Glucocorticoid therapy in respiratory illness: bench to bedside

Abstract

Each year, hundreds of millions of individuals are affected by respiratory disease leading to approximately 4 million deaths. Most respiratory pathologies involve substantially dysregulated immune processes that either fail to resolve the underlying process or actively exacerbate the disease. Therefore, clinicians have long considered immune-modulating corticosteroids (CSs), particularly glucocorticoids (GCs), as a critical tool for management of a wide spectrum of respiratory conditions. However, the complex interplay between effectiveness, risks and side effects can lead to different results, depending on the disease in consideration. In this comprehensive review, we present a summary of the bench and the bedside evidence regarding GC treatment in a spectrum of respiratory illnesses. We first describe here the experimental evidence of GC effects in the distal airways and/or parenchyma, both in vitro and in disease-specific animal studies, then we evaluate the recent clinical evidence regarding GC treatment in over 20 respiratory pathologies. Overall, CS remain a critical tool in the management of respiratory illness, but their benefits are dependent on the underlying pathology and should be weighed against patient-specific risks.

Keywords: anti-inflammatory agents; critical care; glucocorticoids; lung diseases; respiratory system.

Figure 1

Molecular mechanisms of glucocorticoid (GC) action. (A) GCs are most well known for their effects on DNA transcription of inflammation-related genes. GCs in the cytoplasm associate with chaperone proteins and glucocorticoid receptor α (GR). This complex translocates to the nucleus to bind promoter regions of proinflammatory and anti-inflammatory genes. The GR-GC complex can promote or inhibit gene expression through directly binding the DNA promoter region (Direct); by binding to a transcription factor (Tethering); or by binding both the DNA and the transcription factor (Composite). (B) GCs can also interrupt inflammatory cascades by intercepting mRNA transcripts for proinflammatory genes such as NF-κB. GCs complex with GR and other chaperones to form a protein complex that binds to mRNA causing it to lose stability and degrade. GR-GC protein complexes also promote the transcription of the mRNA-degrading enzyme TTP, thereby increasing the degradation of cytoplasmic mRNA. (C) GCs induce immediate, non-genomic changes by intercalating in the cell membrane’s lipophilic interior. The intercalating GCs promote a reduction in intracellular calcium and ATP levels (* marks the GC).

Figure 2

Glucocorticoid mechanism and cellular effects. (A) Glucocorticoids (GCs) inhibit lymphocytes’ production and release of inflammatory cytokines and reduce circulating lymphocyte counts by redirecting circulating lymphocytes to the lymphoid organs. (B) GCs inhibit inflammatory neutrophil behaviors such as degranulation, NETosis, and recruitment. They also increase circulating neutrophil counts by enhancing the maturation of neutrophils in the bone marrow. (C) GCs inhibit inflammatory macrophage and monocyte behaviors including the activation of monocytes into macrophages; the phagocytosis of bacteria; the release of cytokines by activated macrophages; and the recruitment of monocytes to inflamed areas. (D) GCs inhibit the transdifferentiation of alveolar type II pneumocytes into type I to cover damaged tissue. They also inhibit the release of proinflammatory cytokines. However, they also appear to increase the release of von Willebrand factor (VWF) and the expression of endothelial adhesion proteins (* marks the GC).