Table 1 Most relevant biomarkers (Authors’ note: the table should be placed between the paragraphs “future perspectives” and “treatment”)

Dysfunctional alveolar epithelial repair/cellular senescence abnormalities

Surfactant proteins

SP-A

SP-D

Apolipoproteins produced by alveolar type 2 cells. Mutations within genes that codify these proteins, determining increasing of their levels, are associated with worst prognosis

Mucin family

Mucin 5B

Mucin 5B is a cytoplasmic protein encoded by the MUC5B gene. This protein is highly expressed in distal airways, respiratory bronchioles and honeycombing cysts of patients with IPF; furthermore, a single nucleotide polymorphism (SNP) in the promoter region of the gene (rs35705950) is a strong risk factor for developing IPF

Telomerase complex

Telomerase reverse transcriptase (TERT)

Telomerase RNA complex (TERC)

In IPF and familial pulmonary fibrosis there is a reduction of telomeres length both in lung tissue and in peripheral blood. Mutations in TERT and TERC genes play an important role, and are associated with about 1–3% of sporadic IPF and 7–15% of familial interstitial pneumonia. In families with IPF, several telomerase mutations may be found in 15–20% of cases. These mutations are associated with reduced survival

MicroRNAs (miRNAs)

Many different types

miRNAs are short endogenous non-coding RNA molecules, which may influence cellular differentiation, morphogenesis or apoptosis, modifying cellular activity. Fibroblasts and alveolar epithelial cells may undergo significant changes in their function, as epithelial-mesenchymal transition and senescence, interacting with miRNAs

Integrin family

αvβ6

αvβ3

αvβ5

αvβ1

Trans-membrane receptors involved in relationship between cellular membrane and cytoskeleton with ECM. They may activate TGFβ and induce collagen production. αvβ6 integrin is over-expressed in IPF patients, and may be use as diagnostic and prognostic markers. Furthermore, it is a potential therapeutic target

Reactive oxygen species (ROS)

Anion super-oxide (O₂⁻) Hydrogen peroxide (H₂O₂)

An excessive and prolonged exposure of cells to oxidative stress may lead to fibrosis promoting endoplasmic reticulum stress and apoptosis. Patients with IPF probably have decreased levels of antioxidant defences, as catalase, glutathione and superoxide dismutase

ECM remodelling

Matrix metalloproteinases (MMPs)

MMPs 1–2–3-7- 8-9

MMPs are endoproteases that participate to ECM homeostasis. Microarray techniques in peripheral blood and bronchoalveolar lavage fluid of IPF patients may show high expression of these biomarkers; intriguingly, IPF patients have increased values of MMP-1 and 7 compared to other ILD-patients, suggesting the possibility to use a relatively simple analysis in differential diagnosis

Lysyl oxidases (LOXs)

LOXL2

LOXs are enzymes involved in homeostasis of type I collagen; their activity results in a major stiffness of fibrillar collagens, increasing local matrix structural tension and activating fibroblast and TGFβ₁ signalling.

Periostin

Periostin is a fibroblast-secreted ECM protein, involved in adhesion and migration of epithelial cells. In IPF patients it correlates with functional decline.

Fibroblast activation/proliferation

Fibrocytes

Fibrocytes (CD45 and CD34-positive) differentiate into fibroblasts and myofibroblasts if attracted to injured tissues by chemokines and growth factor. Patients with IPF have increased level of circulating fibrocytes. A fibrocyte chemokine receptor (CXCL12) is increased in peripheral blood of IPF patients, correlating with lung function.

Connective tissue growth factor (CTGF)

CTGF is involved in connection between cell membranes and ECM, cell proliferation, angiogenesis and ECM production.

Galectin-3

Molecule involved in fibroblast proliferation, activation and in collagen synthesis, exacerbating ECM deposition and fibrosis.

Fibulin-1

Molecule involved in fibroblast proliferation, activation and in collagen synthesis, exacerbating ECM deposition and fibrosis.

Osteopontin

Molecule involved in fibroblast proliferation, activation and in collagen synthesis, exacerbating ECM deposition and fibrosis.

Immune dysregulation/inflammation

Toll interacting protein (TOLLIP)

Toll interacting protein TOLLIP interacts with components of the Toll-like receptors (TLR), regulating innate immunity. In IPF patients three SNPs play an important role: two of them may be implicated in pathogenesis (rs111521887, rs5743894), whereas the last seems to be protective (rs5743890).

T-cells

T-cells are the prevalent immune population in IPF lung biopsies, particularly close to fibroblastic foci. Interleukin-13 (IL-13) produced by T-cells is a regulator of ECM deposition, and may have a pro-fibrotic effect if over-expressed.