Peripheral blood and molecular biomarkers in idiopathic pulmonary fibrosis (IPF)

Mechanism of actionOutcome of the studyEffect on IPF
Circulating blood biomarkers
 CCL18Alternative macrophage activation
Upregulation of collagen production by lung fibroblasts
Higher mortality in patients with serum CCL18 concentrations >150 ng·mL−1, higher incidence of disease progression in the group with high serum CCL18 concentrations [22]Predicts progression and mortality in IPF
 ICAM-1Adhesion molecule
Marker of oxidative stress in the lungs
Predicts poor overall, transplant-free and progression-free survival [23]Predicts mortality in IPF
 KL-6/MUC1High molecular weight glycoprotein expressed at ECM surface of type II pneumocytesSignificantly higher level in ILDs [24]
Higher levels among patients who died within the study period [25]
Lower survival of patients with high KL-6 [26]
Discriminates ILDs from other benign lung diseases
Predicts mortality in IPF
 SP-ASurfactant proteins produced by type II pneumocytesHigh level in IPF [27]
Independent predictor of survival [28]
Associated with the time to death or lung transplantation [29]
Predictive effect on those with UIP in HRCT [30]
Discriminate IPF from other ILDs
SP-A, SP-D predict mortality in IPF
 SP-BHigher level in IPF [31]
 SP-DHigh level in IPF [25]
Independent predictor of survival time better related to parenchymal involvement [27]
 MMP1Zinc-dependent proteases involved in the breakdown of ECM components
MMP1 the most highly expressed interstitial collagenase degrading fibrillar collagens
MMP7 the smallest member capable of degrading multiple components of ECM
Distinguish between IPF and HP [32]
Elevated levels in IPF [25]
Discriminates IPF from other ILDs
 MMP7Distinguish between IPF and HP [32]
Elevated levels in IPF [25]
Related to FVC decline, to higher prevalence of exertional dyspnoea, to ILAs on HRCT and to higher all-cause mortality [33]
Discriminates IPF from other ILDs
Predicts mortality in IPF
 BNPNatriuretic peptide secreted by cardiac ventriclesCorrelation with clinical status, functional exercise testing parameters, functional WHO class II, III [34]Relates to haemodynamic parameters and prognostic value in patients with left or right heart failure
 VEGFGrowth factor regulating angiogenesis enhancing vascular permeabilityPositive correlation with HRCT interstitial score, influence on monthly FVC decline [35]Reflects severity and predicts progression of IPF
 downregulation on
 CD4+ T52 cells
CD28 co-stimulatory molecule providing signal for activation of naive CD4 lymphocytesCorrelated with decreased FVC and freedom from major adverse events (death or lung transplantation) [36]Predicts progression, mortality in IPF
 HSP70 IgG
HSP70 antibody working against HSP70 autoantigene and activating IL-8 production of monocytesAssociated with decreased FVC and 1-year survival [37]Predicts progression, mortality in IPF
 PeriostinFibroblast activating matrix proteinsNegative correlation with monthly changes in VC, DLCO [38]
Increase of honeycombing score on HRCT, predictor of shortened overall survival, time-to-event [39]
Predicts progression, mortality in IPF
 OsteopontinGlycoprotein secreted by osteoclasts, macrophages and activated T-cellsReverse correlation with arterial oxygen tension [40]Predicts progression in IPF
 YKL40Chitinase-like proteinElevated levels in ILDs, correlated with poor survival [24, 41]Discriminates ILDs from healthy subjects
Predicts mortality in IPF, remains predictive after 3–4 years
 BLysPlasma B lymphocytes stimulating factorCorrelated with pulmonary artery pressures, subjects with higher BLys diminished 1-year survival compared to those with lower BLys [42]Predicts PH and survival in IPF
Produce ECM components, mesenchymal markers
Potential role in myofibroblast differentiation
High levels correlated with poor survival regardless to preservation of lung function, counts increased further during AE-IPF [43]Predicts survival in IPF
 CXCL13Chemokine playing a role in autoimmune processes, mediating B-cell homing to inflammatory fociHigh levels correlated with poor FVC and poor major event-free survival (i.e. transplant-free survival) [44]Predicts progression, mortality in IPF
 EGFREpidermal growth factor required for TGF-β1-induced epithelial-mesenchymal transition
Crucial in signalling in bronchial epithelium
Lower levels in IPF [25]Discriminates IPF from healthy subjects
 ClusterinKnown as apolipoprotein J
Glycoprotein upregulated by cytotoxic stimuli, maintaining epithelium viability during lung repair
Lower levels in IPF [25]Discriminates IPF from healthy subjects
 CRPMC reactive, acute-phase protein degrading by matrix metalloproteaseHigher levels in IPF, could discriminate between stable and progressive subjects and indicated poor overall survival [45]Discriminates IPF from healthy subjects
Predicts progression, mortality in IPF
 CA-19-9Tumor markers, mucous associated carbohydrate antigens increasing in metaplastic epithelium in fibrotic lesions
Associated with mucous secretion within honeycomb cysts
High levels highly predictive of progressive fibrosis [46]Predicts progression, mortality in IPF
 CA-125Rising levels predicted both disease progression and overall survival [46]
 OSMGlycosylated protein, member of IL-6 family of ligandsIdentified baseline prognosis and longitudinal change in individuals with IPF [47]Discriminates ILDs from healthy subjects
Predicts progression, mortality in IPF
 CYFRA-21-1Intermediate filaments in the cytoskeleton of alveolar and bronchiolar epithelial cells
Marker of epithelial cell damage
Identified baseline prognosis and longitudinal change in individuals with IPF [47]Discriminates ILDs from healthy subjects
Predicts progression, mortality in IPF
Molecular biomarkers
 MUC5BMucin associated with the development of both familial interstitial pneumonia and sporadic IPFMUC5B promoter gene polymorphism associated with improved survival independent of clinical factors [48]Predicts survival in IPF
 uPARPlasminogen activator receptor augmenting monocyte adhesionElevated serum levels through macrophage overexpression in IPF compared to controls [49]Discriminates IPF from healthy subjects
 TERTReverse transcriptase maintaining telomere integrityMutation associated with familial interstitial pneumonias [50] and sporadic, adult-onset IPF [51]Discriminates familial ILDs and IPF from healthy subjects
 Telomere lengthLength of nucleoprotein structures that protect chromosomal endsShorter telomere length associated with progression-free survival of IPF [52]Predicts survival in IPF
 TLR3Receptor mediating innate immune response to tissue injury, inflammation and viral infectionPolymorphism associated with early lung function decline and death [53]Predicts progression, mortality in IPF
 α-DefensinAntimicrobial peptides presenting in granules of neutrophils inhibiting activation of the classical complement pathwayIncreased α-defensins localised in the epithelium of the lungs and apoptosis of epithelium in AE-IPF [54]Predicts AE-IPF

CCL18: CC chemokine ligand 18; ICAM-1: intercellular adhesion molecule 1; KL: Krebs von den Lungen; MUC: mucin; SP: surfactant protein; MMP: matrix metallopeptidase; BNP: brain natriuretic peptide; VEGF: vascular endothelial growth factor; HSP: heat shock protein; Ig: immunoglobulin; YKL40: chitinase-like protein; BLys: plasma B lymphocytes stimulating factor; CXCL: C-X-C motif chemokine ligand; EGFR: epidermal growth factor receptor; CRPM: C-reactive protein degraded by metalloproteinase-1/8; CA: cancer antigen; OSM: oncostatin M; CYFRA-21-1: cytokeratin 19 fragment; uPAR: urokinase-type plasminogen activator receptor; TERT: telomerase reverse transcriptase; TLR: toll-like receptor; ECM: extracellular matrix; ILD: interstitial lung disease; UIP: usual interstitial pneumonia; HRCT: high-resolution computed tomography; IL: interleukin; HP: hypersensitivity pneumonitis; FVC: forced vital capacity; ILA: interstitial lung abnormality; WHO: World Health Organization; VC: vital capacity; DLCO: diffusing capacity of the lung for carbon monoxide; PH: pulmonary hypertension; AE-IPF: acute exacerbation of idiopathic pulmonary fibrosis; TGF: transforming growth factor.