Blockade of the pentraxin 3/CD44 interaction attenuates lung injury‐induced fibrosis

Abstract

Background Fibrosing interstitial lung diseases (fILD) are potentially fatal with limited therapeutic options and no effective strategies to reverse fibrogenesis. Myofibroblasts are chief effector cells in fibrosis that excessively deposit collagen in the pulmonary interstitium and lead to progressive impairment of gaseous exchange. Methods Plasma and lung specimens from patients with fILD were applied for detecting pentraxin 3 (PTX3) abundance by ELISA and Immunohistochemistry. Masson's trichrome and Sirius red stains and hydroxyproline assay were performed for assessing collagen accumulation in the lungs of bleomycin‐exposed conditional Ptx3‐deficient and PTX3‐neutralizing antibody (αPTX3i)‐treated mice. Downstream effectors including signaling pathways and fibrotic genes were examined for assessing CD44‐involved PTX3‐induced fibrosis in HFL1 and primary mouse fibroblasts. Results PTX3 was upregulated in the lungs and plasma of bleomycin‐exposed mice and correlated with disease severity and adverse outcomes in fILD patients. Decreased collagen accumulation, attenuation of alveolar fibrosis and fibrotic markers, and improved lung function were observed in bleomycin‐exposed conditional Ptx3‐deficient mice. PTX3 activates lung fibroblasts to differentiate towards migrative and highly collagen‐expressing myofibroblasts. Lung fibroblasts with CD44 inactivation attenuated the PI3K‐AKT1, NF‐κB, and JNK signaling pathways and fibrotic markers. αPTX3i mimic‐based therapeutic studies demonstrated abrogation of the migrative fibroblast phenotype and myofibroblast activation in vitro. Notably, αPTX3i inhibited lung fibrosis, reduced collagen deposition, increased mouse survival, and improved lung function in bleomycin‐induced pulmonary fibrosis. Conclusions The present study reveals new insights into the involvement of the PTX3/CD44 axis in fibrosis and suggests PTX3 as a promising therapeutic target in fILD patients.

Keywords

• CD44
• pentraxin 3
• pulmonary fibrosis