Mitochondria protective and anti-apoptotic effects of peripheral benzodiazepine receptor and its ligands on the treatment of asthma in vitro and vivo

Background: Asthma is a prevalent respiratory inflammatory disease. Abnormal Apoptosis of bronchial epithelial cells is one of the major factors in the progression of asthma. Peripheral benzodiazepine receptors are highly expressed in bronchial epithelial cells, which act as a component of the mitochondrial permeability transition pore to regulate its opening and closing and Apoptosis of bronchial epithelial cells. We aimed to investigate the mechanisms by which peripheral benzodiazepine receptor and its ligands, agonist 4'-Chlorodiazepam (Ro5-4864) and antagonist 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide (PK 11,195), modulate the mitochondrial function and cell Apoptosis in the treatment of asthma.

Methods: In vitro study, Ro5-4864 and PK 11,195 were utilized to pretreat cells prior to the inflammatory injury induced by Lipopolysaccharide. The Reactive Oxygen Species, the Apoptosis of cell, the mitochondrial membrane potentials, the ultrastructures of the mitochondria and the expression levels of peripheral benzodiazepine receptors and apoptosis-related proteins and genes were detected. In vivo study, mice were administrated intraperitoneally with Ro5-4864 and PK 11,195 before sensitized and challenged by ovalbumin. Serum IgE and bronchoalveolar lavage fluid cytokines were detected, and lung tissues were underwent the histopathological examination.

Results: The ligands of peripheral benzodiazepine receptor counteracted the effects of the increase of Reactive Oxygen Species, the elevated extent of Apoptosis, the decrease of mitochondrial membrane potentials and the disruption of mitochondrial ultrastructures induced by Lipopolysaccharide. The ligands also promoted the expression of anti-apoptosis-related proteins and genes and inhibited the expression of pro-apoptosis-related proteins and genes. Besides, the ligands reduced the levels of serum IgE and bronchoalveolar lavage fluid cytokines in asthmatic mice and attenuated the histopathological damage of lungs.

Conclusion: Peripheral benzodiazepine receptor serves as a potential therapeutic target for the treatment of asthma, with its ligands exerting mitochondrial protective and anti-apoptotic effects on bronchial epithelial cells.

Apoptosis; Asthma; Bronchial epithelial cells; Mitochondrial permeability transition pore; Peripheral benzodiazepine receptors.