Glucocorticoids in Asthma: Effects on Inflammation and Exacerbations

Glucocorticoids
Puttatida Chetwong, MD
Topic Review 18-Feb-2022

Introduction Effects
Mechanisms of
action
Factors effecting
GC sensitivity
Table of contents
01 02
Obesity
Smoking
Infection
03 04
On asthmatic inflammation
On inflammatory cells
On immune response
On airways
Pharmacokinetics
Metabolism and excretion
Side effects

Important
Concept
Glucocorticoids, acting through their nuclear
receptor, are highly efficacious anti-inflammatory
drugs used to attenuate and prevent the activation
of inflammatory and allergic pathways in asthma.
Middleton’s Allergy, 9th ed.

Important
Concept
Inhaled glucocorticoids act preferentially in the
airways and have reduced systemic side-effects
related to
• high receptor binding affinity,
• improved airways, and lung retention and
• rapid breakdown with elimination from the
systemic circulation

Important
Concept
Glucocorticoids downregulate the expression of the
majority of mediators including cytokines,
chemokines, and growth factors involved in the
inflammatory response, in addition to the receptors
of these mediators.

Important
Concept
Irrespective of inducing anti-inflammatory or
suppressing inflammatory genes, the
glucocorticoid receptor acts through interactions
with DNA affecting local chromatin modifications,
particularly of histone acetylation.

Important
Concept
Glucocorticoids also modulate the innate immune
response within the airway such as enhancing the
production of antimicrobial peptides and restoring
epithelial barrier function.

Introduction
Pharmacokinetics
Metabolism and excretion
Side effects
01

Chemical Structures
GCs are steroid hormones with a 21-carbon four-ring backbone
The type and position of the substituents on the D
ring markedly affect the GC structure and function

Modifications
• C=C double bond insertion at C1-C2
- Reduce mineralocorticoid receptor binding
• Lipophilic substituents to the ring D
- Increase GR binding affinity
- Increase duration of local topical deposition
- Enhance breakdown in the liver
• Conversion of the 11-ketone group to an 11-hydroxyl group
- Amplify GC activity
• Cleavage of 16α or 17α groups after absorption
- Reduce systemic effects

https://en.wikipedia.org/wiki/File:SEGRAM_basic_mechanism.tif
• The ligand-binding
domain (LBD) of GR has a
pocket on the floor of the
binding cleft that lies
beneath the C17 residue
of the steroid backbone.
• The degree of occupancy
of this pocket affects the
affinity, duration of action
and side effect profile of
ligands
Caramori G, et al. Corticosteroids. Nijkamp and Parnham's Principles of
Immunopharmacology. 2019;661-688.

https://en.wikipedia.org/wiki/File:SEGRAM_basic_mechanism.tif
• Transactivation
• Transrepression
• GRE: glucocorticoid
response elements
• SEGRMs: selective
glucocorticoid receptor
modulators
• SEGRAs: selective
glucocorticoid receptor
agonists
Caramori G, et al. Corticosteroids. Nijkamp and Parnham's Principles of
Immunopharmacology. 2019;661-688.
Experimental drug

Pharmacokinetics
• The lipophilic nature of synthetic topical GCs
allows absorption and extended airway retention.
• The plasma levels of oral GC can vary up to 10-fold
in patients and in healthy volunteers with the same
drug dose.

MDI, DPI – only 10% to 20%
delivered to the airway

Metabolism and Excretion
• Binding to plasma proteins such as the transcortin
(high affinity, low capacity) or to serum albumin
(low affinity, high capacity) captures more than
90% of circulating cortisol.
• More than 98% of cortisol, for example, is
metabolized before being excreted into the urine.

Metabolism and Excretion
• Liver enzymes cytochrome P450-dependent mixed
function oxidases (MFOs) and various
conjugating enzymes affect steroid half-life.
• Diseases and drugs that affect liver function
including barbiturates and ephedrine increase
steroid metabolism and shorten their half-life by
inducing MFOs.

Local Metabolism of ICS within the Airway
• Conversion of low-affinity beclomethasone dipropionate
(BDP) to the high-affinity beclomethasone
17α-monopropionate (BMP)
• Reversible fatty acid conjugation of budesonide that leads to
its prolonged anti-inflammatory effect
• Cleavage of the isobutyryl group at C21 by esters located
within the airways of ciclesonide -> des-ciclesonide

Side Effects: ICS
• Glaucoma, cataracts, tissue atrophy, reduced wound healing
• Increased risk of infection
• Adrenal suppression
• A specific intronic single nucleotide polymorphism (SNP)
within the platelet-derived growth factor-D (PDGFD) gene
locus has recently been identified as increasing the risk of
adrenal suppression by GCs in asthmatic adults and
children.

Side Effects: Oral GC
• Skin and muscle atrophy
• Delayed wound healing
• Osteoporosis and bone necrosis
• Glaucoma and cataracts
• Behavioral changes
• Hypertension
• Peptic ulceration, GI bleeding
• Enhanced risk of infection
• Obesity and redistribution of body fat, and type 2 diabetes

• Cumulative worsening score (CWS) is an
additive record of glucocorticoid-related
toxicities experienced by a patient from
baseline. The score is always ⩾0.
• A CWS of 0 indicates that no new glucocorticoid toxicities
were present.
• The higher the CWS, the greater the number of new
toxicities encountered.
• The aggregate improvement score (AIS)
records present toxicity, allowing both
improvement and worsening.
• A positive score indicates increased total toxicity, whereas
a negative score reflects reduced toxicity.

Effects of GC
On asthmatic inflammation
On inflammatory cells
On immune response
On airways
02

Effects of GC
on asthmatic inflammation

A pragmatic, unblinded, randomized trial involving adults and
adolescents with asthma, in which a personalized self-management
plan that included a temporary quadrupling of the dose of ICS
when asthma control started to deteriorate resulted in fewer severe
asthma exacerbations than a plan in which the ICS dose was not
increased.
N Engl J Med. 2018 Mar 8;378(10):902-910.

N Engl J Med. 2018 Mar 8;378(10):902-910.

In children with mild to moderate persistent asthma who had at least
one asthma exacerbation treated with systemic glucocorticoids in
the previous year, quintupling the dose of ICS at the early signs of
loss of asthma control did not reduce the rate of severe asthma
exacerbations.
N Engl J Med. 2018 Mar 8;378(10):891-901.
Step Up Yellow Zone
Inhaled Corticosteroids to
Prevent Exacerbations
(STICS) trial

N Engl J Med. 2018 Mar 8;378(10):891-901.

N Engl J Med. 2018 May 17;378(20):1877-1887.
N Engl J Med. 2018 May 17;378(20):1865-1876.
SYGMA 1
SYGMA 2

N Engl J Med. 2018 May 17;378(20):1865-1876.

SYGMA 1 and SYGMA 2
Participants
Participants had asthma that required step 2 GINA asthma
management (2018 guidelines)*. Participants mean age was 39.6
years (SD 16.6) in SYGMA 1 and 41 years (SD 17.0) in SYGMA 2.
Patients were recruited from > 300 sites around the world.
*regular preventer therapy with low/med dose regular ICS or
leukotriene receptor antagonist
N Engl J Med. 2018 May 17;378(20):1877-1887.
N Engl J Med. 2018 May 17;378(20):1865-1876.

SYGMA 1 and SYGMA 2
Intervention
In SYGMA 1 participants were randomly assigned to one of 3 groups (A, B, C) in a double-
blind fashion. In SYGMA 2 participants were randomly assigned to one of 2 groups (B, C).
Both studies took place over a 52 week period and involved over 3000 patients in each
study. Electronic monitoring of inhaler use was conducted during both studies.
A = Placebo BD + Terbutaline PRN
B = Placebo BD + Symbicort® PRN
C = Budesonide BD + Terbutaline PRN
SYGMA 2 built upon the findings of SYMGA 1 and used a more pragmatic study design.
There were no daily reminders to take medications and the participant’s clinicians were
blinded as to their patient’s adherence to treatment.
N Engl J Med. 2018 May 17;378(20):1877-1887.
N Engl J Med. 2018 May 17;378(20):1865-1876.

SYGMA 1 and SYGMA 2
Primary Outcome
The primary outcome in SYGMA 1 was the long term efficacy
of PRN Symbicort® vs PRN Terbutaline. This was measured
by the weeks of well-controlled asthma.
The primary outcome in SYGMA 2 was the rate of severe
exacerbations.
N Engl J Med. 2018 May 17;378(20):1877-1887.
N Engl J Med. 2018 May 17;378(20):1865-1876.

SYGMA 1 Conclusion
SYGMA 1
• PRN Symbicort® is superior to PRN Terbutaline in achieving asthma control (4% of
weeks with well-controlled asthma vs 31.1% of weeks)
• PRN Symbicort is superior to PRN Terbutaline in reducing severe asthma
exacerbation rate (64%) and in reducing moderate to severe exacerbation’s (60%)
• PRN Symbicort® was inferior to Budesonide maintenance therapy in achieving
asthma control (34.4% of weeks with well-controlled asthma vs 44.4% of weeks).
• PRN Symbicort® was similar to Budesonide maintenance therapy in reducing asthma
exacerbation rates, but less total steroid dose was used and patients did not need to
remember to take a medication every day.
N Engl J Med. 2018 May 17;378(20):1877-1887.
N Engl J Med. 2018 May 17;378(20):1865-1876.

SYGMA 1 Conclusion
SYGMA 1
Participants had reminders to take medications and it was felt that the high level of
adherence (79%) recorded in the low dose maintenance budesonide group was
unlikely to reflect real-world experience.
This good adherence was hypothesized as the reason for the better findings in the
budesonide group.
SYGMA 2 was designed as a more pragmatic study to represent real-world adherence
levels and evaluate this hypothesis.
N Engl J Med. 2018 May 17;378(20):1877-1887.
N Engl J Med. 2018 May 17;378(20):1865-1876.

SYGMA 2 Conclusion
SYGMA 2
• PRN Symbicort® was non-inferior to low-dose budesonide maintenance treatment in
preventing severe asthma exacerbations.
• PRN Symbicort® prevented a similar rate of severe exacerbation with less than 25%
of the total exposure to inhaled glucocorticoid received with budesonide maintenance
therapy.
• When adherence is at the level seen in the trial (63%); budesonide maintenance
therapy is more effective in addressing symptoms, with larger improvements in FEV1
and ACQ-5 and Quality of life (AQLQ) scores seen in the regular ICS arm. However, it
should be noted that the magnitude of the difference in scores, which though
statistically significant, would not be considered clinically significant.
N Engl J Med. 2018 May 17;378(20):1877-1887.
N Engl J Med. 2018 May 17;378(20):1865-1876.

Effects of GC
on inflammatory cells

Effects of GC on inflammatory cells
• Oral or IV GCs cause an acute (4 to 6 hours) 80% reduction in
circulating leukocytes, particularly basophils, eosinophils, and
monocytes but an increase in neutrophils.
• Levels of cytotoxic CD8+ and natural killer (NK) cells are not
affected by acute GC administration(revert back to baseline
24 to 48 hours after a single administration)

1. Eosinophil
• Eosinophilopoietic factors: IL-5, IL-3, GM-CSF
• Anti–IL-5 therapies in asthma (Mepolizumab): decrease
exacerbation , not others outcome
Outcome of GCs to eosinophil
• Prevent eosinophil migration to the lung
• Decrease blood eosinophil (after antigen challenge)
• Induce eosinophil apoptosis (capase-3 activation)
• ** Do not modulate Eo chemotaxis, adhesion,
degranulation

2. Neutrophil
Opposite effect on neutrophils as on eosinophils
Increasing peripheral blood neutrophil numbers
• Decreased cell migration from blood
• Increased neutrophil survival
• Increased bone marrow production

3. Lymphocyte
Effect to T cell>B cell
GRs are localized to mitochondria (DNA/RNA, gene, transcription factors)
T cell: Reduced number of lymphocyte
• inhibit lymphocyte activation and inflammatory mediator expression
• induce lymphocyte apoptosis
TH1: Delayed-type hypersensitivity (DTH) reactions (e.g., tuberculin test)
• Th1 mediated and blocked by GCs in vivo because of effects on lymphocyte
migration and proliferation
B cell: Small increase in IgG and IgM release after large doses of GCs
CD4+CD25+ Foxp3+ regulatory T cells (Tregs): enhance expression of IL-10
Th17 and NK cells: not well established

4. Monocyte, macrophage, and dendritic cell
In asthmatic patients
• Monocyte and alveolar macrophage numbers are
increased in the airways
• Express both high- (FcεRI) and low-(FcεRII, CD23)
affinity IgE receptors

Effect of GCs
• Reduce the expression of macrophage-derived proinflammatory
cytokines: IL-1, TNF-alpha, IL-6
• Decrease monocyte and their expression of low affinity IgE
receptors (CD23)
• Reduce number of MHC class II
• Inhibit the inducible release of enzymes e.g. plasminogen activator,
elastase, and collagenase
• Reduce intracellular killing of Norcardia, Listeria and Salmonella

Effect of GCs
● Control migration of DCs to local lymphoid node through CCR7
● Prevent the release of Th1- and Th2-polarizing cytokines from DCs
e.g. IL-4, IL-12, IL-13, TSLP → inh. development of Th1 and Th2 cells
● Phagocytosis of apotosis eosinophil and neutrophil
● Enhance monocyte differentiation into phagocytic macrophages
● Enhance DC release of IL-10, enabling Treg development
downstream of glucocorticoid-induced leucine zipper (GILZ)

Although reducing the number of activated macrophages
and DCs, steroids probably counter this by increasing their
phagocytic activity

5. Mast cell
In ICS user
• BAL and lung biopsy: reduce mast cell number, expression of IgE receptor,
mediator release and maturation
• Nasal biopsy: no effect*
• In vitro: human mast cells from lungs and skin do not reduce histamine or
leukotriene release in response to GCs
• Unable to prevent the acute release of mediators from human lung mast cells
→ failure to suppress the early/Acutely asthmatic response
• Patients receiving systemic steroids still have positive skin-prick tests

5. Mast cell
Topical GCs
• Skin: reduced mast cells number (GCs treatment in urticaria
pigmentosa)
• Suppressing epithelial cell release of chemokines (eotaxin CCL11),
monocyte chemoattractant protein-4 (MCP-4, CCL13) and RANTES,
CCL5 from T cell
In INS user
• Reverse allergen-elevated nasal mucosal mast cell numbers

6. Basophil
Similar effect of basophils as on eosinophils
• Reduce airway basophilia
• Induce apoptosis
• Prevent basophil growth factors
• Reduce basophil release of IL-4 and IL-13 in vitro
• Decrease histamine and leukotriene releasing
• In contrast: prolonged treatment with oral GCs→ no effect on number of
blood basophils, which are still able to release histamine in response to IgE
stimulation.

Sparing innate immune response
Some innate immune responses are not reduced, or may even be
enhanced
• Increased production and survival of neutrophils
• Increased macrophage phagocytosis
• Improved epithelial survival
• Expression of innate immune genes such as Toll-like receptors
(TLRs), complement, pentraxins, collectins, SAA, and other host
defense genes are either enhanced or not repressed by GCs.

Effects of GC
on immune response

Immune response
Immunosuppressive property
• GCs spare innate immune response (Toll-like receptor [TLR],
complement, and collectins)
• Increased production and survival of neutrophils, increased
macrophage phagocytosis (Function Not Number), and improved
epithelial survival
• The mechanisms for these effects are not clear but involve, in part,
the transcription factor C/EBPβ and the MAPK pathways

Effects on cell recruitment to the airways
• GCs suppress the expression of most chemokines involved in
recruitment of key asthma inflammatory cells into the airway.
• Major target of GCs is proinflammatory transcription factor nuclear
factor (NF)-κB
Cell adhesion molecules
• Effect on VCAM but NOT ICAM in astmatic patient
• No effect of GCs on ICAM expression
• VCAM1 reduce in nasal polyps and asthma biopsies after GC treatment

Effects on airway epithelial cells
• GCs regulate human airway epithelial barrier function, by
controlling the expression of VCAM-1 and of other CAMs
• Control mucus production and fluid flux across the epithelium
• Enhance expression of surfactant protein (SP)-B and SP-C,
reduced airway surface tension
• Spare complement system

Effects on airway
Smooth muscle cells
• Suppress airway smooth muscle proliferation
Airway vasculature
• Prevent the release of cyclooxygenase (COX) enzyme products (via
suppression of phospholipaseA2 and COX2 expression)
• Prevent nitric oxide (NO) release
• Reduce microvascular leak in the airways of patients with asthma
• Inhibiting VEGF expression→ decrease in angiogenesis and reduced
number of blood vessel

Crosstalk between adrenergic system
and glucocorticoid
• Receptor cross-talk refers to the up- or downregulation of receptors or their
actions via the actions of heterologous receptors and their signaling
intermediates
• Prolonged stimulation of β2-adrenoceptor → downregulation of β2-AR
expression
Glucocorticoid can counteract this effect
• Enhance β2-AR mRNA expression through binding to specific sites in the
promoter region
Asthma patients: low dose fluticasone+ salmeterol = high dose fluticasone
• This results from GR priming by protein kinase (PK) A, which enhances GR
nuclear translocation in sputum cells from asthmatic patients

Glucocorticoid Receptor (GR)
• GR is known to be phosphorylated at three major
sites on its N terminus (Ser203, Ser211 and Ser226)
• Two types of GC receptors: GRα and GRβ
• GCs - Free, or unbound, steroid binds to the GC
receptor in cytoplasm
• After binding with the receptor, the following events
occur (in order):
(1) heat shock proteins dissociate from the receptor
(2) the receptor is phosphorylated
(3) the steroid-receptor complex (GR and chaperone
complex) translocates into the nucleus

Mechanism of action
Genomic action
• Implicates the activation or repression of multiple genes.
• Glucocorticoids significantly suppress airway inflammation,
mainly through genomic mechanism
• Takes effect with a time lag of about 4 to 24 hours
• Dose dependent

Mechanism of action
Nongenomic action
• Do not directly and initially influence gene expression
• Rapid onset (seconds to minutes)
• Short duration of action (60-90 minutes)
• Dose dependent
• Nongenomic action includes many second messengers
(including cAMP and diacylglycerol), kinases (mitogen-activated
protein kinase, protein kinase C) and ion fluxes (calcium)

• Gene activation via binding to a positive glucocorticoid response element (GRE).
• Gene repression via binding to a negative GRE.
• Indirect gene repression via interference with transcription activating factors (NFκB).
• Competition between GC receptor and transcription factors on the surface of
integrator proteins, such as CREB-binding protein (CBP/p300).
• CBP has associated histone acetyltransferase (HAT) activity, which leads to DNA
unwinding and access to transcription factors.
• Steroids inhibit HAT activity and recruit histone deacetylases (HDACs), which
oppose HAT activity.
• Induction of transcription factor inhibitors (i.e., GILZ, IκBα), which interfere with
NFκB.
• Destabilization of target gene mRNA.

1. Induce anti-inflammatory
genes eg. NF-kB inhibitor, IL10 or
non coding RNAs (simple GRE)
2. Bind to nGRE-> prevent
inflammatory gene expression
3. Direct or indirect interact with
transcription factor
4. Increase level of
ribonucleases and mRNA
destabilizing protein such as
HuR and tristertrapolin ->
reducing mRNA
Timmermans et al. Frontiers in immunology, July 2019

Inflammatory gene expression and NF-kB

Nongenomic action
Effect through Binding to Cytosolic Glucocorticoid Receptors

Alangari AA. Annals of Thoracic Medicine. 2010;5(3):133-139.
• When glucocorticoids bind their own receptors in the cytosol→ some GR
protein complex components, like src, dissociate and block the EGF-
mediated cPLA2 activation and subsequently arachidonic acid
production.
• Although several in vitro studies and animal studies have demonstrated
decrease in baseline and post-challenge production of cysteinyl
leukotrienes after treatment
• In vivo studies generally failed to show a similar effect.
• This suggests that the action of glucocorticoids through this pathway is
not likely to be significant in asthma treatment.

Interaction with Cellular Membrane
Glucocorticoids can be incorporated into cell membranes
Changes in the physicochemical properties of the membrane
• Subsequently, this may interfere with mineral transport across
the cell membrane and the cellular production of adenosine
triphosphate (ATP).
• These effects result in immune cell suppression
• This action is noted at high glucocorticoid doses

Effects through Membrane-bound
Glucocorticoid Receptors
• Rapid T-cell immunosuppressive action through
membrane-bound GRs
• These receptors were reported to exist in human mononuclear cells
and to correlate with glucocorticoids’ lytic responses in lymphoma
cells and with disease activity in rheumatoid arthritis.
• Liganded receptors inhibit the function of Lck/Fyn kinases,
downstream from T-cell receptor → suppress major pathways
important in T-cell activation. (Dexamethasone, Prednisolone)

Anti-inflammatory property:
arachidonic acid metabolites

Factors effecting
GC sensitivity
Obesity
Smoking
Infection
04

Obesity and relative GC insensitivity
Emerging relatively steroid-insensitive phenotype in asthma
Non-T2 or eosinophilic mechanisms
• T2-low asthmatics had a lower enrichment of a cytotoxic CD8+ T cell
network that negatively correlated with body mass index
and plasma IL-6 levels.
• Reflect an altered mitochondrial/metabolic function in paucigranulocytic
patient supported by altered NO metabolism in response to a high-fat diet

Obesity and relative GC insensitivity
High-fat diet induce
• Mitochondrial dysfunction
• Severe airway obstruction
• Steroid insensitivity
• Neutrophilic airway inflammation.
High IL-6 levels in the
plasma of obese severe
asthmatic subjects may help
stratify patients for targeted
anti–IL-6 therapy.

Smoking and relative GC insensitivity
Current smokers VS Ex-Smoker
• Current with severe asthma had increased sputum CSF2
• Ex-smokers showed a reduction in proteins and genes
associated with epithelial barrier function

Infection and relative GC insensitivity
Viral infection are associated with up to 80% of asthma
exacerbation.
• Rhinovirus (RV) is the most frequently identified virus in natural asthma
exacerbations.
• RV infection worsens the inflammation in both upper and lower airway of
asthmatic patients.
• This post-infection inflammatory response remains despite anti-
inflammatory treatment.
• Experimental viral challenge is associated with enhanced oxidative and
nitrosative stress and the reduction in HDAC2 expression in COPD
patients, and it is likely that this is also the case in severe asthma.

• Prevention of RV, influenza, and RSV infection may also enhance
steroid responsiveness
• Corticosteroids also have little clinical benefit in bronchiolitis driven
by respiratory syncytial virus (RSV)
• RSV prevent GR nuclear translocation in nasopharyngeal aspirates
from RSV-infected infants (J Infect Dis 2017;217:35–46)
• Th1 cytokines, such as TNF-α and IFN-γ, promote corticosteroid
resistance in adult human ASM

Bacterial infection is also associated with GC-
refractory exacerbations of asthma
• Staphylococcal enterotoxins enhance the inflammatory
response in asthma
• Recruit and activate Th17 cells and suppress Treg cells

Fungal infection has been associated with asthma
severity, and in animal models fungal exposure
enhances allergen-driven Th2 responses, promoting
severe allergic asthma
• Surface molecule β-glucan and abrogated by neutralization of
IL-17A

Glucocorticoids in Asthma: Effects on Inflammation and Exacerbations

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