Inhibition of p38MAP kinase suppresses fibrogenic reaction inconjunctiva in mice

[摘要] Purpose: To examine the effects of blocking p38 mitogen-activatedprotein kinase (MAPK) on post-injury conjunctival scarring in mice. Itseffects on the behaviors of cultured subconjunctival fibroblasts werealso investigated.Methods: An in vivo study was conducted using an adenoviral vectorcarrying a dominant-negative (DN)-p38MAPK gene. A circumferentialincision was made in the equatorial conjunctiva by scissors in the righteye of generally anesthetized adult C57BL/6 mice. DN-p38MAPK-expressingadenoviral vector was topically applied. The left control eye receivednon-functioning adenoviral vector. At 2, 5, and 7 days (each, n=22) theeyes were processed for histological or immunohistochemical examinationto evaluate the tissue scarring. The expressions of type-I collagen andgrowth factors were evaluated by real time-reversetranscriptase-polymerase chain reaction. The effects of p38MAPKinhibitor on the proliferation, migration, and fibrogenic gene/proteinexpression of cultured human fibroblasts were also studied.Results: The in vivo DN-p38MAPK gene introduction blocked thephospho-p38 expression with reduction of myofibroblast generation andsuppression of mRNA expression of connective tissue growth factor(CTGF) and monocyte/macrophage chemoattractant protein-1 (MCP-1) inthe mouse-injured conjunctiva. Blocking p38MAPK signal in thefibroblasts by a chemical inhibitor counteracted TGFβ1'senhancement of expressions of type-I collagen, fibronectin, and CTGF. Italso retarded cell migration, but cell proliferation was unchanged.Conclusions: Inhibiting p38MAPK signal impairs the fibrogenicreaction induced by the subconjunctival fibroblasts in vivo and invitro, suggesting its potential effectiveness in preventing excessivescarring following glaucoma filtering surgery.

[学科分类] 生物化学/生物物理