Affiliation:
1. Nippon Medical School
2. The University of Tokyo
3. Tokyo University of Science
Abstract
Abstract
Macrophage accumulation in the lung tissue during inflammation is important in the pathogenesis of fibrotic lung disease. Deficiencies in chemokine receptors CCR2 and CCR5 and their ligands, which mediate monocyte/macrophage migration, ameliorate bleomycin (BLM)-induced lung fibrosis. Disulfiram (DSF)—used as a drug for alcoholism because of its aldehyde dehydrogenase (ALDH)-inhibiting effect—inhibits monocyte/macrophage migration by inhibiting FROUNT, an intracellular regulator of CCR2/CCR5 signaling. To examine DSF’s antifibrotic effect on BLM-induced lung fibrosis in mice and its impact on macrophage response, oral DSF administration’s effects on lung fibrosis and macrophage infiltration were evaluated in a BLM-induced lung fibrosis mouse model. The DSF direct inhibitory activity on monocyte migration was measured in a Boyden chamber assay and compared with DSF-related inhibitors with different FROUNT-inhibition activities. Quantitative PCR determined the expression of fibrosis-promoting genes in the lung tissue. DSF suppressed macrophage infiltration into the lung tissue and significantly attenuated BLM-indued lung fibrosis. DSF and DSF metabolites, diethyldithiocarbamate (DDC) and copper diethyldithiocarbamate (Cu(DDC)2), inhibited monocyte migration toward the culture supernatant fluid of primary mouse lung cells comprising mainly CCL2, whereas cyanamide—another ALDH inhibitor—did not. DSF, with higher inhibitory activity against FROUNT than DDC and Cu(DDC)2, inhibited monocyte migration most strongly. In BLM-induced fibrotic lung tissues, profibrotic factors were highly expressed but were reduced by DSF treatment. These results suggest DSF inhibited macrophage infiltration probably by a FROUNT-mediated mechanism and attenuated BLM-induced lung fibrosis. DSF therapy as drug repositioning can be practical and feasible for treating fibrotic lung diseases, including idiopathic pulmonary fibrosis.
Publisher
Research Square Platform LLC