Observations on the effects of chronic persistent hypoxia on liver in aged mice and the protective role of pyrroloquinoline quinone
10.3760/cma.j.issn.0254-9026.2025.06.023
- VernacularTitle:慢性持续性缺氧对老年小鼠肝脏的影响及吡咯喹啉醌保护作用的研究
- Author:
Hanyu LI
1
;
Songbai ZHENG
;
Guoyu GUAN
;
Zhuoga SANGDAN
;
Zhiliang YAN
;
Zhang YU
;
Dagui CHEN
Author Information
1. 复旦大学附属华东医院消化内科，上海 200040
- Publication Type:Journal Article
- Keywords:
Hypoxia;
Liver function;
Aging;
Pyrroloquinoline quinone
- From:
Chinese Journal of Geriatrics
2025;44(6):808-815
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To investigate the effects of chronic persistent hypoxia on hepatic function, histological morphology, and ultrastructure in aged mice, and to evaluate the protective role of pyrroloquinoline quinone(PQQ).Methods:Thirty-two 2-month-old (young group)and thirty-two 18-month-old(aged group)male C57BL6/J mice were each randomly divided into four groups (n=8 per group): normoxia+ normal saline (NS)group, normoxia+ PQQ group, hypoxia+ NS group, and hypoxia+ PQQ group.The normoxia+ NS and normoxia+ PQQ groups were housed under normoxic conditions[fraction of inspired oxygen(FiO 2)=21%], while the hypoxia+ NS and hypoxia+ PQQ groups were continuously exposed to a hypoxic environment[FiO 2=(10±0.5)%]simulated by a custom-made hypoxic chamber, maintaining a constant oxygen concentration for 24 hours per day.The normoxia+ NS and hypoxia+ NS groups received daily intragastric administration of NS, whereas the normoxia+ PQQ and hypoxia+ PQQ groups received daily intragastric administration of PQQ disodium salt(8 mg·kg -1·d -1).After 8 weeks of continuous intervention, blood samples were collected to measure red blood cell count, hemoglobin levels, and liver function-related biochemical indicators.Lung tissues were processed for HE staining, and liver tissues were processed for both HE staining and electron microscopy.The histological and ultrastructural features of each group were observed under light and electron microscopy, respectively, and the differences between the groups were compared and analyzed. Results:Compared with the normoxia+ NS groups, both young and aged hypoxia+ NS groups exhibited significant pulmonary arteriole narrowing( P<0.001), with markedly elevated red blood cell count and hemoglobin levels (all P<0.001), which were not alleviated by PQQ.Compared with the young normoxia+ NS group, the young hypoxia+ NS group showed significantly higher alanine aminotransferase (ALT)and lactate dehydrogenase (LDH)levels( Z=2.72, 2.53, P=0.007, 0.011), whereas the young hypoxia+ PQQ group exhibited LDH levels similar to those of the young normoxia+ NS group.The aged hypoxia+ NS group exhibited significant ALT elevation( t=2.66, P=0.013)compared with the aged normoxia+ NS group.Light microscopy revealed hepatocyte ballooning degeneration, mild fatty accumulation, and focal necrosis around central veins in the young hypoxia+ NS group, while the young hypoxia+ PQQ group exhibited no significant pathological damage but displayed numerous deeply stained binucleated hepatocytes.The aged normoxia+ NS group demonstrated hepatocyte ballooning degeneration and inflammatory cell infiltration around central veins, whereas the aged normoxia+ PQQ group exhibited no obvious pathological damage with scattered deeply stained binucleated hepatocytes.The aged hypoxia+ NS group exhibited significant necrosis following physiological oxygen concentration gradient distribution, while the aged hypoxia+ PQQ group displayed no obvious pathological damage with scattered deeply stained binucleated hepatocytes.Electron microscopy revealed that the aged normoxia+ NS group had reduced mitochondrial electron density ( P<0.001)and less developed rough endoplasmic reticulum compared with the young normoxia+ NS group.The young hypoxia+ NS group exhibited a smaller mitochondrial area( P<0.001), decreased mitochondrial matrix electron density( P<0.001), blurred or absent mitochondrial cristae, inactive rough endoplasmic reticulum, and increased accumulation of glycogen and lipid droplets compared with the young normoxia+ NS group, while the young hypoxia+ PQQ group maintained mitochondrial matrix electron density comparable to the young normoxia+ NS group.The aged hypoxia+ NS group exhibited larger mitochondrial area( P=0.001), decreased mitochondrial matrix electron density( P<0.001), blurred or absent mitochondrial cristae, mitochondrial edema, increased lysosomes, and elevated cytoplasmic electron density compared with the aged normoxia+ NS group.The aged hypoxia+ PQQ group exhibited reduced mitochondrial area( P<0.001)and restored mitochondrial matrix electron density to levels comparable with the aged normoxia+ NS group.The aged normoxia+ PQQ group demonstrated increased mitochondrial matrix electron density compared with the aged normoxia+ NS group( P<0.001). Conclusions:Chronic persistent hypoxia induces hepatic functional, histological and ultrastructural damage in mice, with more pronounced effects in aged animals.PQQ provides a certain degree of protection against these injuries.
