Daily Intraperitoneal Administration of Rosiglitazone Does Not Improve Lung Function or Alveolarization in Preterm Rabbits Exposed to Hyperoxia
Abstract
:1. Introduction
2. Materials and Methods
2.1. In Vitro Selectivity Assay for Peroxisome Proliferator-Activated Receptor of Thiazolidinediones
2.2. Plasma Protein Binding, Lung Tissue Binding, and Caco-2 Permeability Assay
2.2.1. Plasma Protein Binding
2.2.2. Lung Tissue Binding
2.2.3. Caco-2 Permeability Assay
2.2.4. Liquid Chromatography–Tandem Mass Spectrometry (LC/MS/MS) Method
2.3. Animal Care and Cesarean Section
2.4. Pharmacokinetic Profiling of Rosiglitazone
2.4.1. In Vivo Phase
2.4.2. Bioanalysis and Pharmacokinetic Analysis
2.5. Pulmonary Efficacy Studies: Daily, Intraperitoneal Rosiglitazone Administration at 1 mg/kg
2.5.1. Lung Function Testing
2.5.2. Radial Alveolar Count
2.6. Daily, Intraperitoneal Rosiglitazone Administration at 10 mg/kg
2.7. Quantification of Blood Lipid Levels
2.8. Quantitative Proteomic Analysis by Mass Spectrometry
2.9. Statistical Analysis
3. Results and Discussion
3.1. RGZ Has the Highest Affinity for Human PPARγ among TZDs
3.2. TZDs Show High Epithelial Permeability and Plasma Protein and Lung Tissue Binding
3.3. Rosiglitazone Displays a High Blood-to-Lung Delivery Irrespective of the Administration Route
3.4. Daily Intraperitoneal Administration of Rosiglitazone Does Not Improve Lung Function or Alveolarization in Preterm Rabbits Exposed to Hyperoxia
3.5. Daily Rosiglitazone Treatment Induces Dyslipidemia in Premature Rabbits
3.6. Lung Proteomics Reveal Dysregulation of Inflammatory Pathways and Protein–Lipid Complex by High-Dose Rosiglitazone
4. Limitations of the Study
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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TZD Type | Plasma Protein Binding (%) | Lung Tissue Binding (%) | Papp (A–B/B–A, cm/sec) | Papp with Pgp Inhibitor (A–B/B–A, cm/sec) |
---|---|---|---|---|
RGZ | 97.5 ± 0.2 | 94.2 ± 0.7 | 1.45 × 10−5 ± 0.06 × 10−5 / 1.00 × 10−5 ± 0.06 × 10−5 | 1.63 × 10−5 ± 0.05 × 10−5 / 1.14 ×10−5 ± 0.04 × 10−5 |
PGZ | 96.7 ± 0.6 | 95.6 ± 2.1 | 1.18 × 10−5 ± 0.05 × 10−5 / 1.53 × 10−5 ± 0.36 × 10−5 | 1.23 × 10−5 ± 0.17 × 10−5 / 2.54 × 10−5 ± 0.55 × 10−5 |
DRF-2546 | 98.4 ± 0.3 | 91.8 ± 1.8 | 2.29 × 10−5 ± 0.03 × 10−5 / 1.87 × 10−5 ± 0.80 × 10−5 | 2.86 × 10−5 ± 0.15× 10−5 / 1.58 × 10−5 ± 0.34 × 10−5 |
Tmax (h) | Cmax (ng/mL) | t1/2 (h) | AUClast (ng/mL∙h) | AUCLung/AUCPlasma | |
---|---|---|---|---|---|
Intratracheal Administration | |||||
Lung | 0.25 | 1067 | 15 | 17,020 | 0.7 |
Plasma | 0.25 | 1950 | 15 | 25,785 | |
Intraperitoneal Administration | |||||
Lung | 0.25 | 1024 | n.c. | 19,752 | 0.7 |
Plasma | 0.25 | 2443 | n.c. | 29,490 |
Pathway Description | Downregulated Log (q-Value) | Upregulated Log (q-Value) | Dysregulated Proteins in the Pathway *** |
---|---|---|---|
1.Neutrophil degranulation | - | −12.0 | AHSG, CAMP, CHIT1, FTL, HK3, HP, ITGAM, LCN2, LTF, MPO, CFP, S100A8, S100A9, S100A12, PGLYRP1, SNAP29, GCA, PYCARD, RETN |
2. MCM * complex | −7.6 | - | MCM2, MCM3, MCM4, MCM5, MCM7 |
3. Regulation of inflammatory response | - | −7.1 | AGT, AHSG, APOE, IL16, LBP, MVK, S100A8, S100A9, S100A12, SNCA, PGLYRP1, PYCARD, PGLYRP2 |
4. Humoral immune response | - | −7.0 | C6, C8A, C8B, C8G, CAMP, CRP, HPX, LTF, CFP, S100A9, S100A12, PGLYRP1 |
5. Transition metal ion homeostasis | −5.4 | FTL, HPX, LCN2, LTF, S100A8, S100A9, ABCB6, STEAP4 | |
6. Positive regulation of reactive oxygen species metabolic process | - | −4.7 | AGT, CRP, ITGAM, LCN2, SNCA, XDH |
7. Protein–lipid complex remodeling | - | −5.0 | AGT, APOB, APOC3, APOE, MPO |
8. Regulation of endopeptidase activity | −5.0 | AGT, AHSG, BAX, LTF, S100A8, S100A9, SNCA, XDH, LAMTOR5, FETUB, PYCARD | |
9. Extracellular matrix organization | −5.1 | COL4A6, HAPLN1, DCN, FBLN2, FBN2, ICAM2, ITGA6, ITGB3, SPARC, PXDN, CRTAP | |
10. NABA CORE MATRISOME ** | −4.6 | COL4A6, HAPLN1, DCN, FBLN2, FBN2, SPARC, PXDN, SPARCL1, POSTN, NPNT |
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Aquila, G.; Regin, Y.; Murgia, X.; Salomone, F.; Casiraghi, C.; Catozzi, C.; Scalera, E.; Storti, M.; Stretti, F.; Aquino, G.; et al. Daily Intraperitoneal Administration of Rosiglitazone Does Not Improve Lung Function or Alveolarization in Preterm Rabbits Exposed to Hyperoxia. Pharmaceutics 2022, 14, 1507. https://doi.org/10.3390/pharmaceutics14071507
Aquila G, Regin Y, Murgia X, Salomone F, Casiraghi C, Catozzi C, Scalera E, Storti M, Stretti F, Aquino G, et al. Daily Intraperitoneal Administration of Rosiglitazone Does Not Improve Lung Function or Alveolarization in Preterm Rabbits Exposed to Hyperoxia. Pharmaceutics. 2022; 14(7):1507. https://doi.org/10.3390/pharmaceutics14071507
Chicago/Turabian StyleAquila, Giorgio, Yannick Regin, Xabier Murgia, Fabrizio Salomone, Costanza Casiraghi, Chiara Catozzi, Enrica Scalera, Matteo Storti, Francesca Stretti, Giancarlo Aquino, and et al. 2022. "Daily Intraperitoneal Administration of Rosiglitazone Does Not Improve Lung Function or Alveolarization in Preterm Rabbits Exposed to Hyperoxia" Pharmaceutics 14, no. 7: 1507. https://doi.org/10.3390/pharmaceutics14071507