Choline and CCL22 Are Prognostic Blood Biomarkers for Hermansky-Pudlak Syndrome Pulmonary Fibrosis.

Identifying molecular biomarkers of pulmonary fibrosis (PF) would improve monitoring the disease progression and response to treatment. Hermansky-Pudlak syndrome (HPS) PF is an inherited type of progressive PF with accelerated onset of PF in patients with HPS type 1 (HPS-1). HPSPF could serve as a model to study biomarkers of progressive PF, given that all HPS-1 subjects eventually develop HPSPF. We utilized a multi-omics strategy to discover progressive blood biomarkers that can recognize factors contributing to the fibrotic cascade in the lungs of HPS subjects. Metabolomic and cytokine/chemokine profiling were performed on serum samples from patients with HPS-1, HPS-1 with PF (HPSPF), HPS-3 or HPS-5, idiopathic PF (IPF), and normal volunteers. Metabolomics, cytokine/chemokine, pulmonary function, and age data from HPS-1 and HPSPF subjects were integrated into a multi-omics network. The analysis highlighted alterations in the transsulfuration pathway, arginine metabolism, and redox balance with the progression of PF in HPS-1. Among those, CCL22 and choline were significantly elevated in HPSPF compared to HPS-1 in two independent cohorts together with age and associated with decline of pulmonary function. In ROC curve analysis, both CCL22 and choline demonstrated high accuracy in predicting PF in HPS-1 subjects, could serve as prognostic blood biomarkers of HPSPF. We noted similarity in molecular signatures of CCL22 in progressive IPF and HPSPF. We found that inducible nitric oxide synthase (iNOS) is an upstream regulator of releasing profibrotic mediators (CCL22, CCL24, IL-18, IL1α, IL1β), suggesting therapeutic potential of iNOS inhibition in progressive HPSPF.