Wang, J.-q. | bioRxiv Science

bioRxiv2026

Local IFNγ signaling contributes to the regenerative decline of aged alveolar progenitor cells

The lungs are highly susceptible to chronic disease in advanced age, likely due to the uniquely compromised repair function of alveolar type II (AT2) cells, facultative progenitor cells that maintain the gas exchange surface. Using aging mouse models, single-cell sequencing, and ex vivo organoid assays, we found that homeostatic aged AT2 cells exhibited an Interferon {gamma} (IFN{gamma}) response associated with IFN{gamma}+ CD8+ T cells in tertiary lymphoid structures (TLS). Aged AT2 cells exhibit impaired regeneration in organoid assays and lost markers of an IFN{gamma} response outside the lung microenvironment, demonstrating that elevated local IFN{gamma} influences the state of AT2 cells. Neutralization of IFN{gamma} signaling and immunoproteasome knockout mice with attenuated IFN{gamma} levels partially rescued aged AT2 cell regeneration. Our findings demonstrate that local IFN{gamma} signaling in aging lungs actively represses alveolar regeneration, establishing chronic inflammatory signaling as a cause of age-related decline in the lung. Halting chronic inflammatory processes restored alveolar regeneration and may provide a means to improve lung health in old age.

cell biology↗

bioRxiv2023

Circulating metabolites of Borneolum syntheticum (Bingpian) inhibit foam-cell formation in macrophages induced by oxidized low-density lipoprotein

Coronary heart disease is caused by the accumulation of atherosclerotic plaques which narrow the arteries over time. The plaques are formed by cholesterol deposits in the arterial intima and lead to the symptom of angina pectoris. Borneolum syntheticum (Bingpian) has been extensively used as a component in Chinese herbal medicines for cardiovascular diseases. This investigation aimed to examine Bingpian metabolism and its effects on anti-atherosclerotic activities. Major circulating Bingpian compounds were detected in human subjects who received a Bingpian-containing medicine. In vitro and rat studies were also conducted to facilitate the understanding of disposition factors that govern the systemic exposure to Bingpian compounds. Although Bingpian constituents, borneol (1) and isoborneol (2), are efficiently absorbed in the intestine, extensive hepatic first-pass glucuronidation, which is mediated predominantly by UGT2B7, coupled with MRP3 and MRP4-mediated efflux of the glucuronides into the blood, and oxidation, which is mediated by CYP2A6, CYP2B6, and CYP3A, result in the formation of metabolites borneol-2-O-glucuronide (M1G), isoborneol-2-O-glucuronide (M2G), and camphor (3) as the major circulating Bingpian compounds instead of the unchanged 1 and 2. Glucuronides are predominantly eliminated through renal excretion, which involves both glomerular filtration and OAT3- and OAT4-mediated tubular secretion. Furthermore, M1G, M2G, and 3, as well as 1 and 2, displayed inhibitory effects on oxidized low-density lipoprotein-induced foam-cell formation in macrophages. The findings emphasized that the metabolites must be given priority in pharmacodynamic studies of Bingpian. Comprehensive integration of pharmacokinetic and pharmacodynamic studies facilitates understanding how Bingpian functions in the body to provide therapeutic benefits.

pharmacology and toxicology↗