Matrix Metalloproteinase 12 Improves the Differentiation of Idiopathic Pulmonary Fibrosis and Fibrotic Hypersensitivity Pneumonitis and Associates With Antigen Response Pathways

Sam B Konkol; Yong Huang; Shwu-Fan Ma; Stephen Humphries; David Lynch; Tessy Paul; Numaan Malik; Emma Strickland; Hannah Mannem; Justin Oldham; Ayodeji Adegunsoye; Chad Newton; Andrea Oh; Fernando Martinez; Anne I Sperling; John Kim; Imre Noth

doi:10.1016/j.chest.2026.01.029

Matrix Metalloproteinase 12 Improves the Differentiation of Idiopathic Pulmonary Fibrosis and Fibrotic Hypersensitivity Pneumonitis and Associates With Antigen Response Pathways

Chest. 2026 Mar 7:S0012-3692(26)00286-2. doi: 10.1016/j.chest.2026.01.029. Online ahead of print.

Authors

Sam B Konkol¹, Yong Huang², Shwu-Fan Ma², Stephen Humphries³, David Lynch³, Tessy Paul², Numaan Malik², Emma Strickland², Hannah Mannem², Justin Oldham⁴, Ayodeji Adegunsoye⁵, Chad Newton⁶, Andrea Oh⁷, Fernando Martinez⁸, Anne I Sperling², John Kim², Imre Noth²

Affiliations

¹ Department of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA. Electronic address: sk8jq@uvahealth.org.
² Department of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA.
³ Department of Radiology, National Jewish, Denver, CO.
⁴ Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, MI.
⁵ Department of Medicine, Section of Pulmonary and Critical Care Medicine, Division of Biological Sciences, University of Chicago, IL.
⁶ Division of Pulmonary and Critical Care Medicine, UT Southwestern, TX.
⁷ Department of Radiology, University of California, Los Angeles, CA.
⁸ Department of Pulmonary and Critical Care Medicine, Weill Cornell Medical Center, New York, NY.

PMID: 41802591
DOI: 10.1016/j.chest.2026.01.029

Abstract

Background: Accurate diagnosis of interstitial lung disease remains challenging. Multidisciplinary discussion is the current gold standard; however, it is resource-intensive and relies on expert opinion. Biologically based markers of disease are needed.

Research question: Can measurements of circulating proteins aid in the differentiation of idiopathic pulmonary fibrosis (IPF) and fibrotic hypersensitivity pneumonitis (FHP), and would such proteins reflect differences in immune function?

Study design and methods: We measured circulating matrix metalloproteinases in patients enrolled in the Pulmonary Fibrosis Foundation Patient Registry and a multisite interstitial lung disease cohort with either IPF or FHP using a high-throughput proteomic platform (Olink Explore 3072). Single-variable logistic regression was used to evaluate each protein's ability to differentiate IPF and FHP. Proteins with an area under the receiver operating characteristic curve > 0.70 were included in multivariable logistic regression. Gene ontology, KEGG, and Gene Set Enrichment Analysis of whole-blood messenger RNA revealed relationships between matrix metalloproteinase 12 (MMP12) abundance and transcriptional expression.

Results: MMP12 was significantly elevated in IPF compared with FHP (IPF, 1.43 ± 0.9; FHP, 0.69 ± 0.9; P < .001). MMP12 improved differentiation by increasing the area under the receiver operating characteristic curve from 0.81 to 0.85 when added to a model developed from clinical, lung function, and radiologic data (OR, 2.16; 95% CI, 1.44-3.25; P < .001). Gene Set Enrichment Analysis comparing patients with high (≥ median) vs low (< median) MMP12 found enrichment in interleukin, granulocyte-monocyte colony-stimulating factor, and CD28 costimulation pathways. Gene ontology showed enrichment in biological processes related to host response to external stimuli, whereas KEGG revealed enrichment in T-cell differentiation and viral signaling.

Interpretation: Our results show that semiquantitative MMP12 measurement improves the differentiation of IPF and FHP compared with clinical, lung function, and radiologic variables. Elevated MMP12 was associated with enrichment of interleukin/granulocyte-monocyte colony-stimulating factor signaling and T-cell regulation pathways.

Keywords: MMP12; fibrotic hypersensitivity pneumonitis; idiopathic pulmonary fibrosis; interstitial lung disease; matrix metalloproteinase.