Peripheral blood and molecular biomarkers in idiopathic pulmonary fibrosis (IPF)
| Mechanism of action | Outcome of the study | Effect on IPF | |
| Circulating blood biomarkers | |||
| CCL18 | Alternative 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-1 | Adhesion molecule Marker of oxidative stress in the lungs | Predicts poor overall, transplant-free and progression-free survival [23] | Predicts mortality in IPF |
| KL-6/MUC1 | High molecular weight glycoprotein expressed at ECM surface of type II pneumocytes | Significantly 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-A | Surfactant proteins produced by type II pneumocytes | High 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-B | Higher level in IPF [31] | ||
| SP-D | High level in IPF [25] Independent predictor of survival time better related to parenchymal involvement [27] | ||
| MMP1 | Zinc-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 |
| MMP7 | Distinguish 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 | |
| BNP | Natriuretic peptide secreted by cardiac ventricles | Correlation 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 |
| VEGF | Growth factor regulating angiogenesis enhancing vascular permeability | Positive correlation with HRCT interstitial score, influence on monthly FVC decline [35] | Reflects severity and predicts progression of IPF |
| CD28 downregulation on CD4+ T52 cells | CD28 co-stimulatory molecule providing signal for activation of naive CD4 lymphocytes | Correlated with decreased FVC and freedom from major adverse events (death or lung transplantation) [36] | Predicts progression, mortality in IPF |
| HSP70 IgG antibodies | HSP70 antibody working against HSP70 autoantigene and activating IL-8 production of monocytes | Associated with decreased FVC and 1-year survival [37] | Predicts progression, mortality in IPF |
| Periostin | Fibroblast activating matrix proteins | Negative 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 |
| Osteopontin | Glycoprotein secreted by osteoclasts, macrophages and activated T-cells | Reverse correlation with arterial oxygen tension [40] | Predicts progression in IPF |
| YKL40 | Chitinase-like protein | Elevated levels in ILDs, correlated with poor survival [24, 41] | Discriminates ILDs from healthy subjects Predicts mortality in IPF, remains predictive after 3–4 years |
| BLys | Plasma B lymphocytes stimulating factor | Correlated 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 |
| Circulating fibrocytes | 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 |
| CXCL13 | Chemokine playing a role in autoimmune processes, mediating B-cell homing to inflammatory foci | High levels correlated with poor FVC and poor major event-free survival (i.e. transplant-free survival) [44] | Predicts progression, mortality in IPF |
| EGFR | Epidermal 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 |
| Clusterin | Known as apolipoprotein J Glycoprotein upregulated by cytotoxic stimuli, maintaining epithelium viability during lung repair | Lower levels in IPF [25] | Discriminates IPF from healthy subjects |
| CRPM | C reactive, acute-phase protein degrading by matrix metalloprotease | Higher 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-19-9 | Tumor 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-125 | Rising levels predicted both disease progression and overall survival [46] | ||
| OSM | Glycosylated protein, member of IL-6 family of ligands | Identified baseline prognosis and longitudinal change in individuals with IPF [47] | Discriminates ILDs from healthy subjects Predicts progression, mortality in IPF |
| CYFRA-21-1 | Intermediate 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 | |||
| MUC5B | Mucin associated with the development of both familial interstitial pneumonia and sporadic IPF | MUC5B promoter gene polymorphism associated with improved survival independent of clinical factors [48] | Predicts survival in IPF |
| uPAR | Plasminogen activator receptor augmenting monocyte adhesion | Elevated serum levels through macrophage overexpression in IPF compared to controls [49] | Discriminates IPF from healthy subjects |
| TERT | Reverse transcriptase maintaining telomere integrity | Mutation associated with familial interstitial pneumonias [50] and sporadic, adult-onset IPF [51] | Discriminates familial ILDs and IPF from healthy subjects |
| Telomere length | Length of nucleoprotein structures that protect chromosomal ends | Shorter telomere length associated with progression-free survival of IPF [52] | Predicts survival in IPF |
| TLR3 | Receptor mediating innate immune response to tissue injury, inflammation and viral infection | Polymorphism associated with early lung function decline and death [53] | Predicts progression, mortality in IPF |
| α-Defensin | Antimicrobial peptides presenting in granules of neutrophils inhibiting activation of the classical complement pathway | Increased 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.