Glucocorticoid therapy for acute respiratory distress syndrome: Current concepts

Abstract

Acute respiratory distress syndrome (ARDS), a fatal critical disease, is induced by various insults. ARDS represents a major global public health burden, and the management of ARDS continues to challenge healthcare systems globally, especially during the pandemic of the coronavirus disease 2019 (COVID-19). There remains no confirmed specific pharmacotherapy for ARDS, despite advances in understanding its pathophysiology. Debate continues about the potential role of glucocorticoids (GCs) as a promising ARDS clinical therapy. Questions regarding GC agent, dose, and duration in patients with ARDS need to be answered, because of substantial variations in GC administration regimens across studies. ARDS heterogeneity likely affects the therapeutic actions of exogenous GCs. This review includes progress in determining the GC mechanisms of action and clinical applications in ARDS, especially during the COVID-19 pandemic.

Keywords: Acute respiratory distress syndrome; COVID-19; Clinical trials; Glucocorticoids; Heterogeneity; Steroids.

Figure 1

GC mechanisms in the exudative phase of ARDS. A: Direct and indirect insults damage the alveolar structure and microvasculature. B: During the exudative phase, alveolar resident macrophages are activated into M1-like macrophages, leading to the production of chemokines and proinflammatory cytokines that promote the accumulation of neutrophils and monocytes in the alveolus. To minimize the damage, activated neutrophils produce proinflammatory mediators such as ROS, NETs, COX-2, iNOS, MPO, and elastase. M1-like macrophages help T cells differentiate into T_h1, T_h2, T_reg, and T_h17 subgroups. AEC I and AEC II are injured, and surfactant production decreases. Platelet aggregation and microthrombus formation cause intra-microvascular and intra-alveolar thrombosis, all of which injure barrier functions, leading to intra-alveolar and interstitial edema and respiratory failure. GCs suppress the NF-κB pathway to inhibit downstream proinflammatory mediator release, enhance antigen uptake in DCs and NKCs, and contribute to anti-inflammation effects by elevating proportions of T_h2, T_reg, and T_h17 subgroups, and reducing the T_h1 subgroup. Despite repressing the expression of adhesion molecules to prevent adhesion and extravasation of neutrophils, GCs also induce expression and secretion of Anx-1 to further induce apoptosis of neutrophils in the inflammatory site. Created by Biorender. AEC: Alveolar epithelial cell; Anx-1: Annexin-1; AQPs: Aquaporins; ARDS: Acute respiratory distress syndrome; COX-2: Cyclooxygenase-2; CXCL: C-X-C motif chemokine ligand; DAMP: Damage-associated molecular pattern; DCs: Dendritic cells; ENaC: Epithelial sodium channels; E-sel: E-selectin; GC: Glucocorticoid; IL: Interleukin; iNOS: Inducible nitric oxide synthase; l-sel: l-selelctin; LTB4: Leukotriene B4; MHC: Major histocompatibility complex; MMPs: Matrix metalloproteinases; MPO: Myeloperoxidase; NETs: Neutrophil extracellular traps; NF-κB: Nuclear factor kappa-B; NKC: Natural killer cell; PAMP: Pathogen-associated molecular patterns; ROS: Reactive oxygen species; TCR: T cell receptor; T_h cell: T helper cell; TNF: Tumor necrosis factor.

Figure 2

GC mechanisms in the proliferative and fibrotic phase of ARDS. A: The proliferative phase aims to resolve inflammation and reconstruct damaged structures. GCs induce phenotypic changes in macrophages from proinflammatory M1 to anti-inflammatory M2, activate macrophages to remove apoptotic cells, and improve the proportion of T_reg cells, which release TGF-β, contributing to inflammation resolution. GCs can augment NETs production for inflammation clearance, but excessive NETs production leads to persistent inflammation and aggressive injuries. Following GC therapy, ion channel (ENaC, Na⁺/K⁺-ATPase, Ca²⁺/Cl⁻/K⁺ pump, and AQPs) activity and quantity increase to hasten edema clearance. Surfactant production is increased with enhanced proliferation of AEC II. B: During the fibrotic phase, despite promoting re-epithelialization, GCs prevent the collagen deposition process and help to maintain the coagulation–fibrinolysis balance. Created by Biorender. AEC: Alveolar epithelial cell; AQPs: Aquaporins; ARDS: Acute respiratory distress syndrome; ENaC: Epithelial sodium channels; GC: Glucocorticoid; IGF: Insulin-like growth factor; IL: Interleukin; NETs: Neutrophil extracellular traps; PAI: Plasminogen activator inhibitor; PDGF: Platelet derived growth factor; TGF: Transforming growth factor; vWF: von Willebrand factor.

Figure 3

ARDS heterogeneity and future perspectives. The ARDS is heterogeneous by nature and markedly impacts treatment efficacy. The center of the donut graph represents four main ARDS heterogeneity factors: clinical, physiological, radiographical, and biological. Circles within each section show identified subphenotypes. Omics approaches (left) and AI-assisted conceptual models (right) may help to identify specific subphenotypes and promote precision medicine. Created by Biorender. AI: Artificial intelligence; AKI: Acute kidney injury; ARDS: Acute respiratory distress syndrome.