment of COVID-19 involves use of antiviral and anti-cytokine drugs. However, both the drugs have low efficacy because they cannot inhibit the production of free radicals and cytokines at the same time. Recently, some researchers have reported the use of methylene blue (MB) in COVID-19 management. MB has been used since a long time as a therapeutic agent, and has been approved by the US FDA for the treatment of other diseases. The additional advantage of MB is its low cost. MB is a safe drug when used in the dose of < 2 mg/kg. In this review, the applicability of MB in COVID-19 and its mechanistic aspects have been explored and compiled. The clinical studies have been explained in great detail. Thus, the potential of MB in the management of COVID-19 has been examined.
The role of nitric oxide in pleural disease
2021, Respiratory Medicine
Nitric oxide (NO) regulates various physiological and pathophysiological functions in the lungs. However, there is much less information about the effects of NO in the pleura. The present review aimed to explore the available evidence regarding the role of NO in pleural disease. NO, has a double-edged role in the pleural cavity. It is an essential signaling molecule mediating various physiological cell functions such as lymphatic drainage of the serous cavities, the immune response to intracellular multiplication of pathogens, and downregulation of neutrophil migration, but also induces genocytotoxic and mutagenic effects when present in excess. NO is implicated in the pathogenesis of asbestos-related or exudative pleural disease and mesothelioma. From a clinical point of view, the fraction of exhaled NO has been suggested as a potential non-invasive tool for the diagnosis of benign asbestos-related disorders. Under experimental conditions, NO-mimetics were found to attenuate hypoxia-induced therapy resistance in mesothelioma. Similarly, hybrid agents consisting of an NO donor coupled with a parent anti-inflammatory drug showed an enhancement of the anti-inflammatory activity of anti-inflammatory drugs. However, given the paucity of research work performed over the last years in this area, further research should be undertaken to establish reliable conclusions with respect to the feasibility of determining or targeting the NO signaling pathway for pleural disease diagnosis and therapeutic management.
The water-soluble non-starch polysaccharides from natural resources against excessive oxidative stress: A potential health-promoting effect and its mechanisms
2021, International Journal of Biological Macromolecules
Citation Excerpt :
Lung diseases refer to the manifestations of the lungs themselves or systemic diseases. Oxidative stress products can cause neutrophils to retain, recruit and activate in the lung microcirculation, and activate transcription factors to regulate the inflammatory mediators, which can result in the occurrence of lung diseases [69]. Studies of exhaled, plasma and bronchoalveolar lavage fluid in patients with chronic obstructive pulmonary disease (COPD) found significantly higher levels of lipid peroxidative metabolites and ethane content in the exhaled breath (a marker of oxidative stress).
The water-soluble non-starch polysaccharides isolated from natural resources have become research hotpots in the field of food science and human health due to widely distributed in nature and low toxicity. It has indicated that the health-promoting effect of water-soluble non-starch polysaccharides were partly attributable to against excessive oxidative stress. Indeed, excessive oxidative stress in the body has been reported in occurrence of disease. The water-soluble non-starch polysaccharides from natural resources exhibit antioxidant activity to against oxidative stress via scavenging free radicals promoting antioxidant enzymes activity and/or regulating antioxidant signaling pathways. In this review, the water-soluble non-starch polysaccharides as medicine agent and the factor affecting antioxidant as well as the relationship between oxidative stress and disease are summarized, and the mechanisms of water-soluble non-starch polysaccharides therapy in disease are also discussed. It will provide a theoretical basis for natural polysaccharides used for the treatment of diseases.
Methylene blue in covid-19
2021, Medical Hypotheses
SARS-CoV-2 infection generally begins in the respiratory tract where it can cause bilateral pneumonia. The disease can evolve into acute respiratory distress syndrome and multi-organ failure, due to viral spread in the blood and an excessive inflammatory reaction including cytokine storm. Antiviral and anti-cytokine drugs have proven to be poorly or in-effective in stopping disease progression, and mortality or serious chronic damage is common in severely ill cases. The low efficacy of antiviral drugs is probably due to late administration, when the virus has triggered the inflammatory reaction and is no longer the main protagonist. The relatively poor efficacy of anti-cytokine drugs is explained by the fact that they act on one or a few of the dozens of cytokines involved, and because other mediators of inflammation – reactive oxygen and nitrogen species – are not targeted. When produced in excess, reactive species cause extensive cell and tissue damage. The only drug known to inhibit the excessive production of reactive species and cytokines is methylene blue, a low-cost dye with antiseptic properties used effectively to treat malaria, urinary tract infections, septic shock, and methaemoglobinaemia. We propose testing methylene blue to contrast Covid-related acute respiratory distress syndrome, but particularly suggest testing it early in Covid infections to prevent the hyper-inflammatory reaction responsible for the serious complications of the disease.
Protective effects of pentoxifylline against chlorine-induced acute lung injury in rats
2023, BMC Pharmacology and Toxicology

View all citing articles on Scopus

: These studies were supported by grants HL51173, HL31197, and P30 DK54781 from the National Institutes of Health.

View full text

Chest

Oxidant-Antioxidant Balance in Acute Lung Injury*

Section snippets

Oxidants and Lung Injury

Increased Levels of NO in the BALF and Edema Fluid of Patients With ARDS

Evidence for the Existence of Nitrated Proteins In Vivo

Oxidant-Antioxidant Balance in ARDS

Conclusion

J Biol Chem

Biochem Biophys Res Commun

J Biol Chem

Arch Biochem Biophys

Arch Biochem Biophys

Immunity

Chest

Chest

Shock

J Biol Chem

Arch Biochem Biophys

Chest

Lancet

Cardioprotective effects of acidified sodium nitrite in myocardial ischemia with reperfusion

J Pharmacol Exp Ther

Inflammation, coagulopathy, and the pathogenesis of multiple organ dysfunction syndrome

Crit Care Med

The acute respiratory distress syndrome

N Engl J Med

Alterations in adenosine triphosphate and energy charge in cultured endothelial and P388D1 cells after oxidant injury

J Clin Invest

Pathogenesis of the adult respiratory distress syndrome: evidence of oxidant activity in bronchoalveolar lavage fluid

J Clin Invest

Nitric oxide and lung injury

Induction of NOS in rat blood PMN in vivo and in vitro: modulation by tyrosine kinase and involvement in bactericidal activity

J Leukoc Biol

Nitric oxide synthase in human and rat lung: immunocytochemical and histochemical localization

Am J Respir Cell Mol Biol

Surfactant protein A mediates mycoplasmacidal activity of alveolar macrophages

Am J Physiol

Nitric oxide and nitrotyrosine in the lungs of patients with acute respiratory distress syndrome

Am J Respir Crit Care Med

Immunochemical detection of inducible NO synthase in human lung

Am J Physiol Lung Cell Mol Physiol

Increased level of exhaled nitric oxide and up-regulation of inducible nitric oxide synthase in patients with primary lung cancer

Br J Cancer

Nitric oxide levels in exhaled air and inducible nitric oxide synthase immunolocalization in pulmonary sarcoidosis

Eur Respir J

Increased production of the potent oxidant peroxynitrite in the lungs of patients with idiopathic pulmonary fibrosis

Am J Respir Crit Care Med

Inducible nitric oxide synthase in pulmonary alveolar macrophages from patients with tuberculosis

J Exp Med

Oxidant-Antioxidant Balance in Acute Lung Injury^*