期刊
AMERICAN JOURNAL OF PATHOLOGY
卷 186, 期 4, 页码 777-793出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2015.11.024
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资金
- Indiana University School of Medicine Indiana Pediatric Scientist Award program through the Child Health Research Career Development Award [K12 HD068371]
- NIH [R01 HL115619]
Septation of the gas-exchange saccules of the morphologically immature mouse lung requires regulated timing, spatial direction, and dosage of transforming growth factor (TGF)-beta signaling. We found that neonatal hyperoxia acutely initially diminished saccular TGF-beta signaling coincident with alveolar simplification. However, sustained hyperoxia resulted in a biphasic response and subsequent up regulation of TGF-beta signaling, ultimately resulting in bronchopulmonary dysplasia. Significantly, we found that the TGF-beta-induced matricellular protein (TGFBI) was similarly biphasically altered in response to hyperoxia. Moreover, genetic ablation revealed that TGFBI was required for normal alveolar structure and function. Although the phenotype was not neonatal lethal, Tgfbi-deficient Lungs were morphologically abnormal. Mutant septal tips were stunted, lacked elastin-positive tips, exhibited reduced proliferation, and contained abnormally persistent alveolar alpha-smooth muscle actin myofibroblasts. In addition, Tgfbi-deficient lungs misexpressed TGF-beta-responsive follistatin and serpine 1, and transiently suppressed myofibroblast platelet-derived growth factor alpha differentiation marker. Finally, despite normal lung volume, Tgfbi-null lungs displayed diminished elastic recoil and gas exchange efficiency. Combined, these data demonstrate that initial suppression of the TGF-beta signaling apparatus, as well as Loss of key TGF-beta effectors (like TGFBI), underlies early alveolar structural defects, as well as long-lasting functional deficits routinely observed in chronic lung disease of infancy patients. These studies underline the complex (and often contradictory) rote of TGF-beta and indicate a need to design studies to associate alterations with initial appearance of phenotypical changes suggestive of bronchopulmonary dysplasia.
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