RESUMEN
Idiopathic pulmonary fibrosis (IPF) (histopathology of usual interstitial pneumonia [UIP]) is a progressive disease with poor prognosis. Characteristic features of IPF/UIP include fibroblastic foci, which are patchy lesions of focal, disarranged myofibroblasts. GATA-6 is a transcription factor linked with cell differentiation. Its role in the development of IPF has not previously been investigated. We hypothesized that GATA-6 participates in the differentiation of fibroblasts into myofibroblasts in IPF/UIP lungs. The expression patterns of GATA-6, the mesenchymal marker alpha-smooth muscle actin (alpha-SMA), and markers for proliferation (Ki67) and apoptosis (caspase-3) were analyzed in human IPF/UIP tissue samples. The effects of GATA-6 overexpression and silencing were studied in cell cultures. The results show that the alpha-SMA-positive fibroblastic foci in IPF/UIP lungs are positive for GATA-6, but negative for Ki67 and caspase-3. Cultured human IPF/UIP fibroblasts expressed GATA-6 mRNA, whereas cells from the normal adult lung did not. In cultured A549 lung epithelial cells, the induction of GATA-6 by transforming growth factor-beta1 resulted in simultaneous expression of alpha-SMA and decrease of E-cadherin. The inhibition of GATA-6 expression in fibroblasts showed that GATA-6 mediates the alpha-SMA-inducing signal of transforming growth factor-beta1. In conclusion, the hallmark of IPF/UIP histopathology, the fibroblast focus, consists of differentiated, quiescent cells that prominently express GATA-6.
Asunto(s)
Fibroblastos/metabolismo , Fibroblastos/patología , Factor de Transcripción GATA6/metabolismo , Fibrosis Pulmonar Idiopática/metabolismo , Fibrosis Pulmonar Idiopática/patología , Actinas/metabolismo , Adulto , Apoptosis/efectos de los fármacos , Biomarcadores/metabolismo , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proteínas de Unión al ADN/metabolismo , Epitelio/efectos de los fármacos , Epitelio/metabolismo , Epitelio/patología , Fibroblastos/efectos de los fármacos , Factor de Transcripción GATA6/genética , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Mesodermo/efectos de los fármacos , Mesodermo/metabolismo , Mesodermo/patología , Transporte de Proteínas/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factores de Transcripción/metabolismo , Factor de Crecimiento Transformador beta1/farmacologíaRESUMEN
BACKGROUND: Premature birth and respiratory distress syndrome (RDS) are risk factors for disturbed lung development and bronchopulmonary dysplasia (BPD). The molecular mechanisms related to prematurity and BPD remain largely unknown. Epithelial expression of the transcription factor GATA-6 has been implicated in normal and abnormal murine lung development. OBJECTIVES: The possible involvement of GATA-6 in the normal development and in RDS and BPD was investigated in the human and baboon lung. METHODS: Immunohistochemistry was used to study the expression of GATA-6 and thyroid transcription factor 1 in lung specimens from different age groups of human and baboon fetuses and newborns with lung disease. Furthermore, the regulatory role of TGF-ß1 in GATA-6 expression was investigated in human pulmonary epithelial cell lines using RT-PCR. RESULTS: GATA-6 expression increased in the developing human airway epithelium along with advancing gestation, but diminished to negligible at birth. In RDS, GATA-6 expression was enhanced at 5-7 days after birth, and decreased thereafter. In BPD, the expression of GATA-6 in alveolar epithelial cells was low. These results were confirmed and extended using an established baboon model of prematurity. The in vitro experiments revealed that TGF-ß1 induces GATA-6 and thyroid transcription factor 1 expression in lung epithelial cells. CONCLUSIONS: Our results suggest that the expression of GATA-6 at the early stages of the preterm lung may be related to impaired postnatal alveolar development.