Matrix Metalloproteinase 12 Improves the Differentiation of Idiopathic Pulmonary Fibrosis and Fibrotic Hypersensitivity Pneumonitis and Associates With Antigen Response Pathways
CHEST, 2026
Konkol S., Huang Y., Ma S., Humphries S., Lynch D., Paul T., Malik N., Strickland E., Mannem H., Oldham J., Adegunsoye A., Newton C., Oh A., Martinez F., Sperling A., Kim J., Noth I.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Respiratory Diseases | Patient Stratification | Plasma |  Olink Explore 3072/384 |
Abstract
Background
Accurate diagnosis of interstitial lung disease remains challenging. Multi-disciplinary discussion (MDD) is the current gold standard; however, MDD 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 multi-site ILD 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 (AUC) >0.70 were included in multivariable logistic regression. Gene ontology, KEGG, and Gene Set Enrichment Analysis of whole-blood mRNA revealed relationships between MMP12 abundance and transcriptional expression.
Results
Matrix metalloproteinase 12 (MMP12) was significantly elevated in IPF compared to FHP (IPF = 1.43 ± 0.9, FHP = 0.69 ± 0.9, P value < 0.001). MMP12 improved differentiation by increasing the AUC 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 value < 0.001). Gene Set Enrichment Analysis comparing patients with high (≥ median) versus low (< median) MMP12 found enrichment in interleukin, GM-CSF, and CD28 co-stimulation pathways. Gene ontology showed enrichment in biological processes related to host response to external stimuli, while KEGG revealed enrichment in T cell differentiation and viral signaling.InterpretationSemi-quantitative 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/GM-CSF signaling and T cell regulation pathways.