TGF-β1/IL-11/MEK/ERK signaling mediates senescence-associated pulmonary fibrosis in a stress-induced premature senescence model of Bmi-1 deficiency

摘要

To study whether TGF-β1/IL-11/MEK/ERK (TIME) signaling mediates senescence-associated pulmonary fibrosis (SAPF) in Bmi-1- deficient ( Bmi-1 ~( ?/? )) mice and determines the major downstream mediator of Bmi-1 and crosstalk between p16 ~(INK4a) and reactive oxygen species that regulates SAPF, phenotypes were compared among 7-week-old p16 ~( INK4a ) and Bmi-1 double-knockout, N -acetylcysteine (NAC)-treated Bmi-1 ~( ?/? ), Bmi-1 ~( ?/? ), and wild-type mice. Pulmonary fibroblasts and alveolar type II epithelial (AT2) cells were used for experiments. Human pulmonary tissues were tested for type Ι collagen, α-smooth muscle actin (α-SMA), p16 ~(INK4a), p53, p21, and TIME signaling by using enzyme-linked immunosorbent assay (ELISA). Our results demonstrated that Bmi-1 deficiency resulted in a shortened lifespan, ventilatory resistance, poor ventilatory compliance, and SAPF, including cell senescence, DNA damage, a senescence-associated secretory phenotype and collagen overdeposition that was mediated by the upregulation of TIME signaling. The signaling stimulated cell senescence, senescence-related secretion of TGF-β1 and IL-11 and production of collagen 1 by pulmonary fibroblasts and the epithelial-to-mesenchymal transition of AT2 cells. These processes were inhibited by anti-IL-11 or the MEK inhibitor PD98059. NAC treatment prolonged the lifespan and ameliorated pulmonary dysfunction and SAPF by downregulating TIME signaling more than p16 ~( INK4a ) deletion by inhibiting oxidative stress and DNA damage and promoting ubiquitin-proteasome degradation of p16 ~(INK4a) and p53. Cytoplasmic p16 ~(INK4a) accumulation upregulated MEK/ERK signaling by inhibiting the translocation of pERK1/2 (Thr202/Tyr204) from the cytoplasm to the nucleus in senescent fibroblasts. The accumulation of collagen 1 and α-SMA in human lungs accompanied by cell senescence may be mediated by TIME signaling. Thus, this signaling in aging fibroblasts or AT2 cells could be a therapeutic target for preventing SAPF. Lung fibrosis: calling TIME on disease progression Targeting cellular signals that are increased in lung fibrosis may help halt disease progression. The build-up of scarred and thickened tissues in the lungs associated with aging and cellular deterioration is known as senescence-associated pulmonary fibrosis (SAPF). There are limited treatment options, and Jianliang Jin at Nanjing Medical University, China, and co-workers believe that targeting a complex of cellular signaling pathways called TGF-β1/IL-11/MEK/ERK (TIME) signals, the disruption of which affects tissue homeostasis, may hold the key to tackling the disease. The team conducted experiments on mouse models of SAPF, deficient in a gene called Bmi-1 . The protein encoded by Bmi-1 is critical for cell division and DNA damage repair. In the Bmi-1 -deficient mice, the researchers found that TIME signals were overexpressed, resulting in premature cellular deterioration, increased inflammation and accelerated collagen production.