Abbreviations: CCSP, clara cell secretory protein; Sec14l3, Sec14-like
protein 3; YKL-40, chitinase-3-like protein 1; ACO, asthma-COPD overlap;
ICS, inhaled corticosteroid
Epithelium-derived biomarkers :
Several studies have reported the role of potential epithelium-derived
biomarkers in asthma due, in part, to the relative ease of obtaining
samples from the respiratory epithelium. Prominent among these are
periostin, ezrin, fibrinogen, CCSP, IL-33, TSLP, claudin 4, claudin 18,
MMP-9 and Sec14l3.
Epithelium- and tissue-associated biomarkers (biomarkers of
mixed origin) :
In this section we focus on a few key current and emerging potential
asthma biomarkers but others including osteopontin, YKL40 and IL-25 have
also been postulated as important.
4.1. Periostin is an extracellular matrix protein induced by IL-4 and
IL-13 in AECs and lung fibroblasts. It is a key molecule connecting T2
airway inflammation and airway remodeling, and is related to
T2high eosinophilic asthma [53]. Mouse models
suggest a role of periostin in subepithelial fibrosis, eosinophil
recruitment, and mucus production from goblet cells [54]. In
childhood asthma, the level of periostin was significantly higher than
that of the healthy control groups [55]. Serum periostin levels in
2-year-old children are 2-3 fold higher than previously observed adult
levels and can predict asthma at aged 6. Previous data in adults found
elevated levels of periostin in the serum of asthmatics and that levels
were associated with fixed and more severe airflow obstruction [56]
and greater decline in lung function [57]. Thus, periostin was
reported to be a systemic and promising biomarker of T2, IL-13-driven,
corticosteroid-responsive asthma. Furthermore, serum periostin levels
were stable during disease progression in adults with asthma and did not
show a seasonal variation [58]. In children between 4 and 11 years
of age, serum periostin was the best predictor of airway eosinophilia
compared with FeNO, blood eosinophil counts and serum IgE [59]. Its
movement from inflamed tissues to the systemic circulation further
supported its use as a biomarker for T2-high asthma.
Serum periostin was used as a biomarker in phase 2 and 3 clinical
studies of the anti-IL-13 antibody lebrikizumab [60]. However,
recent evidence indicates little selectivity of serum periostin for T2
asthma and it is not surprising, therefore, that phase 3 studies of
lebrikizumab were not considered effective [61]. In contrast, high
sputum periostin reflects T2high asthma [62]
whereashigh serum periostin is now considered indicative of omalizumab
efficacy in asthma [63].
While periostin may have prognostic, predictive, and pharmacodynamic
properties, the inconsistency of results, serum levels that change with
age, and increased expression in other diseases limit its clinical
applicability and affect its utility as an independent biomarker
[64].
4.2. Club cell secretory protein 16 (CCSP16) is produced predominantly
by club cells and non-ciliated epithelial cells in the distal airways
and is readily detectable in the peripheral circulation [65].
Mounting evidence suggests that this protein is critical in mediating
anti-inflammatory and anti-oxidant functions within the lung and, by
virtue of these activities, may protect against development of
obstructive lung diseases [66].
CCSP16 is considered to be both a sign of the loss in airway epithelial
barrier integrity and a common participant in the anti-inflammatory
response. Low levels of CCSP16 in the serum are associated with
decreased lung function in childhood, accelerated decline in lung
function in adulthood and restricted airflow [67]. While studies
have shown that CCSP16 and surfactant protein D (SPD) in sputum and BAL
were significantly higher in patients with severe asthma compared to
mild-moderate and healthy controls [68] serum CCSP16 levels were
reduced in asthmatics. BAL levels of CCSP16 correlated with epithelial
detachment suggesting its possible role of in the remodeling process.
Zhai and colleagues [66] using human data from a birth cohort,
suggested that low circulating CCSP16 levels were not only a biomarker
of airway pathology but may be implicated in the pathophysiology of the
progressive airway damage that characterize obstructive lung diseases.
Moreover, urinary CCSP16 may be a useful tool or biomarker for studying
asthma and the integrity of the alveolar epithelium in children with
lung injury [69].Emerging biomarkers:
4.3. Ezrin is a membrane-associated cytoskeleton protein that plays a
role in maintaining cell morphology and adhesion between cells and
protects AEC barrier function. We have proposed that the downregulation
of ezrin indicates AEC injury in asthma and may be a potential marker
for monitoring the severity of disease. This concept is based upon the
functional effect of ezrin on AEC barrier function and the high degree
of correlation between decreased ezrin levels in several asthma
biosamples, including EBCs and serum in humans and BAL in mice, and
decreased lung function [70]. Furthermore, serum ezrin levels
negatively correlated with serum periostin and IL-13 levels. Although
exosome secretion from AECs was suggested as a mechanism by which ezrin
localizes in EBC, BAL and serum, further work is needed to confirm this
[71]. In contrast, acute bronchial challenge of patients with
steroid-naïve mild allergic asthma with Dermatophagoides pteronyssinus
resulted in enhanced serum levels of ezrin and IL-13 after 24 hours
[72]. The authors suggested that acute asthma attacks result in
heightened release of biologically active substances such as ezrin from
damaged AECs, which initiates an IL-13-driven immune cascade that
results in further increases in ezrin levels [72]. Further studies
are required to look at temporal changes in ezrin levels in various
biosamples and the impact of natural asthma exacerbations.
4.4. Chitinase-3-like protein 1 (CHI3L1), also known as YKL40, is
expressed and secreted by various cells such as epithelial cells,
macrophages, neutrophils, and smooth muscle cells. It is significantly
increased in asthma patients and its expression is closely related to
asthma severity and airway remodeling. YKL40 may promote the airway
remodeling of asthma by activating FAK and MAPK signaling pathways,
inducing epithelial mesenchymal transition (EMT) and subepithelial
fibrosis [73]. Tang and colleagues [74] showed that serum YKL40
levels of Chinese patients with asthma were increased and correlated
with the number of exacerbations. Serum YKL40 levels are correlated with
total IgE, blood eosinophils and inversely with lung function and could
predict the longitudinal decline of lung function in response to
cigarette smoke exposure [75]. Two distinct asthma phenotypes were
identified with high YKL40 levels, which were associated with non-T2
inflammatory pathways, one with irreversible airway obstruction disease
and another with severe exacerbations [76]. Hence, the YKL40
clusters are potentially useful for identification of severe or
exacerbation-prone asthma in non-T2 patients. In addition, YKL40 may
also be a blood-based biomarker in neutrophilic asthma [77] as serum
levels correlate with sputum neutrophils [26]. YKL40 has also been
used to distinguish asthma from chronic obstructive pulmonary disease
(COPD) and healthy controls [78], as well as between patients with
asthma-COPD overlap (ACO) and COPD [79]. YKL40 needs to be evaluated
in a larger asthma population to prove the its role in assessing asthma
outcomes and risks.