Abstract
The pathogenesis of bronchopulmonary dysplasia (BPD), involves inflammatory, mechanisms that are not fully characterized. Here we report that overexpression of C-C chemokine receptor 5 (CCR5) and its ligands is associated with BPD development. Lipopolysaccharide-induced BPD rats have increased CCR5 and interleukin-1β (IL-1β) levels, and decreased alveolarization, while CCR5 or IL-1β receptor antagonist treatments decreased inflammation and increased alveolarization. CCR5 enhances macrophage migration, macrophage infiltration in the lungs, IL-1β levels, lysyl oxidase activity, and alveolar development arrest. CCR5 expression on monocytes, and its ligands in blood samples from BPD infants, are elevated. Furthermore, batyl alcohol supplementation reduced CCR5 expression and IL-1β production in lipopolysaccharide-exposed rat lungs. Moreover, receptor-interacting kinase 3 (RIP3) upstream regulator of CCR5-cultured RIP3−/− macrophages exhibited partly blocked lipopolysaccharide-induced CCR5 expression. We conclude that increased CCR5 expression is a key mechanism in BPD development and represents a novel therapeutic target for treatment.
Highlights
Bronchopulmonary dysplasia (BPD), the most common chronic lung disease among infants, is characterized by premature alveolar developmental arrest[1,2]
We assessed the activity of lysyl oxidase (LOX), which plays a key role in regulating the stability of the extracellular matrix (ECM)[22]
In this study, we found a critical role of chemokine receptor 5 (CCR5) signaling in the pathogenesis of BPD and demonstrated that the expression of CCR5 and its ligands was significantly increased in infants with BPD, as well as in an LPSinduced rat model of BPD, which had never been previously reported
Summary
Bronchopulmonary dysplasia (BPD), the most common chronic lung disease among infants, is characterized by premature alveolar developmental arrest[1,2]. The development of BPD is associated with an inflammatory response with elevated growth factor and cytokines levels[3]. Macrophages, which play an important role in the inflammatory process, have been implicated in BPD, as macrophage counts remain elevated in infants that develop the disease[4,5]. Animal models to study BPD have often used intraamniotic lipopolysaccharide (LPS) administration to inhibit postnatal lung development. This results in fewer and larger alveoli in lungs, which mimics the lung morphology of BPD in premature human infants[9,10,11,12].
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