Review ArticlePeripheral blood biomarkers in idiopathic pulmonary fibrosis
Section snippets
IPF Diagnostic Criteria
The most recent American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association consensus statement recognizes IPF as a type of chronic, progressive interstitial lung disease with specific findings on high resolution computed tomography (CT) scan and/or surgical lung biopsy.4 The characteristic CT finding for patients with IPF is a usual interstitial pneumonia (UIP) pattern, consisting of reticular abnormalities in a subpleural/basal
The Need for Biomarkers in IPF
Biomarkers act as surrogates for clinically meaningful outcomes and may or may not reflect the pathogenesis underlying a disease. Examples of clinical utility include diagnosis, the prediction of disease progression or regression, and prognostication of mortality. A biomarker should be easily acquired, reliably measured, and available for serial monitoring. Ideally, it would also provide an advantage over currently used clinical measures in ease, timeframe, or expense.
The identification of
Brain natriuretic peptide (BNP)
Brain natriuretic peptide (BNP) is secreted by cardiac myocytes in response to volume or pressure overload.6 For patients with acute decompensated heart failure, elevated serum BNP levels are independently associated with mortality.7 BNP levels have also been studied as markers of pulmonary hypertension and right ventricular dysfunction.8
Some IPF patients with advanced disease can develop pulmonary hypertension and right ventricular dysfunction. Song and colleagues9 evaluated the relationship
Surfactant Proteins A and D
Pulmonary surfactants are lipoprotein complexes synthesized by airway Clara cells and alveolar epithelial cells, and secreted into a liquid layer that lines the epithelium.25 Surfactant decreases surface tension at the air-liquid interface in the lung, allowing the lung to expand more easily during inhalation and preventing collapse during exhalation. In addition, surfactant plays an important role in the host defense against pathogens. Although surfactant is mainly composed of lipids, proteins
Matrix Metalloproteases 1 and 7 (MMP1, MMP7)
Matrix metalloproteases are a structurally and functionally related family of zinc-dependent proteases involved in the breakdown of extracellular matrix components.35 Members of this family have various target substrates and expression patterns. MMP1 is the most highly expressed interstitial collagenase and degrades fibrillar collagens.36 MMP7 is the smallest member of the MMP family and is capable of degrading multiple components of the extracellular matrix.
There is animal data to support
CC Chemokine Ligand 18
CC chemokine ligand 18 (CCL18) is a small protein that acts as a chemoattractant to guide cell migration. CCL18 is derived from alveolar macrophages in a wide variety of fibrotic lung diseases, including IPF, sarcoidosis, and systemic sclerosis, that stimulates collagen production in pulmonary fibroblasts.43, 44 CCL18 carries additional names in the literature including pulmonary and activation-regulated chemokine (PARC).45
In patients with IPF, CCL18 measured in BALF and serum is significantly
Vascular Endothelial Growth Factor
Vascular endothelial growth factor (VEGF) is a glycoprotein expressed in alveolar epithelial cells48 that induces vascular permeability and is a major regulator of angiogenesis.49 Although many interstitial lung diseases are associated with aberrant angiogenesis, its role in the pathogenesis of fibrosis has not yet been elucidated.50 In 2 separate studies, VEGF levels in BALF from IPF patients were significantly lower than those from healthy non-smoking individuals.51, 52 BALF VEGF
YKL-40
YKL-40 is a chitinase-like protein that regulates cell proliferation and survival. It is not specific for IPF, as increased levels are also seen in fibrotic liver diseases,53 sarcoidosis,54 COPD,55 and asthma.56 Although its exact mechanism of action is unclear, YKL-40 appears to have mitogenic effects on lung fibroblasts57 and induces alveolar macrophages to release profibrotic and proinflammatory cytokines.55 Immunohistochemical staining has demonstrated that YKL-40 localizes to bronchiolar
Osteopontin
Osteopontin is a phosphorylated acidic glycoprotein that functions as a key proinflammatory cytokine involved in immune response and tissue repair.60, 61 Osteopontin promotes migration, adhesion, and proliferation of fibroblasts in bleomycin-induced mouse models of pulmonary fibrosis,62 as well as lung fibroblasts and alveolar epithelial cell lines.63 mRNA expression of osteopontin is significantly higher in the lung tissue of patients with IPF compared with healthy controls.37
Periostin
Periostin is an extracellular matrix protein that contributes to fibrosis in the lungs, heart, and bone marrow,65 and can be excreted by bronchial epithelial cells in response to interleukin-13 (IL-13).66 Immunohistochemical analyses suggest that the percentage of lung tissue expressing periostin is significantly higher in IPF than in other interstitial lung diseases including nonspecific interstitial pneumonia and cryptogenic organizing pneumonia, as well as controls without interstitial lung
Circulating Fibrocytes
Circulating fibrocytes are circulating bone-marrow derived mesenchymal progenitor cells that produce extracellular matrix components and have the ability to differentiate into fibroblasts and myofibroblasts during wound healing.72 Impaired recruitment of fibrocytes has been shown to protect against fibrosis in murine models,73 supporting a mechanistic role for fibrocytes in the development of pulmonary fibrosis. Fibrocytes have been detected in lung tissue from patients with IPF and may be
T Cells
Although the role of T lymphocytes in IPF is controversial, there is an emerging literature that supports their role in the development of IPF.76, 77, 78, 79, 80, 81, 82 T cells have been shown to be a predominant mononuclear cell type in the lungs of IPF patients, and CD3+ cell density was a significant marker for poor survival.78 CD8+ T cells in the lung parenchyma are significantly correlated with decreased lung function,79 and percentages of activated CD4+ T cells have been found to be
Limitations
There are several limitations to the candidate biomarkers reviewed above. First, the diagnostic criteria for IPF have been refined several times. As a result, it is possible that some of the IPF patients who participated in the studies listed above might not meet the most recently published diagnostic criteria.4 Second, many of the serum biomarkers that have been studied in IPF patients were only measured once. Serial measurements may provide additional insight into the course of this disease
Conclusion
While we have reviewed several biomarker candidates, it is likely that additional biomarkers will arise, as understanding of pathogenesis in IPF evolves. The need for surrogates of diagnosis, prognosis, and monitoring of disease course with emerging therapies is great. Based on the current literature, it seems unlikely that a single biomarker will serve these multiple purposes; however, a panel of several biomarkers may accomplish these goals.
Diagnostic biomarkers will continue to evolve as
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Cited by (0)
Conflict of interest: Dr.Vij has no conflicts of interest to disclose. Dr. Noth has received institutional grants from Centacor, Immuneworks, Actelion, and the National Institutes of Health for conduct of clinical trials in IPF. Both authors acknowledge the Journal's policy on disclosure of potential conflicts of interest.