Chitin-Derived AVR-48 Prevents Experimental Bronchopulmonary Dysplasia (BPD) and BPD-Associated Pulmonary Hypertension in Newborn Mice

Abstract

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.

Vitamin D Ameliorates Apoptosis and Inflammation by Targeting the Mitochondrial and MEK1/2-ERK1/2 Pathways in Hyperoxia-Induced Bronchopulmonary Dysplasia

“…Lung morphometry, including mean linear intercept (MLI), radial alveolar count (RAC), and septal thickness were calculated as previously described. 21 , 22 MLI was calculated using Image J software by measuring the average distance between the intersects of alveolar septal tissue and a superimposed counting grid. RAC was calculated as the number of septa intersected by each line drawn from the center of the respiratory bronchiole to the distal acinus.…”

Dopamine, Immunity, and Disease

“…Chemotaxis involves many chemokines, some of which are species- or cell-specific, and is initiated when soluble chemokines bind to their cognate receptors on immune cells ( Rossi and Zlotnik, 2000 ; Hughes and Nibbs, 2018 ). A number of studies have shown that dopamine can impact the production of chemotactic factors, particularly CCL2, which is important in the pathogenesis of many chronic inflammatory conditions, as well as neurologic HIV (neuroHIV) ( Eugenin et al, 2006 ; Covino et al, 2016 ; Fantuzzi et al, 2019 ; Das et al, 2021 ). Dopamine increased the mRNA expression of CXCL8 and CCL2 in activated PBMCs ( Torres et al, 2005 ) and the injection of a D1-like agonist increased the mRNA expression levels of CCL2 and C-C motif chemokine ligand 7 in the rodent PFC ( Saika et al, 2018 ).…”

Strategies to Counteract Oxidative Stress and Inflammation in Chronic-Degenerative Diseases

“…Bandari et al investigated the effects of chitin derivative compounds in alleviating lung inflammatory diseases such as acute lung injury (ALI), acute respiratory distress syndrome (ARDS) [ 1 ], and bronchopulmonary dysplasia (BPD) [ 2 ]. Although many efforts have been made to develop drugs to prevent or counteract these lung diseases, to date there are no effective cures available.…”

“…BPD is an inflammatory disease characterized by high levels of cytokines, chemokines, and inflammatory cells in the lungs and blood serum, and plasma. Das et al [ 2 ] evaluated the safety and efficacy of AVR-48 as prophylactic therapy for preventing experimental BPD in a hyperoxia-induced experimental neonatal mouse model, using different routes of administration. AVR-48 was administered 2 and 4 days after birth.…”