The Therapeutic Efficacy of Inhaled Vitamin D3 Metabolites Initiated During the Acute Phase of Hypersensitivity Pneumonitis: An In Vivo Study.

Our earlier studies have revealed the beneficial impact of vitamin D3 (VD3) metabolites on the development of pulmonary fibrosis in a murine model of hypersensitivity pneumonitis (HP). Despite the discovery of the great antifibrotic potential of both the bioactive form of VD3, 1,25(OH)2-VD3 and its direct precursor, 25(OH)-VD3, study designs based on the co-administration of VD3-metabolites and fibrosis-inducers do not reflect the clinical situation. Thus, the presented study aims to examine the effectiveness of therapeutic interventions based on the mentioned inhalations, initiated during the acute phase of HP at the first signs of pulmonary fibrosis. The research was performed using VD3-deficient mice with HP, while VD3-sufficient mice were used as the main control. The data were collected after 28 days of daily exposure of the mice to a fibrosis-inducer (an antigen of Pantoea agglomerans, a well-known etiological factor in HP), with 25(OH)-VD3 or 1,25(OH)2-VD3 administered daily during the last 14 days of the experiment. The effect of the intervention was monitored by whole-body plethysmography, histological assessment, flow cytometry, RealTime-PCR, and ELISA. Treatment with VD3 metabolites initiated during the acute phase of HP alleviated the disease courses and restored respiratory function, thanks to inhibition of pathological extracellular matrix deposition, immune-cell infiltration of lung parenchyma, profibrotic cytokine production, and EMT progression. Despite the discovery of the beneficial features of the investigated VD3-based therapies, none of them caused full recovery in mice with HP. Nevertheless, after verification in additional animal models and a deeper understanding of the underlying molecular mechanisms, the identified beneficial features of the investigated metabolites have the potential to serve as a foundation for future therapies for HP fibrosis.