Pulmonary fibrosis is a progressive
lung disease that its pathogenic mechanism currently is incompletely understood.
Toll-like receptor (TLR) signaling has recently been identified as a regulator of
inflammation and
pulmonary fibrosis. In addition, mesenchymal stem cells (MSCs) of different origins offer a great promise in treatment of
idiopathic pulmonary fibrosis (IPF). However mechanisms of pathogenic roles of TLR signaling and
therapeutic effects of MSCs in the IPF remain elusive. In present study, the involvement of TLR signaling and the therapeutic role of MSCs were interrogated in MyD88-deficient mice using human placental MSCs of fetal origins (hfPMSCs). The results showed an alleviated
pulmonary inflammation and
fibrosis in myeloid differentiation primary response gene 88 (MyD88)-deficient mice treated with
bleomycin (BLM), accompanied with a reduced TGF-β signaling and production of pro-fibrotic
cytokines, including TNF-α, IL-1β. An exposure of HLF1 lung fibroblasts, A549 epithelial cells and RAW264.7 macrophages to BLM led an increased expression of key components of MyD88 and TGF-β signaling cascades. Of interest, enforced expression and inhibition of
MyD88 protein resulted in an enhanced and a reduced TGF-β signaling in above cells in the presence of BLM, respectively. However, the addition of TGF-β1 showed a marginally inhibitory effect on MyD88 signaling in these cells in the absence of BLM. Importantly, the administration of hfPMSCs could significantly attenuate BLM-induced
pulmonary fibrosis in mice, along with a reduced
hydroxyproline (HYP) deposition, MyD88 and TGF-β signaling activation, and production of pro-fibrotic
cytokines. These results may suggest an importance of MyD88/TGF-β signaling axis in the tissue homeostasis and functional integrity of lung in response to injury, which may offer a novel target for treatment of
pulmonary fibrosis.