RESUMO
Acute lung injury and compromised alveolar development characterize bronchopulmonary dysplasia (BPD) of the premature neonate. High levels of keratinocyte growth factor (KGF), a cell-cell mediator with pleiotrophic lung effects, are associated with low BPD risk. KGF decreases mortality in hyperoxia-exposed newborn rodents, a classic model of injury-induced impaired alveolarization, although the pulmonary mechanisms of this protection are poorly defined. These were explored through in vitro and in vivo approaches in the rat. Hyperoxia decreased by 30% the rate of wound closure of a monolayer of fetal alveolar epithelial cells, due to cell death, which was overcome by recombinant human KGF (100 ng/ml). In rat pups exposed to >95% O2 from birth, increased viability induced by intraperitoneal injection of KGF (2 microg/g body wt) every other day was associated with prevention of neutrophil influx in bronchoalveolar lavage (BAL), prevention of decreases in whole lung DNA content and cell proliferation rate, partial prevention of apoptosis increase, and a markedly increased proportion of surfactant protein B-immunoreactive cells in lung parenchyma. Increased lung antioxidant capacity is likely to be due in part to enhanced CAAT/enhancer binding protein alpha expression. By contrast, KGF neither corrected changes induced by hyperoxia in parameters of lung morphometry that clearly indicated impaired alveolarization nor had any significant effect on tissue or BAL surfactant phospholipids. These findings evidence KGF alveolar epithelial cell protection, enhancing effects on alveolar repair capacity, and anti-inflammatory effects in the injured neonatal lung that may account, at least in part, for its ability to reduce mortality. They argue in favor of a therapeutic potential of KGF in the injured neonatal lung.
Assuntos
Fator 7 de Crescimento de Fibroblastos/farmacologia , Hiperóxia/patologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Líquido da Lavagem Broncoalveolar/citologia , Proteína alfa Estimuladora de Ligação a CCAAT/genética , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , DNA/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Fosfolipídeos/metabolismo , Gravidez , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/patologia , Proteína B Associada a Surfactante Pulmonar/metabolismo , Ratos , Ratos Sprague-Dawley , Análise de Sobrevida , Fator de Crescimento Transformador alfa/genética , Fator de Crescimento Transformador alfa/metabolismoRESUMO
Mutations in the ATP6V1B1 and ATP6V0A4 genes, encoding subunits B1 and 4 of apical H(+) ATPase, cause recessive forms of distal renal tubular acidosis (dRTA). ATP6V1B mutations have been associated with early sensorineural hearing loss (SNHL), whereas ATP6V0A4 mutations are classically associated with either late-onset SNHL or normal hearing. The phenotype and genotype of 39 new kindreds with recessive dRTA, 18 of whom were consanguineous, were assessed. Novel and known loss-of-function mutations were identified in 31 kindreds. Fourteen new and five recurrent mutations of the ATP6V0A4 gene were identified in 21 families. For the ATP6V1B1 gene, two new and two previously described mutations were identified in 10 families. Surprisingly, seven probands with ATP6V0A4 gene mutations developed severe early SNHL between the ages of 2 mo and 10 yr. No mutation was detected in eight families. These data extend the spectrum of disease-causing mutations and provide evidence for genetic heterogeneity in SNHL. The data also demonstrate that mutations in either of these genes may cause early deafness, and they highlight the importance of genetic screening for recessive forms of dRTA independent of hearing status.