| Description |
Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis, which invades the lungs and causes secondary cavitary tuberculosis. Most of the tuberculosis cavities can be healed after treatment, but some of them cannot be healed despite regular anti-TB treatment, and some studies have shown that patients with cavitary TB are prone to TB resurgence after successful drug-sensitive TB treatment. To further understand the risk factors for cavity healing and the effects of anti-tuberculosis drugs on regenerative repair of the lung epithelium, our study assessed the ability of each anti-tuberculosis drug to repair AT2 cells in mice by the lung organoid technique. We found that compared to controls, rifampicin (0.1, 1 μg/mL, 10 μg/mL), pyrazinamide (10ug/mL), ethambutol (1, 10 μg/mL) and levofloxacin (1 μg/mL, 10 μg/mL) decreased the organoid forming efficiency (OFE) of the AT2 cells; rifampicin (0.1 μg/mL, 10 μg/mL) and levofloxacin (10 μg/mL) inhibited the size of organoids derived from AT2 cells. Isoniazid (0.1mg/mL), ethambutol (1mg/mL) and levofloxacin (10 μg/mL) promoted AT1 differentiation Moxifloxacin (1 μg/mL, 10 μg/mL) Only 10 µg/mL of levofloxacin promoted AT2 differentiation. Another quinolone showed different results from the others: moxifloxacin (1µg/mL, 10ug/mL) significantly promoted OFE and clone diameter. Furthermore, stem cell metabolomics was applied to reveal the molecular mechanisms by which anti-tuberculosis drugs at high doses affect the proliferation and differentiation of lung epithelial progenitor cells. We found significant differences in metabolites between rifampicin, levofloxacin, moxifloxacin, ethambutol and controls. Among these differential metabolites, mannitol, L-altose, β-D-Glucopyranuronic acid, glycine and hydroxypropionic acid were common to all four groups, and mannitol, L-altose, β-D-glucuronide, and glycine were down-regulated, which are all organic oxygen and organic acid compounds. Levofloxacin and moxifloxacin resulted in down-regulation of l-alanine in AT2 cells. Unlike the other three groups, arachidonic acid (a fatty acid) was upregulated in response to moxifloxacin stimulation. In addition, KEGG enrichment analysis showed that DEMs play an important role in ABC transporter, oxidative phosphorylation in AT2 cells stimulated by each anti-Mtb drug. All these pathways are closely related to energy metabolism, which is required for cell proliferation and differentiation. It can thus be found that although anti-tuberculosis drugs are effective in treating the tuberculosis lumen, anti-tuberculosis drugs affect cell proliferation and differentiation by affecting cell metabolism while sterilizing the bacteria, affecting the regenerative repair of lung epithelial cells. |
