Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and incurable disease requiring novel therapeutics. High baseline monocyte count associates with increased risk of progression and mortality in IPF. Perturbations in monocyte phenotype and mitochondrial function, IL6 production, ACOD1 gene expression and metabolism have been observed in IPF patients. IPF patients also have reduced biosynthetic capacity for the immunomodulatory gas hydrogen sulfide (H2S) - an endogenous regulator of mitochondrial function and inflammation. However, the impact of H2S modulation in monocytes is unknown.

Aims: Investigate the anti-fibrotic and anti-inflammatory effects of mitochondrial-targeted H2S donor compounds (mtH2SD) in human monocytes. 

Methods: Longitudinal monocyte counts were investigated in a retrospective IPF cohort (n=131). Fresh monocytes were isolated from healthy donors (n=11), stimulated with IFN?/TNF? (20ng/ml) +/- mtH2SD (100nM) for 24 hours prior to multispectral flow cytometry, Seahorse metabolic assays, ELISA, qPCR analysis.

Results: Rising monocyte count (>0.01 K/µL/month) was associated with worse survival (p=0.04). In vitro mtH2SD treatment of stimulated monocytes resulted in reduced pro-fibrotic marker levels (CD206 and CD163; p<0.05), more energetic and glycolytic metabolism, augmentation of anti-fibrotic ACOD1 expression, decreased IL-6 production and gene expression (p<0.01).

Conclusions: Monocytic functionality is implicated in IPF pathogenesis. Modulation of phenotype and metabolism, pro-fibrotic and pro-inflammatory gene expression by mtH2SD may have therapeutic potential. Future work will recapitulate these data in IPF-derived monocytes.