Analysis Tools
mortality/aging
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• although embryonic development is grossly normal, normally delivered homozygotes die within 20-60 minutes after birth due to obvious neonatal respiratory dysfunction
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respiratory system
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• at E18.5, lungs exhibit excessive accumulation of glycogen, with a significant increase in the proportion of glycogen-rich cells in the alveolar epithelium, consistent with the presence of immature AECIIs
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• fetal lung morphogenesis is impaired
• however, early branching morphogenesis (E9.5-E16.5) is unaffected and pulmonary vessel development and distal airways appear normal at E18.5
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• homozygotes show impaired alveogenesis and maturation during fetal lung development
• however, no alterations in cell proliferation, apoptosis, ER stress or activation of ER-associated degradation are observed
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• at E18.5 and P0, all lungs exhibit collapse of the alveolar space, as shown by significantly decreased interalveolar distance measured by mean linear intercept
• at P0, severe alveolar hypoplasia is observed
• however, radial alveolar counts are normal
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• at E18.5, lungs exhibit excessive accumulation of glycogen, with a significant increase in the proportion of glycogen-rich cells in the alveolar epithelium
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• at E18.5, cuboidal alveolar epithelial type II (AECII) cells contain larger cytoplasmic glycogen deposits but fewer lamellar bodies
• functional maturation of AECII cells is severely impaired during alveogenesis
• however, differentiation of both alveolar epithelial type I (AECI) and AECII cells appears normal
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• at E18.5, AECIIs contain fewer lamellar bodies (LBs)
• expression of ABCA3, a lipid transporter protein required for LB formation in AECII cells, is significantly reduced at E18.5
• ABCA3 labeling is abnormally scattered within the cytoplasm, unlike in wild-type lungs where an aggregated pattern is observed
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• at E18.5, the alveolar wall appears compacted due to lack of air inflation
• however, aquaporin-5+ alveolar epithelial type I (AECI) cells are regularly organized along the alveolar wall
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atelectasis
(
J:265611
)
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• lungs from neonatal (P0) pups sink in PBS due to lack of air inflation
• histology confirmed massive atelectasis with collapse of the alveolar space and unexpanded intra-alveolar septae
• however, both trachea and thorax appear structurally normal
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• newborns quickly develop severe respiratory distress with gasping
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• neonatal respiratory failure
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• at E18.5, unorganized tubular myelin-like vesicles (loose roll structures composed of a few lipid layers) are observed in the alveolar space, suggesting altered composition of surfactants
• at E18.5, lungs show a significant decrease in levels of total lipids and a trend of decrease in total phospholipid and cholesteryl ester (CE)
• major phosphatidylcholine (PC) species, including PC32:0 (16:016:0), PC32:1 (16:016:1), and PC34:1 (16:018:1), show a notable decrease along with a trend of decrease for minor PC species; however, the level of total PC shows a decreasing trend relative to wild-type lungs
• the level of phosphatidylglycerol (PG; the second major phospholipid) shows a decreasing trend whereas subspecies of PG34:1 and PG36:4 are significantly reduced
• Lyso-PC level is significantly increased suggesting an abnormality of phosphatidylcholine metabolic homeostasis in lung
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• levels of surfactant proteins A and D (SP-A and SP-D) are significantly reduced in the lung at E18.5
• immunostaining analysis confirmed a dramatic reduction of secreted SP-A staining along with a notable decrease in SP-D expression
• however, the expression level and pattern of SP-B and SP-C are normal
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homeostasis/metabolism
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• at E18.5, lungs exhibit excessive accumulation of glycogen, with a significant increase in the proportion of glycogen-rich cells in the alveolar epithelium, consistent with the presence of immature AECIIs
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• surfactant phospholipid homeostasis is disturbed in E18.5 lungs
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