Interleukin-1 receptor antagonist prevents murine bronchopulmonary dysplasia induced by perinatal inflammation and hyperoxia

Abstract

Bronchopulmonary dysplasia (BPD) is a common lung disease of premature infants, with devastating short-and long-term consequences. The pathogenesis of BPD is multifactorial, but all triggers cause pulmonary inflammation. No therapy exists; therefore, we investigated whether the anti-inflammatory interleukin-1 receptor antagonist (IL-1Ra) prevents murine BPD. We precipitated BPD by perinatal inflammation (lipopolysaccharide injection to pregnant dams) and rearing pups in hyperoxia (65% or 85% O 2 ). Pups were treated daily with IL-1Ra or vehicle for up to 28 d. Vehicle-injected animals in both levels of hyperoxia developed a severe BPD-like lung disease (alveolar number and gas exchange area decreased by up to 60%, alveolar size increased up to fourfold). IL-1Ra prevented this structural disintegration at 65%, but not 85% O 2 . Hyperoxia depleted pulmonary immune cells by 67%; however, extant macrophages and dendritic cells were hyperactivated, with CD11b and GR1 (Ly6G/C) highly expressed. IL-1Ra partially rescued the immune cell population in hyperoxia (doubling the viable cells), reduced the percentage that were activated by up to 63%, and abolished the unexpected persistence of IL-1α and IL-1β on day 28 in hyperoxia/vehicle-treated lungs. On day 3, perinatal inflammation and hyperoxia each triggered a distinct pulmonary immune response, with some proinflammatory mediators increasing up to 20-fold and some amenable to partial or complete reversal with IL-1Ra. In summary, our analysis reveals a pivotal role for IL-1α/β in murine BPD and an involvement for MIP (macrophage inflammatory protein)-1α and TREM (triggering receptor expressed on myeloid cells)-1. Because it effectively shields newborn mice from BPD, IL-1Ra emerges as a promising treatment for a currently irremediable disease that may potentially brighten the prognosis of the tiny preterm patients.anti-inflammatory therapy | cytokines | receptor blockade | neonatal immunity

Epithelial β1 integrin is required for lung branching morphogenesis and alveolarization

“…Increased ROS production has been described in integrin α1-null glomerular mesangial cells (Chen et al, 2007); however, this has not previously been shown to occur in epithelial cells, and β1 integrins have not been linked to MCP-1 expression or ROS production in other systems. Although the role of macrophages during alveolarization is not well understood, we and others have shown that macrophages and macrophage-derived products disrupt branching morphogenesis (Blackwell et al, 2011;Nold et al, 2013). Specifically, we have found that products of activated macrophages can impair expression of molecules by epithelial and mesenchymal cells that are important for control of airway branching, including BMP4, Wnt7b and FGF10 (Benjamin et al, 2010;Blackwell et al, 2011;Carver et al, 2013).…”

Endothelial Monocyte-Activating Polypeptide II Mediates Macrophage Migration in the Development of Hyperoxia-Induced Lung Disease of Prematurity

“…As expected, tracheal aspirates of infants exposed to hyperoxia had elevated inflammatory mediators primarily secreted by macrophages, notably IL-1b and tumor necrosis factor-a (14,15). In infants with sepsis-induced inflammation, inhibitors against the two cytokines showed little improvement in survival rates; in mouse models treated with inhibitors against these cytokines, only some BPD features improved (16)(17)(18)(19)(20). This suggests that alternative, more broadly functioning or upstream targets are needed to prevent BPD.…”

“…After a call for more directed studies on pulmonary inflammation in BPD, clinical studies determined that inflammatory markers are not only elevated in BPD but associated with prognosis (12,15,39). Some studies used untargeted antiinflammatory therapies such as glucocorticoids, direct cytokines, or chemokines, which resulted in minimal improvement in some characteristics of BPD (19).…”

Animal models of bronchopulmonary dysplasia. The term mouse models

“…RT-PCR analysis showed increased inflammation in hyperoxic mice, including higher levels of interleukin (IL)-1␣ and macrophage inflammatory protein-1␣ (MIP-1␣), compared with controls. Administration of an IL-1␣ receptor antagonist in another model of BPD induced with prenatal lipopolysaccharide (LPS) and PN hyperoxia showed decreases in many inflammatory mediators, including but not limited to IL-1 (61). These data suggest that prolonged exposure to hyperoxia produces a physiological and histological picture similar to BPD, which may be mediated in part by inflammatory cytokines.…”