S34 Reduced alveolar macrophage HSD-1 activity is associated with impaired efferocytosis and greater mortality in ARDS patients

Mahida, RY; Bassford, CR; Thickett,

doi:10.1136/thorax-2018-212555.40

Cited by 1 publication

(1 citation statement)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…GC are well-known for their anti-inflammatory effects, supporting our observed induction of pro-inflammatory genes and pathways by AZD4017. Importantly, this has not translated to adverse outcomes during mild / acute inflammation [7,11,24], but could be disadvantageous during severe / chronic inflammation [25,26].…”

Section: Discussionmentioning

confidence: 99%

11β-HSD1 inhibitor efficacy in type 2 diabetes is cortisol-dependent

Wilton-Waddell,

Farraj,

Vasconcelos

et al. 2024

Preprint

View full text Add to dashboard Cite

Cortisol excess drives multiple adverse effects including hypertension, dyslipidemia, and delayed wound healing. Activation of cortisol by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) has shown promise as a therapeutic target for these comorbidities but clinical progress has been hampered by variable 11β-HSD1 inhibitor efficacy. Here, transcriptomic profiling of 11β-HSD1 target genes in primary skin fibroblasts as well as skin biopsies from type 2 diabetes individuals treated with the selective 11β-HSD1 inhibitor AZD4017 provide detailed mechanistic insights highlighting new areas of therapeutic potential. We report correlations between changes in 11β-HSD1 target gene expression, blood pressure, lipids, and wound healing with 1) cortisol levels (serum cortisol / dehydroepiandrosterone sulfate) and 2) peripheral 11β-HSD1 activity (serum cortisol / cortisone). Finally, we demonstrate that baseline cortisol levels and changes in placebo group cortisol levels are key determinants of 11β-HSD1 inhibitor efficacy. In conclusion, our findings pave the way for more effective targeting of 11β-HSD1 inhibitor treatment, improving the accuracy of future clinical studies. Larger trials of longer duration are now warranted to fully explore the therapeutic potential of 11β-HSD1 inhibitors across a range of cardiometabolic and age-associated indications.

show abstract