Objective:
Chronic obstructive pulmonary disease (COPD) is a lung disorder with progressive airflow obstruction, often including emphysema development. Disease progression is accelerated by episodes of acute exacerbation (AE) and is associated with extra-pulmonary consequences, including muscle atrophy. Increased inflammation during an AE and increased levels of glucocorticoids (GCs) are potential triggers for muscle atrophy. 11 beta-hydroxysteroid dehydrogenase 1 (11β-HSD1) activates GCs within muscle, is induced by inflammation, and has previously shown to drive GC-induced muscle wasting. Using animals with a global knock out (KO) of 11β-HSD1, we aim to explore inhibition of 11β-HSD1 as a potential therapeutic target to prevent acute skeletal muscle atrophy in a model of COPD-AE.

Methods:
Emphysema was induced by two intra-trachael (IT) instillations of elastase in global 11β-HSD1 KO animals, followed by one single bolus of IT-LPS or v.c. After 48 hours animals were sacrificed and muscles, serum and lungs harvested. CT scans were used to determine muscle mass changes following LPS and emphysema development with elastase. Muscles were histologically assessed, and anabolic, catabolic and inflammatory gene and protein expression were examined by RT-qPCR and western blot. ELISA was used to assess corticosterone and IL-6 levels in serum.

Results & conclusion:
Preliminary findings show exacerbated muscle wasting in 11β-HSD1/KO mice receiving LPS compared to WT controls. These findings suggest muscle atrophy in response to pulmonary inflammation was increased in emphysematous 11β-HSD1/KO mice compared to WT controls due to reduced activation of endogenous GCs, therefore reducing GC activity and ultimately heightening the inflammatory response.