Chitin-Derived AVR-48 Prevents Experimental Bronchopulmonary Dysplasia (BPD) and BPD-Associated Pulmonary Hypertension in Newborn Mice
| Autor: | Varsha M. Prahaladan, Suchismita Acharya, Alison J. Carey, Shadi N. Malaeb, Vineet Bhandari, Dale J. Christensen, Sumita Behera, Ogan K. Kumova, Beamon Agarwal, Pragnya Das |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
medicine.medical_specialty
Neonatal intensive care unit QH301-705.5 Hypertension Pulmonary Drug Evaluation Preclinical Neovascularization Physiologic Chitin Gastroenterology Catalysis Article Pulmonary function testing Inorganic Chemistry Mice Pharmacokinetics Internal medicine bronchopulmonary dysplasia medicine Animals Physical and Theoretical Chemistry Biology (General) Molecular Biology QD1-999 Spectroscopy Lung business.industry BPD-associated pulmonary hypertension Organic Chemistry General Medicine medicine.disease Pulmonary hypertension Computer Science Applications Rats Pulmonary Alveoli Chemistry Disease Models Animal medicine.anatomical_structure Bronchopulmonary dysplasia Animals Newborn inflammation Toxicity AVR-48 chitohexaose Complication business |
| Zdroj: | International Journal of Molecular Sciences International Journal of Molecular Sciences, Vol 22, Iss 8547, p 8547 (2021) Volume 22 Issue 16 |
| ISSN: | 1422-0067 |
| Popis: | Bronchopulmonary dysplasia (BPD) is the most common complication of prematurity and a key contributor to the large health care burden associated with prematurity, longer hospital stays, higher hospital costs, and frequent re-hospitalizations of affected patients through the first year of life and increased resource utilization throughout childhood. This disease is associated with abnormal pulmonary function that may lead to BPD-associated pulmonary hypertension (PH), a major contributor to neonatal mortality and morbidity. In the absence of any definitive treatment options, this life-threatening disease is associated with high resource utilization during and after neonatal intensive care unit (NICU) stay. The goal of this study was to test the safety and efficacy of a small molecule derivative of chitin, AVR-48, as prophylactic therapy for preventing experimental BPD in a mouse model. Two doses of AVR-48 were delivered either intranasally (0.11 mg/kg), intraperitoneally (10 mg/kg), or intravenously (IV) (10 mg/kg) to newborn mouse pups on postnatal day (P)2 and P4. The outcomes were assessed by measuring total inflammatory cells in the broncho-alveolar lavage fluid (BALF), chord length, septal thickness, and radial alveolar counts of the alveoli, Fulton’s Index (for PH), cell proliferation and cell death by immunostaining, and markers of inflammation by Western blotting and ELISA. The bioavailability and safety of the drug were assessed by pharmacokinetic and toxicity studies in both neonatal mice and rat pups (P3-P5). Following AVR-48 treatment, alveolar simplification was improved, as evident from chord length, septal thickness, and radial alveolar counts total inflammatory cells were decreased in the BALF Fulton’s Index was decreased and lung inflammation and cell death were decreased, while angiogenesis and cell proliferation were increased. AVR-48 was found to be safe and the no-observed-adverse-effect level (NOAEL) in rat pups was determined to be 100 mg/kg when delivered via IV dosing with a 20-fold safety margin. With no reported toxicity and with a shorter half-life, AVR-48 is able to reverse the worsening cardiopulmonary phenotype of experimental BPD and BPD-PH, compared to controls, thus positioning it as a future drug candidate. |
| Databáze: | OpenAIRE |
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