Table 1.

Summary of main potential serum biomarkers in idiopathic pulmonary fibrosis (IPF).

Biomarker	Definition	Significance
Alveolar Epithelial Cell Dysfunction
KL-6 1/MUC1	Glycoprotein mainly expressed at the extracellular membrane surface of type II pneumocytes [10].	Increased serum levels during IPF acute exacerbation [11]. Serum levels correlate with IPF severity and prognosis [11]. Biomarker indicative of the response to nintedanib treatment [12]. Promotion of lung fibroblast migration and proliferation, FMT 2 and EMT 3 [13,14].
CA15-3	Central protein core of MUC1	Serum levels significantly higher in patients with IPF [9]. Elevated serum levels correlate with decreased total lung capacity, decreased diffusing capacity of carbon monoxide and high resolution computed tomography findings [9].
CA125	Peptide epitope of MUC16	Rising concentrations over 3 months are associated with increased risk of IPF mortality [8].
Surfactant proteins (SP-A, SP-D and SP-C)	Lipoprotein complexes synthesized and secreted by type II pneumocytes.	Elevated serum levels in IPF patients [15]. Serum SP-A and SP-D levels are predictors of IPF prognosis [16,17]. Mutations on the genes encoding for SP-C and SP-A2 have been described within families of patients with pulmonary fibrosis [18].
MUC5B	Secreted mucin produced mainly in mucous cells of the submucosal glands [19].	A common gain-of-function promoter variant (rs35705950) has been reported in 30–35% of IPF patients [20].
Extracellular Matrix Remodeling and Fibroproliferation
Matrix metalloproteinases (MMP-1 and MMP-7)	Zinc-dependent peptidases that are mainly responsible for ECM 4 degradation.	Elevated levels in the plasma, BALF 5 and tissue of IPF patients [21]. Elevated MMP-7 serum levels correlate with disease severity [21]
LOXL2 6	Enzymes that facilitate the cross-linking of type 1 collagen molecules and stabilizes ECM.	Serum levels are correlated to IPF progression [22].
Periostin	Protein secreted by bronchial epithelial cells and that promotes ECM deposition and mesenchymal cell proliferation.	Elevated serum levels in IPF patients. Serum levels correlate with IPF physiological progression [23]
Immune Disfunction
CCL18 7	Small protein mainly secreted by monocytes, macrophages and dendritic cells that acts as a chemoattractant [24] and has an important role stimulating fibroblasts to synthesise collagen in fibrotic lung diseases [25].	Serum level is a predictor of IPF outcome and mortality [26].
IL-8 8	Cytokine highly chemo-attractant for neutrophils	Negative correlation between IL-8, pulmonary function tests [27] and survival [28].
YKL-40	Chitinase-like protein produced from alveolar macrophages and type II pneumocytes which regulate proliferation of different cell types.	Serum and BALF YKL-40 levels are predictors of IPF survival [29]
TLR3 9	Receptors that mediate the innate immune response to infection and tissue injury [30].	TLR3 L412F polymorphism is associated with a significantly greater risk of mortality and an accelerated decline in FVC 10 [31].
TLR9 11	Receptors that mediate the innate immune response to infection and tissue injury [30].	Higher concentrations of TLR9 in surgical lung biopsies from IPF rapidly progressive patients than in tissue from IPF slowly progressing patients [32].
TOLLIP 12	Inhibitory adaptor protein within TLRs involved in the regulation of the innate immune system.	Significant correlation between response to N-acetylcysteine therapy and the rs3750920 polymorphism [33]. The rs5743890 minor allele is protective and associated with reduced susceptibility to IPF [34].

¹ KL-6: Krebs von den Lungen-6; ² FMT: fibroblast to mesenchymal transition; ³ EMT: epithelial to mesenchymal transition; ⁴ ECM: extracellular matrix; ⁵ BALF: bronchoalveolar lavage fluid; ⁶ LOXL2: lysyl oxidase-like 2; ⁷ CCL18: CC chemokine ligand 18; ⁸ IL-8: interleukin-8; ⁹ TLR3: Toll-like receptor 3; ¹⁰ FVC: forced vital capacity; ¹¹ TLR9: Toll-like receptor 9; ¹² TOLLIP: Toll-interacting protein.