A high-throughput cigarette smoke-treated bronchosphere model for disease-relevant phenotypic compound screening

Area of Science:

• Respiratory Medicine
• Toxicology
• Drug Discovery

Background:

• Cigarette smoking (CS) is the primary cause of Chronic Obstructive Pulmonary Disease (COPD).
• Identifying CS-induced airway pathogenesis pathways is crucial for developing novel COPD therapies.
• Developing high-throughput models that recapitulate CS-induced transcriptomic and phenotypic changes remains a challenge.

Purpose of the Study:

• To develop and validate a high-throughput bronchosphere model for studying CS-induced airway pathogenesis.
• To identify key molecular drivers and therapeutic targets in CS-induced airway disease.
• To screen for small molecule compounds that can reverse CS-induced pathogenic changes.

Main Methods:

• Developed a 384-well plate cigarette smoke extract (CSE)-treated bronchosphere assay.
• Assessed CSE-induced changes in spheroid size and MUC5AC secretion.
• Performed transcriptomic analysis to compare CSE-treated bronchospheres with human smoker data.
• Screened a diverse small molecule compound deck to identify therapeutic candidates.

Main Results:

• The CSE-treated bronchosphere assay demonstrated reduced spheroid size and increased MUC5AC secretion.
• Transcriptomic profiles of the model closely resembled those of human smokers with and without COPD.
• Compound screening identified hit compounds that attenuated CSE-induced changes, including decreased size and increased mucus secretion.

Conclusions:

• The developed bronchosphere model is a valuable tool for investigating CSE-induced respiratory disease.
• This model effectively captures human smoking signatures and can be used for therapeutic target identification.
• The study identified compounds with the potential to reverse pathogenic changes caused by CSE exposure, offering therapeutic avenues for COPD.