CXCR4 Blockade Attenuates Hyperoxia-Induced Lung Injury in Neonatal Rats

Abstract

Background: Lung inflammation is a key factor in the pathogenesis of bronchopulmonary dysplasia (BPD). Stromal-derived factor-1 (SDF-1) and its receptor chemokine receptor 4 (CXCR4) modulate the inflammatory response. It is not known if antagonism of CXCR4 alleviates lung inflammation in neonatal hyperoxia-induced lung injury. Objective: We aimed to determine whether CXCR4 antagonism would attenuate lung injury in rodents with experimental BPD by decreasing pulmonary inflammation. Methods: Newborn rats exposed to normoxia (room air, RA) or hyperoxia (FiO₂ = 0.9) from postnatal day 2 (P2) to P16 were randomized to receive the CXCR4 antagonist, AMD3100 or placebo (PL) from P5 to P15. Lung alveolarization, angiogenesis and inflammation were evaluated at P16. Results: Compared to the RA pups, hyperoxic PL pups had a decrease in alveolarization, reduced lung vascular density and increased lung inflammation. In contrast, AMD3100-treated hyperoxic pups had improved alveolarization and increased angiogenesis. This improvement in lung structure was accompanied by a decrease in the macrophage and neutrophil counts in the bronchoalveolar lavage fluid and reduced lung myeloperoxidase activity. Conclusion: CXCR4 antagonism decreases lung inflammation and improves alveolar and vascular structure in neonatal rats with experimental BPD. These findings suggest a novel therapeutic strategy to alleviate lung injury in preterm infants with BPD.

Targeting Neutrophils to Prevent Malaria-Associated Acute Lung Injury/Acute Respiratory Distress Syndrome in Mice

“…CXCL12 is mainly produced by bone marrow stromal cells, including vascular endothelial cells, and this receptor/chemokine complex has been associated with the trafficking of immune cells in other infectious diseases [23,30–32] and has been shown to modulate neutrophils with only minimal effects on the monocyte compartment [31]. Various diseases, especially those involving the lungs, are improved by treatments that block CXCR4 [23,33,34]. A specific CXCR4 antagonist has been shown to inhibit neutrophil accumulation into air spaces and attenuate the increase in lung permeability during LPS-induced lung injury [23].…”

Recent advances in the mechanisms of lung alveolarization and the pathogenesis of bronchopulmonary dysplasia

“…These data clearly demonstrate that inflammation plays a key role in aberrant alveolarization in response to hyperoxia. Identical observations were made by Drummond and coworkers (88), who applied AMD3100, an antagonist of Cxcr4 in a similar rat hyperoxia model (90% O 2 from P1 to P16, AMD3100 applied between P5 to P15, in a therapeutic regimen). Cxcr4 antagonism also decreased neutrophil and macrophage infiltration into the lungs, provoked hyperoxia, and improved alveolarization (assessed by MLI) and angiogenesis, and limited aberrant pulmonary vascular remodeling.…”

Combined Treatment with Insulin-Like Growth Factor 1 and AMD3100 Improves Motor Outcome in a Murine Model of Neonatal Hypoxic-Ischemic Encephalopathy

“…The small organic bicyclam molecule AMD3100 is a selective antagonist of the CXCR4 receptor, which binds to stromal cell-derived factor SDF-1, and has been safely administered in neonatal murine models to successfully release bone marrow progenitor cells [11,12]. AMD3100 administration has been shown to improve cardiac and lung injury by decreasing tissue inflammation and increasing recruitment and mobilization of progenitor cells to the injured tissue [12,13]; however, AMD3100 has low efficacy, a monotherapy that is usually administered in combination with other factors. Specifically, the combination of insulin-like growth factor 1 (IGF1) and AMD3100 has resulted in peripheral blood MSC numbers 7-fold higher than AMD3100 alone [14].…”