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

Abstract

BackgroundAcute 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.MethodsWe 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.ResultsNo 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/106 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.ConclusionsAM 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.

Local glucocorticoid synthesis regulates house dust mite-induced airway hypersensitivity in mice

“…It had been previously shown that Toll-like receptor 4 (TLR4) activation by LPS contaminants in HDM extracts and the subsequent release of cytokines and chemokines is indispensable for allergen sensitization, with low doses of LPS promoting a Th2-type eosinophilic immune reaction, whereas high doses of LPS rather initiate a Th17-type neutrophilic response ( 36 – 40 ). In line with this, direct intra-tracheal administration of LPS led to increased neutrophil infiltration into the alveolar space of KO mice ( 41 ). Interestingly, the lack of local 11β-HSD1-mediated GC reactivation does not seem to affect the type 2 phenotype in the acute HDM model, but causes a mixed type 2/type 17 phenotype with enhanced neutrophil infiltration.…”

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

“…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].…”

Dexamethasone impairs the expression of antimicrobial mediators in lipopolysaccharide-activated primary macrophages by inhibiting both expression and function of interferon β

“…AMs were resuspended in RPMI1640 containing 10% FBS, 100U/mL penicillin, 100µg/mL streptomycin and 2mM L-glutamine (Sigma-Aldrich), and plated. This method generates primary human alveolar macrophages with purity >98% as measured by a validated combination of cytospin and flow cytometry using antibodies against CD68 ( 81 ).…”