Calcitriol Administration Attenuates Acute Lung Injury by Improving Angiopoietin/Tie2 Dysregulation and Alveolar-Capillary Barrier Integrity in a Mouse Model of Ovariectomy Complicated With Sepsis.

Abstract

Menopause is associated with excessive weight, increased systemic inflammation, and oxidative stress. Menopause with obesity may aggravate the severity of organ damage when complicated with sepsis. This study investigated the impacts of calcitriol on acute lung injury (ALI)-associated angiopoietin (Ang)/tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domain 2 (Tie2) dysregulation, impairment of the barrier integrity, and ion disturbance in ovariectomized mice with sepsis. 6-month-old female C57BL/6 mice were divided into three groups: the OB group, which contained mice with a sham ovariectomy and high-fat diet (HFD); the OVSS group, which contained mice with an ovariectomy, an HFD, cecal ligation and puncture (CLP), and an intravenous saline injection after CLP; and the OVSD group, which contained mice with an ovariectomy, an HFD, CLP, and a calcitriol injection. The HFD was fed for 12 weeks. Mice in the respective groups were sacrificed on 24 or 72 h after CLP. Results showed that compared to the OB group, the OVSS group had higher oxidative stress, iron and copper overload, whereas the Ang1/Ang2 ratio and tight junction (TJ) protein levels were lower in the lungs. Calcitriol treatment in mice with ovariectomy and CLP enhanced Tie2 levels and the Ang1/Ang2 ratio, increased zona occludens (ZOs)-1, occludin, and claudin-5 levels. Elevated reduced glutathione (GSH) levels and glutathione peroxidase 4 (GPX4) activities, reduced iron and copper contents, and suppressed ferroptosis- and cuproptosis-associated components were found in the lungs. Also, higher survival rates and lower lung injury scores were noted in the OVSD groups. These findings suggest that calcitriol treatment mitigated the dysregulated Ang/Tie2 pathway, improved the integrity of the alveolar-capillary barrier, elicited a more balanced redox status, alleviated ferroptosis and cuproptosis in the lungs in an ovariectomy model complicated with sepsis.