Page 107 - Škrgat, Sabina, ed. 2022. Severe Asthma - Basic and Clinical Views. Koper: University of Primorska Press. Severe Asthma Forum, 1
P. 107
trophylic Asthma either activate a pro‐inflammatory cascade 107
or differentiate into immunomodulatory role.
Key cytokine involved in T2-low asthma, This knowledge is crucial in programming t2-low asthma
IL‐17, promotes neutrophil migration by in- the treatment strategies because the treatment
ducing IL‐6 and IL‐8 release from bronchi- not adapted to the specific underlying patho-
al epithelial cells. IL‐8 (CXCL8) is the most biology may lead to undue adverse effects16.
potent chemoattractant in the lung that cor-
relates with both increased neutrophil per- Impact of Corticosteroids on Sputum
centage and absolute neutrophil counts. Neutrophilia
Moreover, neutrophils have also been demon-
strated to secrete IL‐8 creating a positive feed- Th1 cell activation leads to production of
back loop that promotes further neutrophilic IFN‐γ which in combination with the low se-
inflammation. cretory leukocyte protease inhibitor (SLPI)
expression leads to high airway resistance and
Receptor for advanced glycation end‐ corticosteroid refractoriness. Use of corticos-
products (RAGE) is a pattern‐recognition re- teroids (ICS and OCS) has been even shown
ceptor that interacts with various endogenous to contribute to sputum neutrophilia17 be-
ligands involved in host response to injury, in- cause the corticosteroids, while they promote
fection, and inflammation. Asthmatics with apoptosis of eosinophils, have been demon-
neutrophilic inflammation have a deficiency strated to inhibit neutrophil apoptosis. Spu-
in soluble form of RAGE (sRAGE). sRAGE tum neutrophil count was higher in patients
serves as a decoy receptor by sequestering receiving moderate‐to‐high dose ICS than
RAGE ligands and thus inhibiting RAGE de- those receiving low‐dose ICS.
pendent cellular responses. It is not known
whether that deficiency is causative factor or Paucigranulocytic Asthma
the result of neutrophilic inflammation13.
Paucigranulocytic asthma encompasses pa-
It is wrong to consider neutrophils as tients with absence of airway inflammation
only negative cells in asthma. Activated neu- (eosinophilia and neutrophilia) with persis-
trophils can eliminate pathogens by phagocy- tent symptoms and evidence of AHR5. Acti-
tosis, degranulation or formation of neutro- vation of Type 1 ILCs with excessive IFN‐γ
phil extracellular traps (NETs). Because of production leads to reduced numbers of eo-
their role in mediating persistent inflamma- sinophils and neutrophils resulting in pauci-
tion and causing airway damage, they have granulocytic inflammation. Mechanisms of
been thought of as primitive killers. How- this endotype can be changes in ASM or in-
ever, they can have immunomodulatory ef- flammation not reflected in the bronchial lu-
fects and play a role in tissue repair and heal- men.
ing through production of anti‐inflammatory
cytokines like IL‐1RA, IL‐10, TGFß1 and Numerous stimuli, including inflamma-
TGFß2. High extracellular DNA concen- tory cytokines, pollutants, altered airway mi-
trations in sputum mark a subset of patients crobiome and mechanical strains, can pre-
with more severe asthma who have NETs and dispose ASM to become nonspecifically
markers of inflammasome activation in their hyper‐responsive.
airways14,15.
AHR independent of inflammation can
The particular effect of the neutrophils is be caused by the altered neuronal control
dependent on location of the cells, comorbid- of ASM contractility. Nerve growth factor
ities and surrounding inflammatory milieu (NGF) can induce AHR, activate inflamma-
and nowadays we can recognise multiple neu- tory cells and cause airway remodeling. Neu-
trophil phenotypes with distinct morpholog- roimmune cross‐link dysregulation of critical
ical and functional characteristics. They can
or differentiate into immunomodulatory role.
Key cytokine involved in T2-low asthma, This knowledge is crucial in programming t2-low asthma
IL‐17, promotes neutrophil migration by in- the treatment strategies because the treatment
ducing IL‐6 and IL‐8 release from bronchi- not adapted to the specific underlying patho-
al epithelial cells. IL‐8 (CXCL8) is the most biology may lead to undue adverse effects16.
potent chemoattractant in the lung that cor-
relates with both increased neutrophil per- Impact of Corticosteroids on Sputum
centage and absolute neutrophil counts. Neutrophilia
Moreover, neutrophils have also been demon-
strated to secrete IL‐8 creating a positive feed- Th1 cell activation leads to production of
back loop that promotes further neutrophilic IFN‐γ which in combination with the low se-
inflammation. cretory leukocyte protease inhibitor (SLPI)
expression leads to high airway resistance and
Receptor for advanced glycation end‐ corticosteroid refractoriness. Use of corticos-
products (RAGE) is a pattern‐recognition re- teroids (ICS and OCS) has been even shown
ceptor that interacts with various endogenous to contribute to sputum neutrophilia17 be-
ligands involved in host response to injury, in- cause the corticosteroids, while they promote
fection, and inflammation. Asthmatics with apoptosis of eosinophils, have been demon-
neutrophilic inflammation have a deficiency strated to inhibit neutrophil apoptosis. Spu-
in soluble form of RAGE (sRAGE). sRAGE tum neutrophil count was higher in patients
serves as a decoy receptor by sequestering receiving moderate‐to‐high dose ICS than
RAGE ligands and thus inhibiting RAGE de- those receiving low‐dose ICS.
pendent cellular responses. It is not known
whether that deficiency is causative factor or Paucigranulocytic Asthma
the result of neutrophilic inflammation13.
Paucigranulocytic asthma encompasses pa-
It is wrong to consider neutrophils as tients with absence of airway inflammation
only negative cells in asthma. Activated neu- (eosinophilia and neutrophilia) with persis-
trophils can eliminate pathogens by phagocy- tent symptoms and evidence of AHR5. Acti-
tosis, degranulation or formation of neutro- vation of Type 1 ILCs with excessive IFN‐γ
phil extracellular traps (NETs). Because of production leads to reduced numbers of eo-
their role in mediating persistent inflamma- sinophils and neutrophils resulting in pauci-
tion and causing airway damage, they have granulocytic inflammation. Mechanisms of
been thought of as primitive killers. How- this endotype can be changes in ASM or in-
ever, they can have immunomodulatory ef- flammation not reflected in the bronchial lu-
fects and play a role in tissue repair and heal- men.
ing through production of anti‐inflammatory
cytokines like IL‐1RA, IL‐10, TGFß1 and Numerous stimuli, including inflamma-
TGFß2. High extracellular DNA concen- tory cytokines, pollutants, altered airway mi-
trations in sputum mark a subset of patients crobiome and mechanical strains, can pre-
with more severe asthma who have NETs and dispose ASM to become nonspecifically
markers of inflammasome activation in their hyper‐responsive.
airways14,15.
AHR independent of inflammation can
The particular effect of the neutrophils is be caused by the altered neuronal control
dependent on location of the cells, comorbid- of ASM contractility. Nerve growth factor
ities and surrounding inflammatory milieu (NGF) can induce AHR, activate inflamma-
and nowadays we can recognise multiple neu- tory cells and cause airway remodeling. Neu-
trophil phenotypes with distinct morpholog- roimmune cross‐link dysregulation of critical
ical and functional characteristics. They can
