Abstract Rationale Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease characterized by abnormal alveolar interstitial accumulation of extracellular matrix proteins, particularly type I collagen. Preclinical data indicate that blocking the activity of the arginase 1 enzyme (ARG1) can inhibit pathologic biosynthesis and subsequent deposition of collagen in the lungs, but the contribution of this pathway to IPF disease is unknown. We tested the hypothesis that ARG1 is increased in IPF patients compared to healthy subjects and that quantifiable biomarkers, representative of the arginase pathway, significantly associate with clinical measures of IPF disease. Methods We measured ARG1 protein levels in serum and bronchoalveolar lavage fluid (BALF) by proximity extension assay and ARG1 gene expression levels in blood by RNAseq across multiple cohorts of IPF patients and healthy controls. These data were used to compare arginase levels between cohorts and to stratify patients into arginase high and low groups for comparisons across clinical measures of disease severity, lung function, CT characteristics, and outcomes. Results ARG1 protein was measured in serum and BALF in two cohorts of IPF patients and healthy controls. In the first IPF cohort (n = 39) (mean Forced Vital Capacity (FVC) 89.7 % predicted (IQR: 23.9)), patients were found to have increased ARG1 protein in serum but not in BALF. In the second cohort of IPF (n = 61), characterized by more advanced disease severity (mean FVC 69.7 % predicted (IQR: 23.0)), ARG1 protein was increased in both serum and BALF. In both cohorts, those IPF patients with higher levels of ARG1 in BALF had more severe disease as quantified by GAP index, as well as worse lung function as measured by FVC and Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO). Finally, in a third cohort of IPF (n = 632) (mean FVC 79.5 % predicted (IQR: 26.1)), high ARG1 gene expression in blood was associated with increased mortality within 12 months. Conclusions This work demonstrates that the ARG1 enzyme may be a significant contributor to IPF severity, IPF progression, and poor patient outcome. These data thus provide strong rationale for intervention via targeting the arginase pathway. This abstract is funded by: Astrazeneca
Lovewell et al. (Fri,) studied this question.