Characterization of the systemic impact of glucocorticoid-treated exacerbation of COPD in a novel mouse model

Le résumé fourni par la source

COPD is often accompanied by muscle wasting. Muscle wasting intensifies during exacerbations of COPD (ECOPD), possibly driven by glucocorticoids (GCs) that are given as standard-of-care treatment. 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 (‘COPD’) was induced in male C57BL/6J mice by intratracheal (IT) instillation of elastase, followed by VC or LPS to evoke pulmonary inflammation (‘ECOPD’). Dexamethasone (DEX, a GC) was injected daily (‘GC-ECOPD’). Weekly μCT scans were used to verify emphysema development, and pre/post-LPS to measure muscle volume (MV) using automated segmentation analysis of right limb. Plasma and bronchoalveolar lavage fluid (BALf) TNF-α levels were determined by ELISA. Excised hindlimb muscles were weighed (MW) and used for gene expression analyses. Body weight (BW) reductions were observed in ECOPD (-14%) and GC-ECOPD (-9%) mice. ECOPD mice showed reduced MW compared to COPD (-8.0%). μCT scans showed MV reductions in ECOPD (-10%) and GC-ECOPD mice (-5%). Plasma and BALf TNF-α levels increased in ECOPD (12x and 153x respectively) and GC-ECOPD (6x and 73x) compared to COPD, and were reduced in GC-ECOPD vs ECOPD (0.5x and 0.5x). In muscle, Atrogene expression (Atrogin-1 [9x] and MuRF1 [4x]) was increased in ECOPD vs COPD, but only Atrogin-1 [2.5x] in GC-ECOPD. To conclude, we established a mouse model of GC-ECOPD that manifests the systemic impact of COPD exacerbation and incorporates the biological actions of GCs.

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