Work

OR18-08 Characterization Of The Systemic Impact Of GC-Treated Exacerbation Of COPD In A Novel Mouse Model

Year: 2025

Type: article

Abstract: Disclosure: J.M. Webster: None. S.J. van Krimpen: None. P. Qiu: None. B. Rezaeifar: None. S.O. Simons: None. A.M. Schols: None. H.R. Gosker: None. R.C. Langen: None. Chronic obstructive pulmonary disease (COPD) is not only characterized by respiratory symptoms but often also by muscle wasting. Muscle wasting has negative effects on exercise tolerance and quality of life, and increases mortality, and is accelerated by an exacerbation of COPD (ECOPD). ECOPDs are often evoked by pulmonary inflammation, and synthetic glucocorticoids (GCs) are administered as standard-of-care (SOC) anti-inflammatory treatment. However, GCs may aggravate muscle wasting through their catabolic actions, diminishing their overall therapeutic efficacy. To study the effects of GCs during ECOPD, we developed a mouse model of GC-treated ECOPD (GC-ECOPD). Emphysema was induced in male C57BL/6J mice (n=6/group) by three weekly intratracheal (IT) instillations of elastase, followed by IT-LPS (or vehicle) administration to evoke a pulmonary inflammatory response. The glucocorticoid dexamethasone (DEX, 5 mg/kg bw) or vehicle was injected daily, 4 hours post-LPS (or PBS control) instillation. Micro-cone beam CT (μCBCT) scans were obtained weekly to verify emphysema development and pre/post-LPS to measure muscle volume changes. Plasma and bronchoalveolar lavage fluid (BALf) cytokine levels were determined by ELISA. After sacrifice, hindlimb muscles were weighed and snap-frozen for gene expression analysis. Body weight of emphysematous mice was reduced by LPS (-14%, p<0.01) and LPS+DEX (-9%, p<0.05). Compared to saline (-1.8%), DEX alone did not significantly reduce body weight. Animals receiving LPS showed reduced wet muscle weight compared to control (-8.0%, p<0.05). In addition, initial automated segmentation analysis of right limb muscle volume on μCBCT scans decreased in response to LPS (-10%, p<0.01). LPS+DEX non-significantly reduced muscle volume (-5%, p=0.078). LPS induced both local and systemic inflammatory response shown by an increase in plasma IL-6 levels (p<0.05), BALf and plasma levels of TNF-α (both p<0.05) and Pentraxin-2 (p<0.05 and p<0.001 respectively). Treatment of DEX to LPS-instilled animals did not induce TNF-α and Pentraxin-2 plasma levels. LPS significantly induced atrogene expression (Atrogin-1 and MuRF1) in skeletal muscle (p<0.05), which was not apparent in animals receiving LPS and DEX treatment together. In conclusion, we established a mouse model of GC-treated ECOPD that impacts on skeletal muscle, shows significant body weight loss and incorporates the biological actions of GCs. This model will be used to investigate GC-treated ECOPD-associated wasting of body and muscle mass, and test compounds aiming to improve the therapeutic index of GCs in this setting. Presentation: Sunday, July 13, 2025

Source: Journal of the Endocrine Society

DOI: 10.1210/jendso/bvaf149.280