| Pulmonary fibrosis(PF)is both a progressive chronic disease,idiopathic PF(IPF),and the pathologic basis for pulmonary fibroproliferative diseases.This lung disorder is characterized by alveolar structure distortion and tissue remodeling after persistent epithelium injury.Excessive proliferation and activation of fibroblasts lead to extracellular matrix accumulation and thickening of alveolar septum.The patients with PF exhibit final respiratory failure with poor prognosis due to the complex pathogenesis and limited therapeutic options,typically leading to death within 3 to 5 years.Compared with placebo cohorts,PF patients using previous triple therapy,the combination of anti-inflammatory drugs prednisone,azathioprine and N-acetylcysteine,have showed increased risk of hospitalization and death.Two drugs approved by FDA in 2014,pirfenidone and nintedanib,along with lung transplantation are only effective therapeutic options available on clinic.However,limitation of donors,high complexity of surgery and following lifelong immunosuppression therapy restrict the application of lung transplantation.Besides,the two approved drugs show less decline in forced vital capacity(FVC),yet it remains unclear whether the beneficial effect on disease progression can translate into higher survival.Hence,in-depth understanding of PF pathogenesis helps us find new drug targets and solve chronic pulmonary diseases.As the end-stage pathological changes of chronic inflammatory diseases,fibrosis closely relates to repetitive injuries of alveolar epithelium,abnormal inflammatory responses and excessive collagen deposition.The first study investigates the relationship between chemokine CCL1 and fibroblasts which act as PF effector cells.The pulmonary macrophages and T cells upregulate CCL1 after chronic lung injury,and CCL1 interacts with autocrine motility factor receptor(AMFR)to activate fibroblasts into myofibroblasts.The CCL1-AMFR interactions cause PKCα-mediated AMFR phosphorylation,through which AMFR acquires E3 ligase activity that enables it to ubiquitinate and translocate the endogenous ERK inhibitor Spryl to the plasma membrane.Spryl at the membrane binds to RasGAP,thereby relieving the inhibitory effect of Spryl on Ras-ERK-p70S6K signaling activity and enhancing profibrotic protein synthesis.Genetic and pharmacological inhibition of the CCL1 signaling pathway exhibits potent therapeutic efficacy against PF.Our study reveals the CCL1-AMFR-ERK axis promoting PF development and suggesting potential targets for treating fibroproliferative lung diseases.In the repair course following lung injury,stem cell alveolar epithelial type 2 cell(AT2)is able to self-renew and differentiate into alveolar epithelial type 1 cell(AT1)to maintain respiratory homeostasis.Except for abnormal inflammatory microenvironment and persistently accumulated myofibroblasts,impaired stemness of AT2 and following regeneration failure of alveolar epithelium also closely correlate with PF.The second study investigates the relationship between cell cycle inhibitor p21 and lung regeneration failure in PF progression.Following multiple bleomycin induced PF,the repetitive injury of AT2 results in telomere shortening and elevated p21 expression in a time dependent manner.The deposition of p21 not only impedes self-renewal of AT2 via G1 phase arrest but also inhibits AT2-to-AT1 differentiation by disturbing p300-β-catenin interaction.The senescent AT2 with enhanced p21 lose the ability of self-renewal and differentiation.Meantime,the fibrotic AT2 exhibiting senescent cellular feature triggers myofibroblast activation by releasing profibrotic cytokines.Knockdown of p21 restores the AT2 mediated lung alveolar regeneration in mice with chronic PF.Our study reveals the mechanism of p21-mediated lung regeneration failure during PF development,which provides new insights into PF pathogenesis and also suggests a potential strategy for treatment of fibrotic lung diseases. |
