Antioxidants as Potential Therapeutics for Lung Fibrosis

Day, Brian J.

doi:10.1089/ars.2007.1916

Cited by 124 publications

(93 citation statements)

References 221 publications

(193 reference statements)

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“…The delayed nature of the ROS response suggests a reason why antioxidants such as N-acetylcysteine, GSH, or AEOL 10150 have beneficial effects even when administered after CEES exposure. The ability of a catalytic antioxidant like AEOL 10150 that has been show to have both SOD and catalase activity (Milano and Day, 2000;Day, 2008) to rescue cells from CEES further demonstrates a role for ROS in CEES injury.…”

Section: Discussionmentioning

confidence: 99%

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A Role for Mitochondrial Oxidative Stress in Sulfur Mustard Analog 2-Chloroethyl Ethyl Sulfide-Induced Lung Cell Injury and Antioxidant Protection

Gould¹,

White²,

Day³

2008

J Pharmacol Exp Ther

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Sulfur mustards (SMs) have been used as warfare agents since World War I and still pose a significant threat against civilian and military personnel. SM exposure can cause significant blistering of the skin, respiratory injury, and fibrosis. No antidote currently exists for SM exposure, but recent studies, using the SM analog 2-chloroethyl ethyl sulfide (CEES), have focused on the ability of antioxidants to prevent toxicity. Although antioxidants can prevent CEES-induced toxicity, the mechanisms by which these compounds are effective against SM agents are largely unknown. Using human bronchial epithelial (16HBE) cells and primary small airway epithelial cells, we show that CEES causes a significant increase in mitochondrial dysfunction as early as 4 h, which is followed by increases in mitochondrial reactive oxygen species (ROS), peaking 12 h after exposure. We also have identified a catalytic antioxidant metalloporphyrin that can rescue airway cells from CEES-induced toxicity when added 1 h after CEES exposure. In addition, the cytoprotective effects of the catalytic antioxidant are associated with correcting mitochondrial dysfunction ROS, DNA oxidation, and decreases in intracellular GSH. These findings suggest a role for oxidative stress in CEES toxicity and provide a rationale to investigate antioxidants as rescue agents in SM exposures.Bis(2-chloroethyl sulfide) or sulfur mustard (SM) was first synthesized in the late 1880s and since has been used as a warfare agent on a number of occasions. SM was first used in World War I and has been used in warfare as recently as the Iran-Iraq conflict of the late 1980s (Blanc, 1999). Although SM is less of a threat in warfare as it once was, it still posses a threat to military and civilian personnel because of current concerns for its deployment in a terrorist attack.Sulfur mustards are classic vesicating agents that mainly affect the skin, eyes, and respiratory system. There is no known antidote or specific treatment for SM exposure, and the current therapy is largely supportive. SM on the skin can be decontaminated with soap and water or a dilute bleach solution, but internal exposure, such as the respiratory system, is considerably more difficult to treat (Munro et al., 1990;Watson and Griffin, 1992). SM produces airway damage that includes necrosis, inflammation, and edema (Kehe and Szinicz, 2005). The exact mechanism of SM toxicity is unknown. 2-Chloroethyl ethyl sulfide (CEES; half mustard) is a monofunctional analog of SM (Fig. 1) that provides a useful model for SM injury without the need for a specialized containment facility. CEES, like SM, is an alkylating agent that can bind DNA and other macromolecules within the cell. Recent research into counteragents has focused on bolstering the endogenous antioxidant defenses by supplementation with N-acetyl-cysteine (McClintock et al

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Section: Discussionmentioning

confidence: 99%

“…We have developed a class of small-molecule metalloporphyrin catalytic antioxidants that possess both high SOD and catalase activities among other detoxifying properties (Day, 2008). Metalloporphyrins have also shown promise as therapeutic agents in several ROS-mediated animal models of human disease states (Day, 2004).…”

mentioning

confidence: 99%

A Role for Mitochondrial Oxidative Stress in Sulfur Mustard Analog 2-Chloroethyl Ethyl Sulfide-Induced Lung Cell Injury and Antioxidant Protection

Gould¹,

White²,

Day³

2008

J Pharmacol Exp Ther

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“…Consequently, disease-promoting processes that are at least in part caused by oxidative damage can be targeted by increasing the antioxidant defense, for example, by the intake of, or supplementation with, antioxidants (19,28,59). Consistently, antioxidant treatment with the SOD mimetic EUK207 during the first month after thorax irradiation was able to protect against excessive collagen synthesis during the fibrotic stage (25-30 weeks) (29).…”

Section: Murine Wt Bm (Xrt/bm) Cells From C57bl/6 Donor Mice Into Thementioning

confidence: 99%

Mesenchymal Stem Cell Therapy Protects Lungs from Radiation-Induced Endothelial Cell Loss by Restoring Superoxide Dismutase 1 Expression

Klein

Steens

Wiesemann

et al. 2017

Antioxidants & Redox Signaling

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Aims: Radiation-induced normal tissue toxicity is closely linked to endothelial cell (EC) damage and dysfunction (acute effects). However, the underlying mechanisms of radiation-induced adverse late effects with respect to the vascular compartment remain elusive, and no causative radioprotective treatment is available to date. Results: The importance of injury to EC for radiation-induced late toxicity in lungs after whole thorax irradiation (WTI) was investigated using a mouse model of radiation-induced pneumopathy. We show that WTI induces EC loss as long-term complication, which is accompanied by the development of fibrosis. Adoptive transfer of mesenchymal stem cells (MSCs) either derived from bone marrow or aorta (vascular wall-resident MSCs) in the early phase after irradiation limited the radiation-induced EC loss and fibrosis progression. Furthermore, MSC-derived culture supernatants rescued the radiation-induced reduction in viability and longterm survival of cultured lung EC. We further identified the antioxidant enzyme superoxide dismutase 1 (SOD1) as a MSC-secreted factor. Importantly, MSC treatment restored the radiation-induced reduction of SOD1 levels after WTI. A similar protective effect was achieved by using the SOD-mimetic EUK134, suggesting that MSCderived SOD1 is involved in the protective action of MSC, presumably through paracrine signaling. Innovation: In this study, we explored the therapeutic potential of MSC therapy to prevent radiation-induced EC loss (late effect) and identified the protective mechanisms of MSC action. Conclusions: Adoptive transfer of MSCs early after irradiation counteracts radiation-induced vascular damage and EC loss as late adverse effects. The high activity of vascular wall-derived MSCs for radioprotection may be due to their tissue-specific action. Antioxid. Redox Signal. 26, 563-582.

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“…Other researcher reported that bleomycin increases lung epithelial cell apoptosis in a reactive oxygen species (ROS)-dependent manner [28]. BLM-induced pulmonary fibrosis was explained by some authors who reported that the chemotherapeutic mechanism of BLM results from the chelation of iron ions with oxygen, which leads to production of DNA-cleaving superoxide, and also hydroxide free radicals [29].…”

Section: Discussionmentioning

confidence: 99%

Modulatory effects of green tea and aloe vera extracts on experimentally-induced lung fibrosis in rats: histological and immunohistochemical study

Salem¹,

El-Azab²,

Faruk³

2014

J Histol Histopathol

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Background: Pulmonary fibrosis (PF) is a multifactorial disease in the human. The existing therapeutic agents display unfavorable adverse effects. Consequently, the discovery of novel therapeutic agents for the prevention and treatment of PF remains a challenge. Aim of the work: Evaluation of the modulatory effect of green tea and aloe vera (AV) extracts on bleomycin induced pulmonary fibrosis in rats. Material and methods: Fifty adult male rats were utilized and divided equally into 5 groups. The first was served as control group, the second was the bleomycin (BLM) group (daily I.P. dose 10 mg/kg body weight for 10 days), the third was the green tea (GTE) group which was given daily oral dose of GTE (150 mg/ kg b.w.) for 14 days with concomitant IP administration of BLM for 10 consecutive days, the fourth was the Aloe vera (AV) group which was given daily oral dose of AV (300 mg/kg b.w.) for 14 days with concomitant IP administration of BLM for 10 consecutive days, the fifth was the GTE and AV group. Lung samples were taken 14 days after the treatment. Paraffin sections were prepared for histological; H&E and Masson's trichrome staining and immunohistochemical study. Results: Green tea group revealed normal bronchioles, alveoli with apparently thin interalveolar septa, few cellular infiltration and extravasated RBCs and induced a significant decreased (P≤0.05) in collagen fibers accumulation and in caspase-3 expression compared with BLM group. Group IV (AV) and group V (GTE and AV) revealed alveoli with apparently thicker interalveolar septa, more cellular infiltration, congested blood vessels and extravasated RBCs in comparison with GTE group. Group IV showed insignificant decreased (P≤0.05) in collagen fibers accumulation compared with BLM group while the decrease was significant in caspase-3 expression. Group V showed insignificant decreased (P≤0.05) in collagen fibers accumulation and in caspase-3 expression compared with BLM group. Conclusion: Green tea and aloe vera partially alleviate pulmonary fibrosis induced by bleomycin in rats. Supporting the potential benefits of using aloe vera and green tea as a potential novel therapeutic agents by diet.

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Antioxidants as Potential Therapeutics for Lung Fibrosis

Cited by 124 publications

References 221 publications

A Role for Mitochondrial Oxidative Stress in Sulfur Mustard Analog 2-Chloroethyl Ethyl Sulfide-Induced Lung Cell Injury and Antioxidant Protection

A Role for Mitochondrial Oxidative Stress in Sulfur Mustard Analog 2-Chloroethyl Ethyl Sulfide-Induced Lung Cell Injury and Antioxidant Protection

Mesenchymal Stem Cell Therapy Protects Lungs from Radiation-Induced Endothelial Cell Loss by Restoring Superoxide Dismutase 1 Expression

Modulatory effects of green tea and aloe vera extracts on experimentally-induced lung fibrosis in rats: histological and immunohistochemical study

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