Associations of High Attenuation Area-related Proteomic Biomarkers with Fibrotic or Subpleural Interstitial Lung Abnormalities.

Abstract

RATIONALE High attenuation area (HAA) is a computed tomography (CT) tool that correlates with lung inflammation and fibrosis. Systemic molecular correlates of HAA (e.g., plasma proteins) may inform biological process involved in interstitial lung disease (ILD). OBJECTIVES Identify plasma proteins that associate with HAA and correlate with a higher probability of developing new-onset fibrotic or subpleural interstitial lung abnormalities (ILA). METHODS Plasma protein levels were measured using a semiquantitative aptamer-based platform in the Multi-Ethnic Study of Atherosclerosis (MESA, n=5486) and Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS, n=1761). Linear regression models identified HAA-associated proteins after adjustment for demographic and socioeconomic factors, CT scanner parameters, study center, and batch. Associations of HAA-related proteins with new-onset fibrotic or subpleural ILA were examined in MESA participants with ILA assessments on full-lung CT 10 years later. Immunohistochemical staining of select proteins was performed in lung tissue from pulmonary fibrosis cases. MEASUREMENTS AND MAIN RESULTS There were 75 proteins detected that were significantly associated with HAA in MESA and SPIROMICS. Gene ontology analysis of these proteins identified processes involved in immune cell chemotaxis and cellular growth and apoptosis. Seven proteins were associated with a higher probability of new-onset fibrotic or subpleural ILA in MESA and two of these, junctional adhesion molecule-like protein and GTP cyclohydrolase 1 feedback regulatory protein, stained in areas of fibrosis in lung tissue from patients with ILD. CONCLUSIONS Plasma proteins associated with more HAA are involved in immune and cellular processes and associate with new onset fibrotic-subpleural ILA.