Chronic obstructive pulmonary disease (COPD), a major cause of death worldwide, is characterized by chronic bronchitis and emphysema. Current treatments primarily manage symptoms but offer limited impact on disease progression. While cigarette smoke remains the leading risk factor, exposure to airborne particulate matter (PM) also contributes to the development and acceleration of COPD.
Recent research has focused on the role of macrophages – immune cells that play a key role in inflammation and tissue destruction – in the pathogenesis of COPD. Studies indicate that dysregulated macrophages contribute to COPD by releasing excessive amounts of cytokines, reactive oxygen and nitrogen species and proteases. A new study published in in Redox Biology, sheds light on a specific molecular mechanism driving this process and identifies a potential therapeutic target.
Researchers discovered that exposure to particulate matter induces changes in the way chromatin – the complex of DNA and proteins that makes up chromosomes – is organized within macrophages. This reorganization is driven by a protein kinase called CK2, which activates a protein called CTCF. CTCF then binds to DNA, altering gene expression and promoting inflammation. Specifically, the study found that PM exposure enhances CTCF binding to the promoters of genes involved in the kynurenine pathway (KP), reducing the production of NAD+, a crucial molecule for cellular energy and function. This, in turn, inactivates SIRT1, a protein involved in regulating inflammation and cellular health, and increases histone acetylation, further fueling the inflammatory response.
Interestingly, the researchers observed similar aberrant CTCF activation in both PM-induced and cigarette smoke-induced COPD, suggesting this mechanism is a common pathway in the development of the disease, regardless of the primary exposure. Analysis of publicly available data from COPD patients’ lung cells confirmed altered expression of genes regulated by CTCF, further supporting its role in the disease process.
To identify potential therapeutic interventions, the researchers screened a panel of stilbenoids – naturally occurring compounds found in plants – for their ability to inhibit the effects of PM on macrophages. They found that gaylussacin, a stilbene glycoside, and pterostilbene were particularly effective at suppressing CTCF binding to chromatin. Further investigation revealed that gaylussacin not only reduced CTCF binding but also decreased the production of reactive oxygen species (ROS) and nitric oxide (NO) without exhibiting significant toxicity to normal cells.
The study demonstrated that gaylussacin works by inhibiting CK2, thereby preventing the phosphorylation and activation of CTCF. This, in turn, restored NAD+ levels and SIRT1 activity within the macrophages. In silico modeling and biochemical assays confirmed that gaylussacin directly binds to and inhibits CK2, effectively disrupting the inflammatory cascade.
To test the therapeutic potential of gaylussacin, researchers administered the compound to mice exposed to particulate matter. They found that gaylussacin significantly reduced the development of COPD-like pathology, including alveolar enlargement, matrix metalloproteinase activation, apoptosis, mucus hypersecretion, and inflammation in the lungs. The beneficial effects were observed even when treatment was initiated after the PM exposure, suggesting a potential for reversing established disease processes.
Importantly, the body metabolizes gaylussacin into pinosylvic acid, which appears to have greater metabolic stability and bioavailability. Both gaylussacin and pinosylvic acid were well-tolerated by the mice, with no adverse effects on body weight or liver function.
These findings suggest that gaylussacin, or its metabolite pinosylvic acid, represents a promising therapeutic candidate for mitigating macrophage-driven inflammation in COPD. However, the researchers emphasize the need for further studies to investigate the role of CTCF in COPD using patient tissues and to evaluate the efficacy, pharmacokinetics, and safety of gaylussacin in clinical trials. Future research will also need to determine whether the observed benefits are solely attributable to effects on macrophages or involve other cell types within the lung.
This research highlights the complex interplay between environmental exposures, cellular signaling pathways, and epigenetic modifications in the development of COPD, offering new avenues for therapeutic intervention. The identification of CK2 and CTCF as key regulators of macrophage function provides a novel target for developing more effective treatments for this debilitating disease.
