Idiopathic pulmonary fibrosis is a chronic, progressive and lethal disease of unknown etiology that ranks among the most frequent
interstitial lung diseases.
Idiopathic pulmonary fibrosis is characterized by dysregulated healing mechanisms that lead to the accumulation of large amounts of
collagen in the lung tissue that disrupts the alveolar architecture. The two currently available treatments,
nintedanib and
pirfenidone, are only able to slow down the disease without being curative. We demonstrated in the past that HSPB5, a low molecular weight
heat shock protein, was involved in the development of
fibrosis and therefore was a potential therapeutic target. Here, we have explored whether
NCI-41356, a chemical inhibitor of HSPB5, can limit the development of
pulmonary fibrosis. In vivo, we used a mouse model in which
fibrosis was induced by intratracheal injection of
bleomycin. Mice were treated with NaCl or
NCI-41356 (six times intravenously or three times intratracheally).
Fibrosis was evaluated by
collagen quantification, immunofluorescence and TGF-β gene expression. In vitro, we studied the specific role of
NCI-41356 on the chaperone function of HSPB5 and the inhibitory properties of
NCI-41356 on HSPB5 interaction with its partner SMAD4 during
fibrosis. TGF-β1 signaling was evaluated by immunofluorescence and Western Blot in epithelial cells treated with TGF-β1 with or without
NCI-41356. In vivo,
NCI-41356 reduced the accumulation of
collagen, the expression of TGF-β1 and pro-fibrotic markers (PAI-1, α-SMA). In vitro,
NCI-41356 decreased the interaction between HSPB5 and SMAD4 and thus modulated the SMAD4 canonical nuclear translocation involved in TGF-β1 signaling, which may explain
NCI-41356 anti-fibrotic properties. In this study, we determined that inhibition of HSPB5 by
NCI-41356 could limit
pulmonary fibrosis in mice by limiting the synthesis of
collagen and pro-fibrotic markers. At the molecular level, this outcome may be explained by the effect of
NCI-41356 inhibiting HSPB5/SMAD4 interaction, thus modulating SMAD4 and TGF-β1 signaling. Further investigations are needed to determine whether these results can be transposed to humans.