RESUMO
Mechanical ventilation may cause ventilatorinduced lung injury (VILI). Canonical Wnt signaling has been reported to serve an important role in the pathogenesis of VILI. Bioinformatics analysis revealed that canonical and noncanonical Wnt signaling pathways were activated in VILI. However, the role of noncanonical Wnt signaling in the pathogenesis of VILI remains unclear. The present study aimed to analyze the potential role of noncanonical Wnt signaling in VILI pathogenesis. Lung injury was assessed via Evans blue albumin permeability and histological scoring, as well as by inflammatory cytokine expression and total protein concentration in bronchoalveolar lavage fluid. The relative protein expression of canonical and noncanonical Wnt signaling pathway components were examined via western blotting and immunohistochemistry. The results demonstrated that 6 h of mechanical ventilation at low tidal volume (LTV; 6 ml/kg) or moderate tidal volume (MTV; 12 ml/kg) induced lung injury in sensitive A/J mice. Ventilation with MTV increased the protein levels of Wntinduced secreted protein 1 (WISP1), Rhoassociated protein kinase 1 (ROCK1), phosphorylated (p)Ras homolog gene family, member A and pCJun Nterminal kinase (JNK). Inhibition of ROCK1 by Y27632 and JNK by SP600125 attenuated MTVinduced lung injury and decreased the expression of proteins involved in noncanonical Wnt signaling, including WISP1. In conclusion, noncanonical Wnt signaling participates in VILI by modulating WISP1 expression, which has been previously noted as critical for VILI development. Therefore, the noncanonical Wnt signaling pathway may provide a preventive and therapeutic target in VILI.
Assuntos
Proteínas de Sinalização Intercelular CCN/genética , Regulação da Expressão Gênica , Proteínas Proto-Oncogênicas/genética , Lesão Pulmonar Induzida por Ventilação Mecânica/genética , Lesão Pulmonar Induzida por Ventilação Mecânica/metabolismo , Via de Sinalização Wnt , Animais , Biomarcadores , Proteínas de Sinalização Intercelular CCN/metabolismo , Citocinas/metabolismo , Feminino , Perfilação da Expressão Gênica , Masculino , Camundongos , Proteínas Proto-Oncogênicas/metabolismo , Transcriptoma , Lesão Pulmonar Induzida por Ventilação Mecânica/patologiaRESUMO
Interleukin (IL)-33, a member of the IL-1 cytokine super-family, acts as both a traditional cytokine and an intracellular nuclear factor. It is generally released from damaged immune cells and signals through its receptor ST2 in an autocrine and paracrine fashion, plays important roles in type-2 innate immunity, and functions as an "alarmin" or a danger signal for cellular damage or cellular stress. Here, we review recent advances of the role of IL-33 in lung injury and explore its potential significance as an attractive therapeutic target.