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Bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP) are among the most common morbidities affecting extremely premature infants who receive oxygen therapy. Many clinical studies indicate that BPD is associated with advanced ROP. However, the mechanistic link between hyperoxia, BPD, and ROP remains to be explored. Gasdermin D (GSDMD) is a key executor of inflammasome-induced pyroptosis and inflammation. Inhibition of GSDMD has been shown to attenuate hyperoxia-induced BPD and brain injury in neonatal mice. The objective of this study was to further define the mechanistic roles of GSDMD in the pathogenesis of hyperoxia-induced BPD and ROP in mouse models. Here we show that global GSDMD knockout (GSDMD-KO) protects against hyperoxia-induced BPD by reducing macrophage infiltration, improving alveolarization and vascular development, and decreasing cell death. In addition, GSDMD deficiency prevented hyperoxia-induced ROP by reducing vasoobliteration and neovascularization, improving thinning of multiple retinal tissue layers, and decreasing microglial activation. RNA sequencing analyses of lungs and retinas showed that similar genes, including those from inflammatory, cell death, tissue remodeling, and tissue and vascular developmental signaling pathways, were induced by hyperoxia and impacted by GSDMD-KO in both models. These data highlight the importance of GSDMD in the pathogenesis of BPD and ROP and suggest that targeting GSDMD may be beneficial in preventing and treating BPD and ROP in premature infants., (© 2023. The Author(s).)

Mesenchymal stem cell (MSC) extracellular vesicles (EVs) have beneficial effects in preclinical bronchopulmonary dysplasia and pulmonary hypertension (BPD-PH) models. The optimal source, dosing, route, and duration of effects are however unknown. The objectives of this study were to (a) compare the efficacy of GMP-grade EVs obtained from Wharton's Jelly MSCs (WJ-MSCs) and bone marrow (BM-MSCs), (b) determine the optimal dosing and route of administration, (c) evaluate its long-term effects, and (d) determine how MSC EVs alter the lung transcriptome. Newborn rats exposed to normoxia or hyperoxia (85% O2) from postnatal day (P)1-P14 were given (a) intra-tracheal (IT) BM or WJ-MSC EVs or placebo, (b) varying doses of IT WJ-MSC EVs, or (c) IT or intravenous (IV) WJ-MSC EVs on P3. Rats were evaluated at P14 or 3 months. Early administration of IT BM-MSC or WJ-MSC EVs had similar beneficial effects on lung structure and PH in hyperoxia-exposed rats. WJ-MSC EVs however had superior effects on cardiac remodeling. Low, medium, and high dose WJ-MSC EVs had similar cardiopulmonary regenerative effects. IT and IV WJ-MSC EVs similarly improved vascular density and reduced PH in hyperoxic rats. Gene-set enrichment analysis of transcripts differentially expressed in WJ-MSC EV-treated rats showed that induced transcripts were associated with angiogenesis. Long-term studies demonstrated that a single early MSC EV dose has pulmonary vascular protective effects 3 months after administration. Together, our findings have significant translational implications as it provides critical insight into the optimal source, dosing, route, mechanisms of action, and duration of effects of MSC-EVs for BPD-PH., (© The Author(s) 2022. Published by Oxford University Press.)

Lung inflammation plays a key role in the pathogenesis of bronchopulmonary dysplasia (BPD), a chronic lung disease of premature infants. The challenge in BPD management is the lack of effective and safe antiinflammatory agents. Leukadherin-1 (LA1) is a novel agonist of the leukocyte surface integrin CD11b/CD18 that enhances leukocyte adhesion to ligands and vascular endothelium and thus reduces leukocyte transendothelial migration and influx to the injury sites. Its functional significance in preventing hyperoxia-induced neonatal lung injury is unknown. We tested the hypothesis that administration of LA1 is beneficial in preventing hyperoxia-induced neonatal lung injury, an experimental model of BPD. Newborn rats were exposed to normoxia (21% O2) or hyperoxia (85% O2) and received twice-daily intraperitoneal injection of LA1 or placebo for 14 days. Hyperoxia exposure in the presence of the placebo resulted in a drastic increase in the influx of neutrophils and macrophages into the alveolar airspaces. This increased leukocyte influx was accompanied by decreased alveolarization and angiogenesis and increased pulmonary vascular remodeling and pulmonary hypertension (PH), the pathological hallmarks of BPD. However, administration of LA1 decreased macrophage infiltration in the lungs during hyperoxia. Furthermore, treatment with LA1 improved alveolarization and angiogenesis and decreased pulmonary vascular remodeling and PH. These data indicate that leukocyte recruitment plays an important role in the experimental model of BPD induced by hyperoxia. Targeting leukocyte trafficking using LA1, an integrin agonist, is beneficial in preventing lung inflammation and protecting alveolar and vascular structures during hyperoxia. Thus, targeting integrin-mediated leukocyte recruitment and inflammation may provide a novel strategy in preventing and treating BPD in preterm infants.

Bronchopulmonary dysplasia (BPD) is the most common and serious chronic lung disease of preterm infants. The development of pulmonary hypertension (PH) significantly increases the mortality and morbidity of this disease. β-Catenin signaling plays an important role in tissue development and remodeling. Aberrant β-catenin signaling is associated with clinical and experiment models of BPD. To test the hypothesis that inhibition of β-catenin signaling is beneficial in promoting alveolar and vascular development and preventing PH in experimental BPD, we examined the effects of ICG001, a newly developed pharmacological inhibitor of β-catenin, in preventing hyperoxia-induced BPD in neonatal rats. Newborn rat pups were randomized at postnatal day (P)2 to room air (RA) + DMSO (placebo), RA + ICG001, 90% FiO2 (O2) + DMSO, or O2 + ICG001. ICG001 (10 mg/kg) or DMSO was given by daily intraperitoneal injection for 14 days during continuous exposure to RA or hyperoxia. Primary human pulmonary arterial smooth muscle cells (PASMCs) were cultured in RA or hyperoxia (95% O2) in the presence of DMSO or ICG001 for 24 to 72 hours. Treatment with ICG001 significantly increased alveolarization and reduced pulmonary vascular remodeling and PH during hyperoxia. Furthermore, administering ICG001 decreased PASMC proliferation and expression of extracellular matrix remodeling molecules in vitro under hyperoxia. Finally, these structural, cellular, and molecular effects of ICG001 were associated with down-regulation of multiple β-catenin target genes. These data indicate that β-catenin signaling mediates hyperoxia-induced alveolar impairment and PH in neonatal animals. Targeting β-catenin may provide a novel strategy to alleviate BPD in preterm infants.

The pathological hallmarks of bronchopulmonary dysplasia (BPD), a chronic lung disease of premature infants, include inflammation, arrested alveolarization, and dysregulated angiogenesis. Severe BPD is often complicated by pulmonary hypertension (PH) that significantly increases morbidity and mortality. Glycogen synthase kinase (GSK)-3β plays a pivotal role in embryonic development, cell proliferation and survival, and inflammation by modulating multiple signaling pathways, particularly the nuclear transcription factor, NF-κB, and Wnt/β-catenin pathways. Aberrant GSK-3β signaling is linked to BPD. We tested the hypothesis that inhibition of GSK-3β is beneficial in preventing hyperoxia-induced neonatal lung injury, an experimental model of BPD. Newborn rats were exposed to normoxia or hyperoxia (90% oxygen), and received daily intraperitoneal injections of placebo (DMSO) or SB216763, a specific pharmacological inhibitor of GSK-3β, for 14 days. Hyperoxia exposure in the presence of the placebo increased GSK-3β phosphorylation, which was correlated with increased inflammation, decreased alveolarization and angiogenesis, and increased pulmonary vascular remodeling and PH. However, treatment with SB216763 decreased phosphorylation of NF-κB p65, expression of monocyte chemotactic protein-1, and lung inflammation during hyperoxia. Furthermore, treatment with the GSK-3β inhibitor also improved alveolarization and angiogenesis, and decreased pulmonary vascular remodeling and PH. These data indicate that GSK-3β signaling plays an important role in the pathogenesis of hyperoxia-induced neonatal lung injury, and that inhibition of GSK-3β is beneficial in preventing inflammation and protecting alveolar and vascular structures during hyperoxia. Thus, targeting GSK-3β signaling may offer a novel strategy to prevent and treat preterm infants with BPD.

Despite recent advances in neonatal intensive care and surfactant therapy, bronchopulmonary dysplasia (BPD) continues to be one of the most common long-term pulmonary complications associated with preterm birth. Clinical efforts to prevent and treat BPD have been largely unsuccessful due to its multifactorial nature and poorly understood disease process. Connective tissue growth factor (CTGF) is a matricellular protein that plays an important role in tissue development and remodeling. Previous studies have demonstrated that hyperoxia exposure up-regulates CTGF expression in neonatal rat lungs. Whether CTGF overexpression plays a role in the pathogenesis of BPD, and whether CTGF antagonism has a therapeutic potential for BPD, are unknown. In the present study, we examined CTGF expression in lung autopsy specimens from patients with BPD and control subjects with no BPD. We assessed the effect of a CTGF-neutralizing monoclonal antibody (CTGF Ab) on preventing hyperoxia-induced lung injury in neonatal rats. Our study demonstrates that CTGF expression is increased in BPD lungs. In newborn rats, exposure to 90% oxygen for 14 days resulted in activation of β-catenin signaling, decreased alveolarization and vascular development, and physiological and histological evidence of pulmonary hypertension (PH). However, treatment with CTGF Ab prevented β-catenin signaling activation, improved alveolarization and vascular development, and attenuated PH during hyperoxia. These data indicate that CTGF-β-catenin signaling plays a critical role in the pathogenesis of experimental BPD. CTGF antagonism may offer a novel therapeutic strategy to alleviate BPD and PH in neonates.

Hyperoxia-induced lung injury plays a key role in the development of bronchopulmonary dysplasia (BPD), characterized by inflammatory injury and impaired lung development in preterm infants. Although BPD is a predictor of poor neurodevelopmental outcomes, currently it is uncertain how lung injury contributes to brain injury in preterm infants. Extracellular vesicles (EVs) are a heterogeneous group of cell-derived membranous structures that regulate intercellular and inter-organ communications. Gasdermin D (GSDMD) has emerged as a key executor of inflammasome-mediated cell death and inflammation. In this study, we utilized a neonatal rat model of BPD to assess if hyperoxia stimulates lung release of circulating EVs and if these EVs induce lung and brain injury. We found that hyperoxia-exposed rats had elevated numbers of plasma-derived EVs compared to rats maintained in room air. These EVs also had increased cargos of surfactant protein C, a marker of type II alveolar epithelial cells (AEC), and the active (p30) form of GSDMD. When these EVs were adoptively transferred into normal newborn rats via intravenous injection, they were taken up both by lung and brain tissues. Moreover, EVs from hyperoxic animals induced not only the pathological hallmarks of BPD, but also brain inflammatory injury in recipient rats, as well as inducing cell death in cultured pulmonary vascular endothelial cells and neural stem cells (NSC). Similarly, hyperoxia-exposed cultured AEC-like cells released EVs that also contained increased GSDMD-p30 and these EVs induced pyroptotic cell death in NSC. Overall, these data indicate that hyperoxia-activated circulating EVs mediate a lung to brain crosstalk resulting in brain injury and suggest a mechanism that links lung injury and neurodevelopmental impairment in BPD infants. [ABSTRACT FROM AUTHOR]

Background: Inflammatory injury, particularly the production of active interleukin (IL)-1β plays a major role in the pathogenesis of bronchopulmonary dysplasia (BPD) in preterm infants. The release of active IL-1β is controlled by posttranscriptional modifications of its proform (pro-IL-1β) through the inflammasome. Rac1 is a member of the Rho family of GTPases that regulate the inflammatory process. Objective: This study tested the hypothesis that Rac1 signaling increases inflammasome activation that results in damaging inflammation, and that the inhibition of Rac1 signaling prevents lung injury, by inhibiting inflammasome activation in a newborn rat model of BPD induced by hyperoxia. Methods: Newborn rat pups were exposed to room air or hyperoxia (85% O2) and received daily intraperitoneal injections of placebo (normal saline) or NSC23766, a specific Rac1 inhibitor, for 10 days. The effects on lung inflammation, alveolarization, vascular development, vascular remodeling, right ventricular systolic pressure, and right ventricular hypertrophy (RVH) were then assessed. Results: Hyperoxia exposure upregulated Rac1 and increased the production of active IL- 1β, which was accompanied by increasing expression of the inflammasome. In addition, hyperoxia induced the pathological hallmarks of BPD. However, treatment with NSC23766 significantly decreased inflammasome activation and macrophage infiltration, improved alveolar and vascular development, and reduced pulmonary vascular remodeling and RVH. Conclusion: These results indicate that Rac1 signaling regulates the expression of the inflammasome and plays a pivotal role in the pathogenesis of hyperoxia-induced neonatal lung injury. Therefore, targeting Rac1 signaling may provide a novel strategy to prevent and treat BPD in preterm infants. [ABSTRACT FROM AUTHOR]