Associations of High Attenuation Area–Related Proteomic Biomarkers with Fibrotic or Subpleural Interstitial Lung Abnormalities

<b>Rationale:</b> 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 processes involved in interstitial lung disease. <b>Objectives:</b> To identify plasma proteins that associate with HAA and correlate with a higher probability of developing new-onset fibrotic or subpleural interstitial lung abnormalities (ILAs). <b>Methods:</b> Plasma protein levels were measured using a semiquantitative aptamer-based platform in MESA (the Multi-Ethnic Study of Atherosclerosis; <i>N</i> = 5,486) and SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study; <i>N</i> = 1,781). 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 ILAs 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. <b>Measurements and Main Results:</b> 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 ILAs 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 interstitial lung disease. <b>Conclusions:</b> Plasma proteins associated with more HAA are involved in immune and cellular processes and associate with new-onset fibrotic-subpleural ILA.

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Publication Details

Journal
American Journal of Respiratory and Critical Care Medicine
Published
2025-08-22
DOI
https://doi.org/10.1164/rccm.202503-0610oc
Citations
1
Primary Topic
Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
Type
article
Field-Weighted Citation Impact
1.52
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article

Associations of High Attenuation Area–Related Proteomic Biomarkers with Fibrotic or Subpleural Interstitial Lung Abnormalities

John S. Kim, Ruth F. Dubin, Daniel E. Guzman, Mary Salvatore et al.
1 citations
American Journal of Respiratory and Critical Care Medicine
Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
1.52
article

Associations of High Attenuation Area–Related Proteomic Biomarkers with Fibrotic or Subpleural Interstitial Lung Abnormalities

John S. Kim, Ruth F. Dubin, Daniel E. Guzman, Mary Salvatore, Julie C. Fanburg–Smith, Imre Noth, Justin M. Oldham, Eric A. Hoffman, Janelle Vu Pugashetti, Russell Paul Bowler, Riley T. Hannan, Ani Manichaikul, Anna J. Podolanczuk, Jeffrey M. Sturek, Claire McGroder, Christopher A. Moskaluk, Christine Kim Garcia, Yong Huang, Victor E. Ortega, Rajat Deo, Catherine L. Debban, Prescott G. Woodruff, Jennifer M. Wang, Shwu‐Fan Ma, Stephen S. Rich, Peter Ganz, Daniel A. Duprez, MeiLan K. Han, Edward B. Stelow, David Zhang, Jerome I. Rotter, R. Graham Barr
article en
1 citations

Abstract

<b>Rationale:</b> 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 processes involved in interstitial lung disease. <b>Objectives:</b> To identify plasma proteins that associate with HAA and correlate with a higher probability of developing new-onset fibrotic or subpleural interstitial lung abnormalities (ILAs). <b>Methods:</b> Plasma protein levels were measured using a semiquantitative aptamer-based platform in MESA (the Multi-Ethnic Study of Atherosclerosis; <i>N</i> = 5,486) and SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study; <i>N</i> = 1,781). 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 ILAs 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. <b>Measurements and Main Results:</b> 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 ILAs 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 interstitial lung disease. <b>Conclusions:</b> Plasma proteins associated with more HAA are involved in immune and cellular processes and associate with new-onset fibrotic-subpleural ILA.

American Journal of Respiratory and Critical Care MedicineVol. 211(10)
Human Genome Sciences (United States) (US), University of Iowa (US), University of Minnesota (US), Cleveland Clinic (US), NewYork–Presbyterian Hospital (US), The Lundquist Institute (US), University of California, San Francisco (US), Cornell University (US), University of Michigan (US), Columbia University Irving Medical Center (US), Jacobi Medical Center (US), New York Hospital Queens (US), UCLA Medical Center (US), WinnMed (US), Southwestern Medical Center (US), Twin Cities Orthopedics (US), Michigan United (US), Michigan Medicine (US), Mayo Clinic in Arizona (US), Twin Cities Spine Center (US), Charlottesville Medical Research (US), Mayo Clinic in Florida (US), Harbor–UCLA Medical Center (US), University of Virginia (US), Columbia University (US), University of Pennsylvania (US), University of California, Davis (US), The University of Texas Southwestern Medical Center (US)
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Openalex Percentile: Top 15%
Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
1.52
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