RESUMO
Pulmonary fibrosis is a relentlessly progressive and often fatal disease with a paucity of available therapies. Genetic evidence implicates disordered epithelial repair, which is normally achieved by the differentiation of small cuboidal alveolar type 2 (AT2) cells into large, flattened alveolar type 1 (AT1) cells as an initiating event in pulmonary fibrosis pathogenesis. Using models of pulmonary fibrosis in young adult and old mice and a model of adult alveologenesis after pneumonectomy, we show that administration of ISRIB, a small molecule that restores protein translation by EIF2B during activation of the integrated stress response (ISR), accelerated the differentiation of AT2 into AT1 cells. Accelerated epithelial repair reduced the recruitment of profibrotic monocyte-derived alveolar macrophages and ameliorated lung fibrosis. These findings suggest a dysfunctional role for the ISR in regeneration of the alveolar epithelium after injury with implications for therapy.
Assuntos
Acetamidas/farmacologia , Células Epiteliais Alveolares/efeitos dos fármacos , Cicloexilaminas/farmacologia , Proteostase/efeitos dos fármacos , Fibrose Pulmonar/tratamento farmacológico , Acetamidas/uso terapêutico , Fatores Etários , Células Epiteliais Alveolares/citologia , Animais , Amianto , Bleomicina , Diferenciação Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Cicloexilaminas/uso terapêutico , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Proteostase/fisiologia , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Estresse Fisiológico/efeitos dos fármacosRESUMO
MECP2 mutations are identifiable in approximately 80% of classic Rett syndrome (RTT), but less frequently in atypical RTT. We recruited 110 patients who fulfilled the diagnostic criteria for Rett syndrome and were referred to Cardiff for molecular analysis, but in whom an MECP2 mutation was not identifiable. Dosage analysis of MECP2 was carried out using multiplex ligation dependent probe amplification or quantitative fluorescent PCR. Large deletions were identified in 37.8% (14/37) of classic and 7.5% (4/53) of atypical RTT patients. Most large deletions contained a breakpoint in the deletion prone region of exon 4. The clinical phenotype was ascertained in all 18 of the deleted cases and in four further cases with large deletions identified in Goettingen. Five patients with large deletions had additional congenital anomalies, which was significantly more than in RTT patients with other MECP2 mutations (2/193; p<0.0001). Quantitative analysis should be included in molecular diagnostic strategies in both classic and atypical RTT.