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 individuals with HPS-1 eventually develop HPSPF. We used a multiomics strategy to discover progressive blood biomarkers that can recognize factors contributing to the fibrotic cascade in the lungs of individuals with HPS. Metabolomic and cytokine/chemokine profiling were performed on serum samples from patients with HPS-1, HPS-1 with PF (HPSPF), HPS-3, HPS-5, or idiopathic PF and healthy volunteers. Metabolomics, cytokine/chemokine, pulmonary function, and age data from subjects with HPS-1 and HPSPF were integrated into a multiomics 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 with HPS-1 in two independent cohorts together with age and were associated with decline of pulmonary function. In receiver operating characteristic curve analysis, both CCL22 and choline demonstrated high accuracy in predicting PF in subjects with HPS-1 and therefore could serve as prognostic blood biomarkers of HPSPF. We noted similarity in molecular signatures of CCL22 in progressive idiopathic PF and HPSPF. We found that inducible nitric oxide synthase is an upstream regulator of releasing profibrotic mediators (CCL22, CCL24, IL-18, IL-1α, IL-1β), suggesting the therapeutic potential of inducible nitric oxide synthase inhibition in progressive HPSPF.