Newborn Lung Injury Research Articles

Nitric oxide regulation of fetal and newborn lung development and function

In the developing lung, nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) signaling are essential in regulating lung formation and vascular tone. Animal studies have linked many anatomical and pathophysiological features of newborn lung disease to abnormalities in the NO/cGMP signaling system. They have demonstrated that driving this system with agonists and antagonists alleviates many of them. This research has spurred the rapid clinical development, testing, and application of several NO/cGMP-targeting therapies with the hope of treating and potentially preventing significant pediatric lung diseases. However, there are instances when the therapeutic effectiveness of these agents is limited. Studies indicate that injury-induced disruption of several critical components within the signaling system may hinder the promise of some of these therapies. Recent research has identified basic mechanisms that suppress NO/cGMP signaling in the injured newborn lung. They have also pinpointed biomarkers that offer insight into the activation of these pathogenic mechanisms and their influence on the NO/cGMP signaling system's integrity in vivo. Together, these will guide the development of new therapies to protect NO/cGMP signaling and safeguard newborn lung development and function. This review summarizes the important role of the NO/cGMP signaling system in regulating pulmonary development and function and our evolving understanding of how it is disrupted by newborn lung injury.

Antimicrobial peptides modulate lung injury by altering the intestinal microbiota

BackgroundMammalian mucosal barriers secrete antimicrobial peptides (AMPs) as critical, host-derived regulators of the microbiota. However, mechanisms that support microbiota homeostasis in response to inflammatory stimuli, such as supraphysiologic oxygen, remain unclear.ResultsWe show that supraphysiologic oxygen exposure to neonatal mice, or direct exposure of intestinal organoids to supraphysiologic oxygen, suppresses the intestinal expression of AMPs and alters intestinal microbiota composition. Oral supplementation of the prototypical AMP lysozyme to hyperoxia-exposed neonatal mice reduced hyperoxia-induced alterations in their microbiota and was associated with decreased lung injury.ConclusionsOur results identify a gut-lung axis driven by intestinal AMP expression and mediated by the intestinal microbiota that is linked to lung injury in newborns. Together, these data support that intestinal AMPs modulate lung injury and repair.3_VV6W6G7-4iXhiNAne3huVideo

L-citrulline attenuates lipopolysaccharide-induced inflammatory lung injury in neonatal rats.

Prenatal or postnatal lung inflammation and oxidative stress disrupt alveolo-vascular development leading to bronchopulmonary dysplasia (BPD) with and without pulmonary hypertension. L-citrulline (L-CIT), a nonessential amino acid, alleviates inflammatory and hyperoxic lung injury in preclinical models of BPD. L-CIT modulates signaling pathways mediating inflammation, oxidative stress, and mitochondrial biogenesis-processes operative in the development of BPD. We hypothesize that L-CIT will attenuate lipopolysaccharide (LPS)-induced inflammation and oxidative stress in our rat model of neonatal lung injury. Newborn rats during the saccular stage of lung development were used to investigate the effect of L-CIT on LPS-induced lung histopathology and pathways involved in inflammatory, antioxidativeprocesses, and mitochondrial biogenesis in lungs in vivo, and in primary culture of pulmonary artery smooth muscle cells, in vitro. L-CIT protected the newborn rat lung from LPS-induced: lung histopathology, ROS production, NFκB nuclear translocation, and upregulation of gene and protein expression of inflammatory cytokines (IL-1β, IL-8, MCP-1α, and TNF-α). L-CIT maintained mitochondrial morphology, increased protein levels of PGC-1α, NRF1, and TFAM (transcription factors involved in mitochondrial biogenesis), and induced SIRT1, SIRT3, and superoxide dismutases protein expression. L-CIT may be efficacious in decreasing early lung inflammation and oxidative stress mitigating progression to BPD. The nonessential amino acid L-citrulline (L-CIT) mitigated lipopolysaccharide (LPS)-induced lung injury in the early stage of lung development in the newborn rat. This is the first study describing the effect of L-CIT on the signaling pathways operative in bronchopulmonary dysplasia (BPD) in a preclinical inflammatory model of newborn lung injury. If our findings translate to premature infants, L-CIT could decrease inflammation, oxidative stress and preserve mitochondrial health in the lung of premature infants at risk for BPD.

Protective technologies of modern methods of respiratory support in neonatal practice

The article presents an analysis of literature data on modern protective regimens for invasive respiratory support in premature newborns with respiratory distress syndrome. We have considered positive and negative aspects of the used methods of invasive ventilation of the lungs, which are currently widely used as a method of respiratory therapy in obstetric hospitals at any level, even in the category of children with extremely and very low birth weight. Modern protective mechanical ventilation provides for 2 main directions for reducing ventilator-induced lung damage: a decrease in tidal volume (Vt) and the principle of tolerable (permissive) hypercapnia. The use of the technique of permissive hypercapnia and regimens with a target volume can reduce the likelihood of ventilator-induced lung injury in newborns. Despite the limited indications for mechanical ventilation in modern neonatology and the widespread use of non-invasive ventilation, for patients who really need mechanical ventilation, the use of volume-targeted regimens offers the best chance of reducing ventilation complications.

Lysyl oxidase regulation and protein aldehydes in the injured newborn lung.

During newborn lung injury, excessive activity of lysyl oxidases (LOXs) disrupts extracellular matrix (ECM) formation. Previous studies indicate that TGFβ activation in the O2-injured mouse pup lung increases lysyl oxidase (LOX) expression. But how TGFβ regulates this, and whether the LOXs generate excess pulmonary aldehydes are unknown. First, we determined that O2-mediated lung injury increases LOX protein expression in TGFβ-stimulated pup lung interstitial fibroblasts. This regulation appeared to be direct; this is because TGFβ treatment also increased LOX protein expression in isolated pup lung fibroblasts. Then using a fibroblast cell line, we determined that TGFβ stimulates LOX expression at a transcriptional level via Smad2/3-dependent signaling. LOX is translated as a pro-protein that requires secretion and extracellular cleavage before assuming amine oxidase activity and, in some cells, reuptake with nuclear localization. We found that pro-LOX is processed in the newborn mouse pup lung. Also, O2-mediated injury was determined to increase pro-LOX secretion and nuclear LOX immunoreactivity particularly in areas populated with interstitial fibroblasts and exhibiting malformed ECM. Then, using molecular probes, we detected increased aldehyde levels in vivo in O2-injured pup lungs, which mapped to areas of increased pro-LOX secretion in lung sections. Increased activity of LOXs plays a critical role in the aldehyde generation; an inhibitor of LOXs prevented the elevation of aldehydes in the O2-injured pup lung. These results reveal new mechanisms of TGFβ and LOX in newborn lung disease and suggest that aldehyde-reactive probes might have utility in sensing the activation of LOXs in vivo during lung injury.

Biomarkers of Oxidative Stress for Neonatal Lung Disease.

The transition from prenatal to postnatal life causes a significant increase in arterial oxygen tension and the activation of metabolic pathways enabling the newborn's adaptation to the extra-uterine environment. The balance between pro-oxidant and anti-oxidant systems is critical to preserve cellular functions. Indeed, oxidative stress (OS) occurs when the production of free radicals is not balanced by the activity of intracellular antioxidant systems, contributing to cellular and tissue damage. Perinatal OS may have serious health consequences during the postnatal period and later in life. Namely, OS has been recognized as the major cause of lung injury in newborns, especially those preterm born, due to their immature lung and antioxidant systems. The development of OS biomarkers has gained increasing research interest since they may provide useful insights about pathophysiological pathways underlying OS-mediated pulmonary diseases in newborns. Moreover, their implementation in clinical settings may help to early identify high risk-newborns and to provide targeted treatment. Ideally, a biomarker should demonstrate ease of use, biological validity and reproducibility, high sensitivity and specificity. However, none of the clinically validated biomarkers so far have been qualified for neonatal lung disease. Additionally, the complex technical procedures and the high cost of such determinations have hampered the use of OS biomarkers in clinical practice. This review aims to evaluate the current evidence on the application of biomarkers of oxidative stress for neonatal lung disease and exploring the most relevant issues affecting their implementation in practice, as well as the associated evidence gaps and research limitations.

IL-1β dysregulates cGMP signaling in the newborn lung.

Cyclic guanosine monophosphate (cGMP) signaling is an important regulator of newborn lung function and development. Although cGMP signaling is decreased in many models of newborn lung injury, the mechanisms are poorly understood. We determined how IL-1β regulates the expression of the α1-subunit of soluble guanylate cyclase (sGCα1), a prime effector of pulmonary cGMP signaling. Physiologic levels of IL-1β were discovered to rapidly decrease sGCα1 mRNA expression in a human fetal lung fibroblast cell line (IMR-90 cells) and protein levels in primary mouse pup lung fibroblasts. This sGCα1 expression inhibition appeared to be at a transcriptional level; IL-1β treatment did not alter sGCα1 mRNA stability, although it reduced sGCα1 promoter activity. Transforming growth factor-β (TGFβ)-activated kinase-1 (TAK1) was determined to be required for IL-1β's regulation of sGCα1 expression; TAK1 knockdown protected sGCα1 mRNA expression in IL-1β-treated IMR-90 cells. Moreover, heterologously expressed TAK1 was sufficient to decrease sGCα1 mRNA levels in those cells. Nuclear factor-κB (NF-κB) signaling played a critical role in the IL-1β-TAK1-sGCα1 regulatory pathway; chromatin immunoprecipitation studies demonstrated enhanced activated NF-κB subunit (RelA) binding to the sGCα1 promoter after IL-1β treatment unless treated with an IκB kinase-2 inhibitor. Also, this NF-κB signaling inhibition protected sGCα1 expression in IL-1β-treated fibroblasts. Lastly, using transgenic mice in which active IL-1β was conditionally expressed in lung epithelial cells, we established that IL-1β expression is sufficient to stimulate TAK1 and decrease sGCα1 protein expression in the newborn lung. Together these results detail the role and mechanisms by which IL-1β inhibits cGMP signaling in the newborn lung.

IL‐1β inhibits cGMP signaling enzyme expression in perinatal fibroblasts via NF‐κB signaling

Lung injury causes important morbidity and mortality in newborns by disrupting pulmonary vascular function and alveolar development. Recent evidence suggests that IL‐1β signaling plays a primary role in the pathogenesis of newborn lung disease. But the mechanisms are incompletely understood. Previously we showed that nitric oxide (NO) and cGMP signaling regulate pulmonary blood flow and development in newborns. Furthermore, we determined that disruption of cGMP signaling during newborn lung injury accentuates pulmonary disease. Accordingly, here we determined whether IL‐1β inhibits cGMP signaling in the newborn lung.We used a human fetal lung fibroblast cell line (IMR‐90 cells) and primary mouse pup lung fibroblasts to test whether IL‐1β down‐regulates the expression of soluble guanylate cyclase α1 subunit (sGCα1). This is because fibroblasts have an important role in regulating newborn lung function and alveolar development and sGCα1 is a prime initiator of cGMP signaling upon NO stimulation. We determined that physiologic levels of recombinant IL‐1β rapidly decreased sGCα1 mRNA expression in the IMR‐90 cells and protein levels in the primary lung fibroblasts. This inhibition of sGCα1 expression appeared to be at a transcriptional level. This is because IL‐1β treatment did not further decrease sGCα1 mRNA levels in the fetal lung fibroblasts treated with actinomycin D. TGFβ‐activated kinase 1 (TAK1) was determined to mediate IL‐1β’s regulation of sGCα1 expression; TAK1 knock‐down protected sGCα1 mRNA expression in IL‐1β‐treated IMR‐90 cells. Moreover, heterologous expression of TAK1 in these cells revealed that this kinase is sufficient to decrease sGCα1 mRNA levels. Nuclear factor‐kappaB (NF‐κB) signaling played a critical role in the IL‐1β‐TAK1‐sGCα1 regulatory pathway; NF‐κB signaling inhibition by an IKK2 inhibitor PHA‐408 was determined to protect sGCα1 mRNA and protein expression in IL‐1β‐treated perinatal lung fibroblasts. Lastly, using tissue samples and soluble proteins obtained from transgenic mice in which active IL‐1β was conditionally expressed in lung epithelial cells, we established that IL‐1β expression is sufficient to stimulate TAK1 activation and decrease sGCα1 protein expression in the newborn lung. Together these results indicate that IL‐1β has a direct role in decreasing cGMP signaling in the newborn lung. We speculate that targeting IL‐1β and NF‐κB signaling might protect cGMP signaling in injured newborn lungs.Support or Funding InformationNIH HL096779 and HL147863 and the Swedish Government’s Grants for Medical Research supported this work.

Attenuation of Hyperoxic Lung Injury in Newborn Thioredoxin-1-Overexpressing Mice through the Suppression of Proinflammatory Cytokine mRNA Expression.

The role of thioredoxin-1 (TRX), a small redox-active protein with antioxidant effects, during hyperoxic lung injury in newborns remains undetermined. We investigated TRX impact on hyperoxic lung injury in newborn TRX transgenic (TRX-Tg) and wildtype (WT) mice exposed to 21% or 95% O2 for four days, after which some mice were allowed to recover in room air for up to 14 days. Lung morphology was assessed by hematoxylin/eosin and elastin staining, as well as immunostaining for macrophages. The gene expression levels of proinflammatory cytokines were evaluated using quantitative real-time polymerase chain reaction. During recovery from hyperoxia, TRX-Tg mice exhibited an improved mean linear intercept length and increased number of secondary septa in lungs compared with the WT mice. Neonatal hyperoxia enhanced the mRNA expression levels of proinflammatory cytokines in the lungs of both TRX-Tg and WT mice. However, interleukin-6, monocyte chemoattractant protein-1, and chemokine (C-X-C motif) ligand 2 mRNA expression levels were reduced in the lungs of TRX-Tg mice compared with the WT mice during recovery from hyperoxia. Furthermore, TRX-Tg mice exhibited reduced macrophage infiltration in lungs during recovery. These results suggest that in newborn mice TRX ameliorates hyperoxic lung injury during recovery likely through the suppression of proinflammatory cytokines.

Acid Sphingomyelinase Inhibition Attenuates Cell Death in Mechanically Ventilated Newborn Rat Lung.

Premature infants subjected to mechanical ventilation (MV) are prone to lung injury that may result in bronchopulmonary dysplasia. MV causes epithelial cell death and halts alveolar development. The exact mechanism of MV-induced epithelial cell death is unknown. To determine the contribution of autophagy to MV-induced epithelial cell death in newborn rat lungs. Newborn rat lungs and fetal rat lung epithelial (FRLE) cells were exposed to MV and cyclic stretch, respectively, and were then analyzed by immunoblotting and mass spectrometry for autophagy, apoptosis, and bioactive sphingolipids. Both MV and stretch first induce autophagy (ATG 5-12 [autophagy related 5-12] and LC3B-II [microtubule-associated proteins 1A/1B light chain 3B-II] formation) followed by extrinsic apoptosis (cleaved CASP8/3 [caspase-8/3] and PARP [poly(ADP-ribose) polymerase] formation). Stretch-induced apoptosis was attenuated by inhibiting autophagy. Coimmunoprecipitation revealed that stretch promoted an interaction between LC3B and the FAS (first apoptosis signal) cell death receptor in FRLE cells. Ceramide levels, in particular C16 ceramide, were rapidly elevated in response to ventilation and stretch, and C16 ceramide treatment of FRLE cells induced autophagy and apoptosis in a temporal pattern similar to that seen with MV and stretch. SMPD1 (sphingomyelin phosphodiesterase 1) was activated by ventilation and stretch, and its inhibition prevented ceramide production, LC3B-II formation, LC3B/first apoptosis signal interaction, caspase-3 activation, and, ultimately, FLRE cell death. SMPD1 inhibition also attenuated ventilation-induced autophagy and apoptosis in newborn rats. Ventilation-induced ceramides promote autophagy-mediated cell death, and identifies SMPD1 as a potential therapeutic target for the treatment of ventilation-induced lung injury in newborns.

Transforming growth factor-β downregulates sGC subunit expression in pulmonary artery smooth muscle cells via MEK and ERK signaling.

TGFβ activation during newborn lung injury decreases the expression of pulmonary artery smooth muscle cell (PASMC)-soluble guanylate cyclase (sGC), a critical mediator of nitric oxide signaling. Using a rat PASMC line (CS54 cells), we determined how TGFβ downregulates sGC expression. We found that TGFβ decreases sGC expression through stimulating its type I receptor; TGFβ type I receptor (TGFβR1) inhibitors prevented TGFβ-1-mediated decrease in sGCα1 subunit mRNA levels in the cells. However, TGFβR1-Smad mechanisms do not regulate sGC; effective knockdown of Smad2 and Smad3 expression and function did not protect sGCα1 mRNA levels during TGFβ-1 exposure. A targeted small-molecule kinase inhibitor screen suggested that MEK signaling regulates sGC expression in TGFβ-stimulated PASMC. TGFβ activates PASMC MEK/ERK signaling; CS54 cell treatment with TGFβ-1 increased MEK and ERK phosphorylation in a biphasic, time- and dose-dependent manner. Moreover, MEK/ERK activity appears to be required for TGFβ-mediated sGC expression inhibition in PASMC; MEK and ERK inhibitors protected sGCα1 mRNA expression in TGFβ-1-treated CS54 cells. Nuclear ERK activity is sufficient for sGC regulation; heterologous expression of a nucleus-retained, constitutively active ERK2-MEK1 fusion protein decreased CS54 cell sGCα1 mRNA levels. The in vivo relevance of this TGFβ-MEK/ERK-sGC downregulation pathway is suggested by the detection of ERK activation and sGCα1 protein expression downregulation in TGFβ-associated mouse pup hyperoxic lung injury, and the determination that ERK decreases sGCα1 protein expression in TGFβ-1-treated primary PASMC obtained from mouse pups. These studies identify MEK/ERK signaling as an important pathway by which TGFβ regulates sGC expression in PASMC.

Experimental models of acute lung injury in the newborns.

Acute lung injury in the preterm newborns can originate from prematurity of the lung and insufficient synthesis of pulmonary surfactant. This situation is known as respiratory distress syndrome (RDS). In the term neonates, the respiratory insufficiency is related to a secondary inactivation of the pulmonary surfactant, for instance, by action of endotoxins in bacterial pneumonia or by effects of aspirated meconium. The use of experimental models of the mentioned situations provides new information on the pathophysiology of these disorders and offers unique possibility to test novel therapeutic approaches in the conditions which are very similar to the clinical syndromes. Herewith we review the advantages and limitations of the use of experimental models of RDS and meconium aspiration syndrome (MAS) and their value for clinics.

Newborn Mice Lacking the Gene for Cyp1a1 Are More Susceptible to Oxygen-Mediated Lung Injury, and Are Rescued by Postnatal β-Naphthoflavone Administration: Implications for Bronchopulmonary Dysplasia in Premature Infants.

Prolonged hyperoxia contributes to bronchopulmonary dysplasia (BPD) in preterm infants. β-Naphthoflavone (BNF) is a potent inducer of cytochrome P450 (CYP)1A enzymes, which have been implicated in hyperoxic injuries in adult mice. In this investigation, we tested the hypothesis that newborn mice lacking the Cyp1a1 gene would be more susceptible to hyperoxic lung injury than wild-type (WT) mice and that postnatal BNF treatment would rescue this phenotype by mechanisms involving CYP1A and/or NAD(P)H quinone oxidoreductase (NQO1) enzymes. Newborn WT or Cyp1a1-null mice were treated with BNF (10 mg/kg) or the vehicle corn oil (CO) i.p., from postnatal day (PND) 2 to 14 once every other day, while being maintained in room air or hyperoxia (85% O2) for 14 days. Both genotypes showed lung injury, inflammation, and alveolar simplification in hyperoxia, with Cyp1a1-null mice displaying increased susceptibility compared to WT mice. BNF treatment resulted in significant attenuation of lung injury and inflammation, with improved alveolarization in both WT and Cyp1a1-null mice. BNF exposed normoxic or hyperoxic WT mice showed increased expression of hepatic CYP1A1/1A2, pulmonary CYP1A1, and NQO1 expression at both mRNA and protein levels, compared with vehicle controls. However, BNF caused greater induction of hepatic CYP1A2 and pulmonary NQO1 enzymes in the Cyp1a1-null mice, suggesting that BNF protects against hyperoxic lung injury in WT and Cyp1a1-null mice through the induction of CYP1A and NQO1 enzymes. Further studies on the protective role of flavonoids against hyperoxic lung injury in newborns could lead to novel strategies for the prevention and/or treatment of BPD.

The Effect of Continuous Positive Airway Pressure in a Mouse Model of Hyperoxic Neonatal Lung Injury

Background: Continuous positive airway pressure (CPAP) and supplemental oxygen have become the mainstay of neonatal respiratory support in preterm infants. Although oxygen therapy is associated with respiratory morbidities including bronchopulmonary dysplasia (BPD), the long-term effects of CPAP on lung function are largely unknown. We used a hyperoxia-induced mouse model of BPD to explore the effects of daily CPAP in the first week of life on later respiratory system mechanics. Objective: We wanted to test the hypothesis that daily CPAP in a newborn-mouse model of BPD improves longer-term respiratory mechanics. Methods: Mouse pups from C57BL/6 pregnant dams were exposed to room air (RA) or hyperoxia (50% O₂, 24 h/day) for the first postnatal week with or without exposure to daily CPAP (6 cm H₂O, 3 h/day). Respiratory system resistance (Rrs) and compliance (Crs) were measured following a subsequent 2-week period of RA recovery. Additional measurements included radial alveolar and macrophage counts. Results: Mice exposed to hyperoxia had significantly elevated Rrs, decreased Crs, reduced alveolarization and increased macrophage counts at 3 weeks when compared to RA-treated mice. Daily CPAP treatment significantly improved Rrs, Crs and alveolarization and decreased lung macrophage infiltration in the hyperoxia-exposed pups. Conclusions: We have demonstrated that daily CPAP had a longer-term benefit on baseline respiratory system mechanics in a neonatal mouse model of BPD. We speculate that this beneficial effect of CPAP was the consequence of a decrease in the inflammatory response and resultant alveolar injury associated with hyperoxic lung injury in newborns.

Foxm1 regulates resolution of hyperoxic lung injury in newborns.

Current treatments for inflammation associated with bronchopulmonary dysplasia (BPD) fail to show clinical efficacy. Foxm1, a transcription factor of the Forkhead box family, is a critical mediator of lung development and carcinogenesis, but its role in BPD-associated pulmonary inflammation is unknown. Immunohistochemistry and RNA analysis were used to assess Foxm1 in lung tissue from hyperoxia-treated mice and patients with BPD. LysM-Cre/Foxm1(-/-) mice, in which Foxm1 was deleted from myeloid-derived inflammatory cells, including macrophages, monocytes, and neutrophils, were exposed to neonatal hyperoxia, causing lung injury and remodeling. Measurements of lung function and flow cytometry were used to evaluate the effects of Foxm1 deletion on pulmonary inflammation and repair. Increased Foxm1 expression was observed in pulmonary macrophages of hyperoxia-exposed mice and in lung tissue from patients with BPD. After hyperoxia, deletion of Foxm1 from the myeloid cell lineage decreased numbers of interstitial macrophages (CD45(+)CD11b(+)Ly6C(-)Ly6G(-)F4/80(+)CD68(-)) and impaired alveologenesis and lung function. The exaggerated BPD-like phenotype observed in hyperoxia-exposed LysM-Cre/Foxm1(-/-) mice was associated with increased expression of neutrophil-derived myeloperoxidase, proteinase 3, and cathepsin g, all of which are critical for lung remodeling and inflammation. Our data demonstrate that Foxm1 influences pulmonary inflammatory responses to hyperoxia, inhibiting neutrophil-derived enzymes and enhancing monocytic responses that limit alveolar injury and remodeling in neonatal lungs.

Cathepsin K overexpression modifies lung development in newborn mice

Cathepsin K (CatK), contributes to the development of chronic lung disease in newborn infants, but the impact of CatK for the lungs may be multifaceted. We have previously demonstrated that low level of CatK is associated with newborn lung injury and CatK deficiency aggravates lung injury in hyperoxia-exposed newborn mice. Thus, we hypothesized that sustained/higher expression of CatK could ameliorate hyperoxia-induced injury and restrain the development of pulmonary fibrosis. We studied the lungs of newborn wild-type (WT) and CatK overexpressing transgenic mice (TG) that were exposed to hyperoxia or room air for 7 or 14 days after birth. Fourfold pulmonary overexpression of CatK did not affect the growth or lung weight in room-air bred TG mice. The distal airspaces in TG mice were, however, enlarged on postnatal days (PN) 7 and 14, the latter together with increased apoptosis, compared with WT controls. Survival rate was normal and no respiratory distress was observed in air-bred TG mice. Hyperoxia inhibited alveolarization and increased collagen accumulation in WT mice. In TG mice, hyperoxia for 1 week did not aggravate the lung injury, and the lung morphology and already enlarged alveoli remained unchanged in TG mice at PN7. Prolonged hyperoxic exposure caused significant lung injury and mortality similarly in both group of mice, and only few mice survived until PN14. In summary, CatK overexpression slightly enlarges distal airways in infant mice, but hyperoxic environment is initially better tolerated when compared to WT mice. These findings suggest multifaceted role for CatK in lung development and newborn lung injury.

Cell apoptosis and bile acid induced newborn lung injury

Cell apoptosis and bile acid induced newborn lung injury

Prenatal administration of the cytochrome P4501A inducer, Β-naphthoflavone (BNF), attenuates hyperoxic lung injury in newborn mice: Implications for bronchopulmonary dysplasia (BPD) in premature infants

Supplemental oxygen contributes to the development of bronchopulmonary dysplasia (BPD) in premature infants. In this investigation, we tested the hypothesis that prenatal treatment of pregnant mice (C57BL/6J) with the cytochrome P450 (CYP)1A1 inducer, ß-napthoflavone (BNF), will lead to attenuation of lung injury in newborns (delivered from these dams) exposed to hyperoxia by mechanisms entailing transplacental induction of hepatic and pulmonary CYP1A enzymes. Pregnant mice were administered the vehicle corn oil (CO) or BNF (40 mg/kg), i.p., once daily for 3 days on gestational days (17–19), and newborns delivered from the mothers were either maintained in room air or exposed to hyperoxia (> 95% O 2) for 1–5 days. After 3–5 days of hyperoxia, the lungs of CO-treated mice showed neutrophil infiltration, pulmonary edema, and perivascular inflammation. On the other hand, BNF-pretreated neonatal mice showed decreased susceptibility to hyperoxic lung injury. These mice displayed marked induction of ethoxyresorufin O-deethylase (EROD) (CYP1A1) and methoxyresorufin O-demethylase (MROD) (CYP1A2) activities, and levels of the corresponding apoproteins and mRNA levels until PND 3 in liver, while CYP1A1 expression alone was augmented in the lung. Prenatal BNF did not significantly alter gene expression of pulmonary NAD(P)H quinone reductase (NQO1). Hyperoxia for 24–72 h resulted in increased pulmonary levels of the F 2-isoprostane 8-iso-PGF 2α, whose levels were decreased in mice prenatally exposed to BNF. In conclusion, our results suggest that prenatal BNF protects newborns against hyperoxic lung injury, presumably by detoxification of lipid hydroperoxides by CYP1A enzymes, a phenomenon that has implications for prevention of BPD in infants.

A Role for Matrix Metalloproteinase 9 in IFNγ-Mediated Injury in Developing Lungs

We noted a marked increase in IFNγ mRNA in newborn (NB) murine lungs after exposure to hyperoxia. We sought to evaluate the role of IFNγ in lung injury in newborns. Using a unique triple-transgenic (TTG), IFNγ-overexpressing, lung-targeted, externally regulatable NB murine model, we describe a lung phenotype of impaired alveolarization, resembling human bronchopulmonary dysplasia (BPD). IFNγ-mediated abnormal lung architecture was associated with increased cell death and the upregulation of cell death pathway mediators caspases 3, 6, 8, and 9, and angiopoietin 2. Moreover, an increase was evident in cathepsins B, H, K, L, and S, and in matrix metalloproteinases (MMPs) 2, 9, 12, and 14. The IFNγ-mediated abnormal lung architecture was found to be MMP9-dependent, as indicated by the rescue of the IFNγ-induced pulmonary phenotype and survival during hyperoxia with a concomitant partial deficiency of MMP9. This result was concomitant with a decrease in caspases 3, 6, 8, and 9 and angiopoietin 2, but an increase in the expression of angiopoietin 1. In addition, NB IFNγ TTG mice exhibited significantly decreased survival during hyperoxia, compared with littermate controls. Furthermore, as evidence of clinical relevance, we show increased concentrations of the downstream targets of IFNγ chemokine (C-X-C motif) ligands (CXCL10 and CXCL11) in baboon and human lungs with BPD. IFNγ and its downstream targets may contribute significantly to the final common pathway of hyperoxia-induced injury in the developing lung and in human BPD.

Mitochondrial respiratory chain and hyperoxia induced lung injury in newborn

高氧肺损伤是新生儿尤其早产儿常见的并发症之一.迄今新生儿高氧肺损伤的详细发病机制尚未完全阐明.最近的研究表明,线粒体呼吸链与新生儿高氧性肺损伤也有密不可分的关系.该文综述高浓度氧暴露对肺组织线粒体呼吸链酶复合体组成成分表达的影响;线粒体呼吸链在高氧肺损伤中可能发挥的作用以及与此相关的治疗与展望。