Fetal breathing deficiency and lung hypoplasia in osteogenesis imperfecta

Authors

• E Makareeva
• B Radant
• M Sousa
• M Sellamani
• E Mertz
• S Otsuru
• S Leikin

Abstract

Pulmonary pathology is the leading cause of death and a major factor affecting the quality of life in osteogenesis imperfecta (OI). Mounting evidence suggests that lung function in OI is affected by skeletal defects and intrinsic lung tissue pathology. The present study aims to provide mechanistic insights into the development of pulmonary pathology in OI using a G610C mouse model. Our observations of perinatal lethal lung hypoplasia in G610C homozygous (Hom) embryos, severe lung parenchyma damage in young G610C heterozygous (Het) animals and gradual repair after puberty suggested deficient fetal lung development. Histology, immunofluorescence, and spatial transcriptomics of embryonic lungs at E16.5-E18.5 revealed that the onset of the pathology coincides with the initiation of fetal breathing movements (FBM), which are essential for the proper development of saccular structures. Monitoring of the FBM in vivo by ultrasound backscatter microscopy confirmed the lack of lung inflation in E18.5 Hom embryos despite the observed overall movements consistent with FBM activation. Apparently, the weakness of G610C collagen fibers in Hom embryos prevented proper diaphragm movement and/or transmission of the mechanical stress from this movement, which is needed for saccular inflation. Lung inflation observed in E18.5 Het embryos was consistent with the less severe, nonlethal lung hypoplasia at birth. Taken together, these findings indicate that prenatal diagnosis of deficient lung inflation during FBM by ultrasound in OI fetuses and the corresponding treatment of neonatal lung hypoplasia may prevent acute respiratory distress in OI babies and reduce the life-long lung pathology in OI patients.

Scientific Focus Area: Developmental Biology

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