The Mechanism Of Ibrutinib Accelerating Bleomycin Induced Pulmonary Fibrosis

ObjectivesIdiopathic pulmonary fibrosis(IPF)is a chronic idiopathic interstitial pneumonia with a high mortality rate.The etiology is unknown currently,and treatment choices are rare except for lung transplantation.Many fundamental and clinical researches have revealed that the over activated T cells,NK cells,macrophages and other immune cells many contribute to the etiology of IPF.Ibrutinib,specifically irreversible inhibitor of BTK,can modulate the function of immune cells and has been approved for the clinical therapy of lymphocytic leukemia.It has also been investigated in the pre-clinical studies of autoimmune diseases.However,the role of ibrutinib in IPF has not been studied till now.Our study aims to investigate the role of ibrutinib in the bleomycin induced pulmonary fibrosis and discuss the potential mechanism.Materials&methods32 C57BL/6J mice were separated into control group(n=16)and experimental group(n=16)randomly.Bleomycin was administrated intranasally to establish the fibrosis model.The experimental group was given ibrutinib orally from dl,and the control group was given saline.All groups were sacrificed at d14.The lungs were collected and disposed for H&E or Masson's trichrome staining,hydroxyrpoline assay and immunohistochemistry to assess the degree of fibrosis.The BALF and lung tissue was used by flow cytometry assay,RT-PCR,Western Blot,ELISA to assess the cellular component,the expression of relative mRNA,protein and signal pathway.ResultIbrutinib treated mice showed more serious to bleomycin-induced lung fibrosis compared to control group.The inflammatory cell infiltration,the protein exudation and inflammatory cytokines in the BALF was greatly increased compared to the control group.Also,the level of mesenchymal associated molecules Vimentin and Snail expression in the lung epithelium was increased and the TGF-?/Smad signal pathway phosphorylation was shown to be elevated.ConclusionIbrutinib administration can increase inflammation and inflammatory cell infiltration in the lung,elevate the TGF-? expression,EMT progress and myofibroblast generation,in order to accelerated bleomycin induced pulmonary fibrosis.