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N-Acetyl cysteine abrogates silver-induced reactive oxygen species in human cells without altering silver-based
Kush N Shah1, Parth N Shah1, Andrew R Mullen2
1Department of Microbial Pathogenesis & Immunology, Texas A&M University Health Science Center, College Station, TX, USA.
Abstract:
Silver-based antimicrobials are widely used topically to treat infections associated with multi-drug resistant (MDR) pathogens. Expanding this topical use to aerosols to treat lung infections requires understanding and preventing silver toxicity in the respiratory tract. A key mechanism resulting in silver-induced toxicity is the production of reactive oxygen species (ROS). In this study, we have verified ROS generation in silver-treated bronchial epithelial cells prompting evaluation of three antioxidants, N-acetyl cysteine (NAC), ascorbic acid, and melatonin, to identify potential prophylactic agents. Among them, NAC was the only candidate that abrogated the ROS generation in response to silver acetate exposure resulting in the rescue of these cells from silver-associated toxicity. Further, this protective effect directly translated to preservation of metabolic activity, as demonstrated by the normal levels of citric acid cycle metabolites in NAC-pretreated silver acetate-exposed cells. Because the citric acid cycle remained functional, silver-exposed cells pre-incubated with NAC demonstrated significantly higher levels of adenosine triphosphate levels compared with NAC-free controls. Moreover, we found that this prodigious capacity of NAC to rescue silver acetate-exposed cells was due not only to its antioxidant activity, but also to its ability to directly bind silver. Despite binding to silver, NAC did not alter the antimicrobial activity of silver acetate.
Insights
N-acetyl cysteine (NAC) prevents silver toxicity in lung cells by reducing reactive oxygen species (ROS) and preserving metabolic function. NAC also binds silver without affecting its antimicrobial properties, offering a potential protective agent for aerosolized silver treatments.
Area of Science:
- Biomedical research
- Antimicrobial agents
- Toxicology
Background:
- Silver-based antimicrobials are effective against multi-drug resistant (MDR) pathogens.
- Topical silver use is expanding to aerosolized treatments for lung infections.
- Silver-induced respiratory toxicity is a concern, primarily mediated by reactive oxygen species (ROS).
Purpose of the Study:
- To investigate the protective effects of antioxidants against silver toxicity in bronchial epithelial cells.
- To identify potential prophylactic agents to mitigate silver-induced lung toxicity.
- To understand the mechanisms underlying NAC's protective action.
Main Methods:
- Exposure of bronchial epithelial cells to silver acetate.
- Evaluation of ROS generation and cellular metabolic activity.
- Assessment of antioxidant candidates: N-acetyl cysteine (NAC), ascorbic acid, and melatonin.
- Measurement of citric acid cycle metabolites and adenosine triphosphate (ATP) levels.
- Analysis of NAC's direct binding to silver and its effect on antimicrobial activity.
Main Results:
- Silver acetate exposure induced ROS generation and toxicity in bronchial epithelial cells.
- NAC was the only antioxidant that effectively abrogated ROS production and rescued cells from toxicity.
- NAC pretreatment preserved metabolic activity, maintaining normal citric acid cycle function and elevated ATP levels.
- NAC demonstrated a dual protective mechanism: antioxidant activity and direct silver binding.
- NAC binding to silver did not compromise the antimicrobial efficacy of silver acetate.
Conclusions:
- N-acetyl cysteine (NAC) shows significant promise as a prophylactic agent against silver-induced respiratory toxicity.
- NAC's protective effects stem from its antioxidant properties and direct silver-binding capacity.
- NAC can be a valuable adjunct for aerosolized silver antimicrobial therapies, ensuring safety without sacrificing efficacy.
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