Journal Article

Impaired alveolar macrophage 11β-hydroxysteroid dehydrogenase type 1 reductase activity contributes to increased pulmonary inflammation and mortality in sepsis-related ARDS

Mahida, Rahul Y., Perkins, Gavin D., Stewart, Paul M., Cooper, Mark C., Scott, Aaron, Hardy, Rowan S., Lax, Siân, Naidu, Babu, Matthay, Michael A., Thickett, David R., Bassford, Christopher R., Parekh, Dhruv

2023

Overview

Acute Respiratory Distress Syndrome (ARDS) is a devastating pulmonary inflammatory disorder, commonly precipitated by sepsis. Glucocorticoids are immunomodulatory steroids that can suppress inflammation. Their anti-inflammatory properties within tissues are influenced by their pre-receptor metabolism and amplification from inactive precursors by 11β-hydroxysteroid dehydrogenase type-1 (HSD-1). We hypothesised that in sepsis-related ARDS, alveolar macrophage (AM) HSD-1 activity and glucocorticoid activation are impaired, and associated with greater inflammatory injury and worse outcomes. We analysed broncho-alveolar lavage (BAL) and circulating glucocorticoid levels, AM HSD-1 reductase activity and Receptor for Advanced Glycation End-products (RAGE) levels in two cohorts of critically ill sepsis patients, with and without ARDS. AM HSD-1 reductase activity was also measured in lobectomy patients. We assessed inflammatory injury parameters in models of lung injury and sepsis in HSD-1 knockout (KO) and wild type (WT) mice. No difference in serum and BAL cortisol: cortisone ratios are shown between sepsis patients with and without ARDS. Across all sepsis patients, there is no association between BAL cortisol: cortisone ratio and 30-day mortality. However, AM HSD-1 reductase activity is impaired in patients with sepsis-related ARDS, compared to sepsis patients without ARDS and lobectomy patients (0.075 v 0.882 v 0.967 pM/hr/10 AMs, p=0.004). Across all sepsis patients (with and without ARDS), impaired AM HSD-1 reductase activity is associated with defective efferocytosis (r=0.804, p=0.008) and increased 30-day mortality. AM HSD-1 reductase activity negatively correlates with BAL RAGE in sepsis patients with ARDS (r=-0.427, p=0.017). Following intra-tracheal lipopolysaccharide (IT-LPS) injury, HSD-1 KO mice demonstrate increased alveolar neutrophil infiltration, apoptotic neutrophil accumulation, alveolar protein permeability and BAL RAGE concentrations compared to WT mice. Caecal Ligation and Puncture (CLP) injury in HSD-1 KO mice results in greater peritoneal apoptotic neutrophil accumulation compared to WT mice. AM HSD-1 reductase activity does not shape total BAL and serum cortisol: cortisone ratios, however impaired HSD-1 autocrine signalling renders AMs insensitive to the anti-inflammatory effects of local glucocorticoids. This contributes to the decreased efferocytosis, increased BAL RAGE concentrations and mortality seen in sepsis-related ARDS. Upregulation of alveolar HSD-1 activity could restore AM function and improve clinical outcomes in these patients.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: 11-beta-Hydroxysteroid Dehydrogenase Type 1 - genetics / 11-beta-Hydroxysteroid Dehydrogenase Type 1 - metabolism / 11b-hydroxysteroid dehydrogenase type-1 / 11β-Hydroxysteroid dehydrogenase / Advanced glycosylation end products / alveolar macrophage (AM) / Alveoli / Animals / Anti-Inflammatory Agents / Apoptosis / ARDS (acute respiratory disease syndrome) / autocrine action / Autocrine signalling / Bronchoscopy / Clinical trials / Cortisol / Cortisone / Dehydrogenases / Glucocorticoids / Hormones / Hospitals / Hydrocortisone / Hydroxysteroid Dehydrogenases - metabolism / Immunology / Immunomodulation / Inflammation / Inflammatory diseases / Leukocytes (neutrophilic) / Lipopolysaccharides / Lungs / Macrophages / Macrophages, Alveolar - metabolism / Metabolism / Mice / Mortality / Ostomy / Patients / Peritonitis / Pneumonia / Proteins / Receptor for Advanced Glycation End Products / Recovery of function / Reductase / Respiratory Distress Syndrome / Sepsis / Sepsis - complications / Steroid hormones / Steroids / Thoracic surgery / Ventilators