Journal article
Associations of High Attenuation Area-related Proteomic Biomarkers with Fibrotic or Subpleural Interstitial Lung Abnormalities
American journal of respiratory and critical care medicine, Vol.211(10), pp.1811-1822
10/2025
DOI: 10.1164/rccm.202503-0610OC
PMCID: PMC12555059
PMID: 40845333
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.
Details
- Title: Subtitle
- Associations of High Attenuation Area-related Proteomic Biomarkers with Fibrotic or Subpleural Interstitial Lung Abnormalities
- Creators
- John S. Kim - University of VirginiaCatherine L. Debban - University of VirginiaDaniel Guzman - Columbia University Irving Medical CenterRiley T. Hannan - University of VirginiaMary Salvatore - Jacobi Medical CenterClaire McGroder - New York Hospital QueensDavid Zhang - Columbia University Irving Medical CenterAnna J. Podolanczuk - Cornell UniversityDaniel A. Duprez - University of MinnesotaShwu-Fan MaYong Huang - University of VirginiaJeffrey M. Sturek - University of VirginiaStephen S. Rich - University of VirginiaJerome I Rotter - Harbor–UCLA Medical CenterRajat Deo - University of PennsylvaniaRuth F Dubin - The University of Texas Southwestern Medical CenterJanelle Vu Pugashetti - Michigan MedicineJennifer M Wang - Michigan MedicineMeiLan K. Han - Michigan MedicineJustin M. Oldham - University of California, DavisImre Noth - University of VirginiaPrescott G. Woodruff - University of California, San FranciscoVictor E. Ortega - Mayo Clinic in ArizonaJulie C. Fanburg-Smith - University of VirginiaEdward B. Stelow - University of VirginiaChristopher A. Moskaluk - University of VirginiaEric A. Hoffman - University of IowaChristine Kim Garcia - Columbia University Irving Medical CenterRussell P. Bowler - Cleveland ClinicPeter Ganz - University of California, San FranciscoR. Graham Barr - Columbia UniversityAni Manichaikul - University of Virginia
- Resource Type
- Journal article
- Publication Details
- American journal of respiratory and critical care medicine, Vol.211(10), pp.1811-1822
- DOI
- 10.1164/rccm.202503-0610OC
- PMID
- 40845333
- PMCID
- PMC12555059
- NLM abbreviation
- Am J Respir Crit Care Med
- ISSN
- 1073-449X
- eISSN
- 1535-4970
- Publisher
- AMER THORACIC SOC
- Grant note
- National Heart, Lung, and Blood Institute: R01-HL077612, R01-HL093081, RC1-HL100543, R01-HL103676, R01-HL159081, R01-HL137880, K23-HL-150301, F32HL175973, T32HL007749, F32HL170760, R01-HL179312, 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1-TR001881, DK063491, R01-HL105756, HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C, HSN268200900020C Forest Research Institute Inc.Ikaria IncTakeda Pharmaceutical CompanyRegeneron Pharmaceuticals, Inc.SanofiAstraZenecaBellerophon TherapeuticsBoehringer Ingelheim Inc.Chiesi Farmaceutici SpAGlaxoSmithKlineGrifols IncNycomed GmbHNovartis
Supported by National Heart, Lung, and Blood Institute grants R01-HL077612, R01-HL093081, RC1-HL100543, R01-HL103676, R01-HL159081, R01-HL137880, K23-HL-150301 (J.S.K.) , F32HL175973 (J.M.W.) , T32HL007749 (J.M.W.) , F32HL170760 (R.T.H.) , and R01-HL179312 (J.M.S.) ; contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1-TR001881, DK063491, R01-HL105756, HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C, and HSN268200900020C; AstraZeneca; Bellerophon Therapeutics; Boehringer Ingelheim Inc.; Chiesi Farmaceutici SpA; Forest Research Institute Inc.; GlaxoSmithKline; Grifols Inc; Ikaria Inc; Nycomed GmbH; Takeda Pharmaceutical Company; Novartis; Regeneron Pharmaceuticals, Inc.; and Sanofi.
- Language
- English
- Electronic publication date
- 08/22/2025
- Date published
- 10/2025
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Radiology; Internal Medicine
- Record Identifier
- 9984949224802771
Metrics
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