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Amiodarone induces two different types of disorders in mouse alveolar macrophages
1Department of Pharmacology, Toho University School of Medicine, Tokyo, Japan.
Abstract:
It has been reported that amiodarone induces disorders of alveolar macrophages and pulmonary fibrosis, but the mechanism is not well-understood. This study was performed to elucidate the toxic mechanism from the standpoint of cellular function. Using alveolar macrophages obtained from a male Slc:ICR mouse, several injuries caused by amiodarone were compared to those caused by amantadine and mianserin as cationic amphiphilic drugs (CADs). As parameters for the drug effects, H(+)-ATPase and acid sphingomylinase activities, cellular pH, cytokine and prostaglandin releases, phagocytosis and neutral red uptake were measured. Amiodarone decreased H(+)-ATPase activity initially and subsequently increased cellular pH and decreased acid sphingomyelinase activity. These changes, which were also observed with amantadine and mianserin, were considered to be CAD-related. Amiodarone increased cytokine and prostaglandin releases and suppressed neutral red uptake and phagocytosis. These changes, being not induced by amantadine and mianserin, were considered to be specific for amiodarone. The above data suggest that amiodarone has two types of toxic effects on alveolar macrophages.
Insights
Amiodarone causes two distinct toxic effects on alveolar macrophages: general cationic amphiphilic drug-related cellular changes and amiodarone-specific functional impairments, contributing to lung injury.
Area of Science:
- Toxicology
- Cell Biology
- Pulmonary Medicine
Background:
- Amiodarone is known to cause alveolar macrophage dysfunction and pulmonary fibrosis.
- The precise toxic mechanisms underlying amiodarone-induced lung injury remain unclear.
Purpose of the Study:
- To elucidate the toxic mechanisms of amiodarone on alveolar macrophages at the cellular level.
- To differentiate amiodarone's specific toxic effects from general cationic amphiphilic drug (CAD) effects.
Main Methods:
- Alveolar macrophages from male Slc:ICR mice were treated with amiodarone, amantadine, and mianserin (CADs).
- Assessed cellular parameters included H(+)-ATPase activity, cellular pH, acid sphingomyelinase activity, cytokine and prostaglandin release, neutral red uptake, and phagocytosis.
Main Results:
- Amiodarone, like other CADs, decreased H(+)-ATPase activity, increased cellular pH, and reduced acid sphingomyelinase activity.
- Amiodarone uniquely increased cytokine and prostaglandin release while suppressing neutral red uptake and phagocytosis, indicating drug-specific toxicity.
Conclusions:
- Amiodarone exerts dual toxic effects on alveolar macrophages.
- These effects include general CAD-related cellular alterations and amiodarone-specific functional impairments contributing to pulmonary toxicity.