In Aging Cell, researchers have published their findings that mice exposed to influenza experience long-term consequences that can be partially ameliorated with senolytics.
Post-viral syndromes
Long before the spread of the SARS-CoV-2 virus that causes COVID-19, it had been well-established that viral lung diseases such as influenza lead to lasting damage [1, 2]. Increased risks of idiopathic pulmonary fibrosis (IPF), emphysema, chronic obstructive pulmonary disease (COPD), and further infection by bacteria have all been documented [3].
Cellular senescence has been previously found to be linked to chronic lung diseases [4]. Viral infection in the lungs has been found to drive cells senescent, including both influenza [5] and SARS-CoV-2 [6]. However, not every lung disease can be properly treated by removing senescent cells [7]. These researchers, therefore, investigated the links between senescence and viral infection and aimed to determine if senolytics would be harmful or helpful.
Long-term damage is visible in mice
This study began with a population of pathogen-free Black 6 male mice that were 8-10 weeks old when exposed to a sublethal dose of H1N1 influenza. Without treatment, these mice developed lesions in their lungs four days after infection, which grew in the first two weeks, including inflammatory infiltrates and abrasion of the epithelial tissue in the airway. Four weeks after infection, much of this damage had been healed, but the epithelium was still abraded and there were visible signs of emphysema development and fibrosis. Three months after infection, the epithelium had partially healed but the emphysema and fibrosis were still around: the mice had developed chronic lung disease.
This infection was linked to cellular senescence: the senescence biomarkers p16 and p21 spiked strongly within the first two weeks of infection and were decreased but still at four weeks, even though the virus had been cleared out of the mice’s systems. These biomarkers were not significantly elevated at three months, even though lung disease had been firmly established. This rise and fall of senescence were linked to an increase in one DNA damage marker, γH2AX, but a decrease in another, 53BP1.
Despite this lack of overall senescence, however, it still persisted in some specific areas, showing different levels of damage in the same animal. Some lung bronchi had no signs of cellular senescence and were completely restored to normal three months after infection. Other bronchi had visible damage, which coincided with p16-expressing senescent cells still in the area. This finding was confirmed with an examination of lungs derived from monkeys.
Removing senescent cells has a significant benefit
Intrigued by these findings, the researchers used a genetically engineered mouse model whose senescent cells are very easy to remove. Doing this as the mice were infected, and continuing for four weeks, led to better healing: the mice whose senescent cells were removed had less emphysema, less fibrosis, and faster epithelial repair. As expected, it had no effects on the overall inflammation that occurred as a reaction to infection.
Some of these findings were recapitulated in wild-type mice given the powerful senolytic compound ABT-263s (navitoclax) one day after infection, continuing for 4 weeks. Like with the genetically engineered mice, there was no significant effect on overall inflammation; however, the senescent cell population was significantly reduced, and viral load was decreased slightly as well.
Unfortunately, navitoclax was unable to affect emphysema or fibrosis 28 days after infection, although it did lead to significantly better epithelial repair. The researchers suggest that these mixed results may be due to the negative effects of cellular death by apoptosis and note that some previous work has suggested that apoptosis may actually promote fibrosis [8].
Even with these mixed results, however, the existence of a clear benefit in the form of epithelial repair leads these researchers to believe that senolytics with different mechanisms of action, such as the well-known combination of dasatinib and quercetin, may be instrumental in treating the long-term effects of viral lung diseases. If this approach is able to remove lasting harm from the lungs, people suffering from emphysema, IPF, and COPD may be able to breathe a lot easier.
Literature
[1] Herold, S., Becker, C., Ridge, K. M., & Budinger, G. S. (2015). Influenza virus-induced lung injury: pathogenesis and implications for treatment. European Respiratory Journal, 45(5), 1463-1478.
[2] Umeda, Y., Morikawa, M., Anzai, M., Sumida, Y., Kadowaki, M., Ameshima, S., & Ishizaki, T. (2010). Acute exacerbation of idiopathic pulmonary fibrosis after pandemic influenza A (H1N1) vaccination. Internal Medicine, 49(21), 2333-2336.
[3] Sheng, G., Chen, P., Wei, Y., Yue, H., Chu, J., Zhao, J., … & Zhang, H. L. (2020). Viral infection increases the risk of idiopathic pulmonary fibrosis: a meta-analysis. Chest, 157(5), 1175-1187.
[4] Barnes, P. J., Baker, J., & Donnelly, L. E. (2019). Cellular senescence as a mechanism and target in chronic lung diseases. American journal of respiratory and critical care medicine, 200(5), 556-564.
[5] Schulz, L., Hornung, F., Häder, A., Radosa, L., Brakhage, A. A., Löffler, B., & Deinhardt-Emmer, S. (2023). Influenza virus-induced paracrine cellular senescence of the lung contributes to enhanced viral load. Aging and Disease, 14(4), 1331.
[6] Lee, S., Yu, Y., Trimpert, J., Benthani, F., Mairhofer, M., Richter-Pechanska, P., … & Schmitt, C. A. (2021). Virus-induced senescence is a driver and therapeutic target in COVID-19. Nature, 599(7884), 283-289.
[7] Born, E., Lipskaia, L., Breau, M., Houssaini, A., Beaulieu, D., Marcos, E., … & Abid, S. (2023). Eliminating senescent cells can promote pulmonary hypertension development and progression. Circulation, 147(8), 650-666.
[8] Victorelli, S., Salmonowicz, H., Chapman, J., Martini, H., Vizioli, M. G., Riley, J. S., … & Passos, J. F. (2023). Apoptotic stress causes mtDNA release during senescence and drives the SASP. Nature, 622(7983), 627-636.
