Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242706 (hyperoxia)
 5,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alveolar epithelial cell (AEC) injury is central to the pathogenesis of pulmonary fibrosis. Epithelial FGF (fibroblast growth factor) signaling is essential for recovery from hyperoxia- and influenza-induced lung injury, and treatment with FGFs is protective in experimental lung injury. The cell types involved in the protective effect of FGFs are not known. We hypothesized that FGF signaling in type II AECs (AEC2s) is critical in bleomycin-induced lung injury and fibrosis. To test this hypothesis, we generated mice with tamoxifen-inducible deletion of FGFR1-3 (fibroblast growth factor receptors 1, 2, and 3) in surfactant protein C-positive (SPC+) AEC2s (SPC triple conditional knockout [SPC-TCKO]). In the absence of injury, SPC-TCKO mice had fewer AEC2s, decreased Sftpc (surfactant protein C gene) expression, increased alveolar diameter, and increased collagen deposition. After intratracheal bleomycin administration, SPC-TCKO mice had increased mortality, lung edema, and BAL total protein, and flow cytometry and immunofluorescence revealed a loss of AEC2s. To reduce mortality of SPC-TCKO mice to less than 50%, a 25-fold dose reduction of bleomycin was required. Surviving bleomycin-injured SPC-TCKO mice had increased collagen deposition, fibrosis, and ACTA2 expression and decreased epithelial gene expression. Inducible inactivation of individual Fgfr2 or Fgfr3 revealed that Fgfr2, but not Fgfr3, was responsible for the increased mortality and lung injury after bleomycin administration. In conclusion, AEC2-specific FGFR2 is critical for survival in response to bleomycin-induced lung injury. These data also suggest that a population of SPC+ AEC2s require FGFR2 signaling for maintenance in the adult lung. Preventing epithelial FGFR inhibition and/or activating FGFRs in alveolar epithelium may therefore represent a novel approach to treating lung injury and reducing fibrosis.
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PMID:FGFR2 Is Required for AEC2 Homeostasis and Survival after Bleomycin-induced Lung Injury. 3194 Apr 43

Early administration of mesenchymal stromal cell (MSC)-derived small extracellular vesicles (MEx) has shown considerable promise in experimental models of bronchopulmonary dysplasia (BPD). However, the ability of MEx to reverse the long-term pulmonary complications associated with established BPD remains unknown. In this study, MEx were isolated from media conditioned by human Wharton's Jelly-derived MSC cultures. Newborn mice (FVB strain) were exposed to hyperoxia (HYRX (75% O2)) before returning to room air at postnatal day 14 (PN14). Following prolonged HYRX-exposure, animals received a single MEx dose at PN18 or serial MEx treatments at PN18-39 ("late" intervention). This group was compared to animals that received an early single MEx dose at PN4 ("early" intervention). Animals were harvested at PN28 or 60 for assessment of pulmonary parameters. We found that early and late MEx interventions effectively ameliorated core features of HYRX-induced neonatal lung injury, improving alveolar simplification, pulmonary fibrosis, vascular remodelling and blood vessel loss. Exercise capacity testing and assessment of pulmonary hypertension (PH) showed functional improvements following both early and late MEx interventions. In conclusion, delivery of MEx following prolonged HYRX-exposure improves core features of experimental BPD, restoring lung architecture, decreasing pulmonary fibrosis and vascular muscularization, ameliorating PH and improving exercise capacity. Taken together, delivery of MEx may not only be effective in the immediate neonatal period to prevent the development of BPD but may provide beneficial effects for the management and potentially the reversal of cardiorespiratory complications in infants and children with established BPD.
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PMID:Mesenchymal stromal cell-derived small extracellular vesicles restore lung architecture and improve exercise capacity in a model of neonatal hyperoxia-induced lung injury. 3293 35


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