Hyperoxic Lung Research Articles

Hydrogen gas reduces hyperoxic lung injury via the Nrf2 pathway in vivo

Hyperoxic lung injury is a major concern in critically ill patients who receive high concentrations of oxygen to treat lung diseases. Successful abrogation of hyperoxic lung injury would have a huge impact on respiratory and critical care medicine. Hydrogen can be administered as a therapeutic medical gas. We recently demonstrated that inhaled hydrogen reduced transplant-induced lung injury and induced heme oxygenase (HO)-1. To determine whether hydrogen could reduce hyperoxic lung injury and investigate the underlying mechanisms, we randomly assigned rats to four experimental groups and administered the following gas mixtures for 60 h: 98% oxygen (hyperoxia), 2% nitrogen; 98% oxygen (hyperoxia), 2% hydrogen; 98% balanced air (normoxia), 2% nitrogen; and 98% balanced air (normoxia), 2% hydrogen. We examined lung function by blood gas analysis, extent of lung injury, and expression of HO-1. We also investigated the role of NF-E2-related factor (Nrf) 2, which regulates HO-1 expression, by examining the expression of Nrf2-dependent genes and the ability of hydrogen to reduce hyperoxic lung injury in Nrf2-deficient mice. Hydrogen treatment during exposure to hyperoxia significantly improved blood oxygenation, reduced inflammatory events, and induced HO-1 expression. Hydrogen did not mitigate hyperoxic lung injury or induce HO-1 in Nrf2-deficient mice. These findings indicate that hydrogen gas can ameliorate hyperoxic lung injury through induction of Nrf2-dependent genes, such as HO-1. The findings suggest a potentially novel and applicable solution to hyperoxic lung injury and provide new insight into the molecular mechanisms and actions of hydrogen.

Expressions of Caveolin-1 and Transforming growth factor betal 1 in A549 cells exposed to hyperoxia and their relationship

Objective To observe the expressions of Caveolin-1 (CAV-1) and transforming growth factor bata 1 (TGF-β1) in human adenocarcinoma of lung A549 cells exposed to hyperoxia, and to explore the changes in CAV-1 and TGF-β1 expressions and the role in hyperoxic lung injury. Methods After the A549 human lung cancer cell lines were resuscitated, the cells were packaged and cultured in 50 mL/L CO2 culture chamber, when approaching to the condition of confluence in CO2 culture chamber(37 ℃, 50 mL/L CO2), the cells were randomly divided into control group and hyperoxia group.Eighteen bottles of A549 cells in each group.The hyperoxia group received attacking factor that was mixed with oxygen (950 mL/L)and CO2(50 mL/L) at a velocity of 3 L/min for 10 min; then the flasks were enclosed and cultured in culture chamber, while those in control group were still exposed to 5 mL/L CO2.After cells were cultured for 12 h, 24 h, 48 h, the changes in morphology were observed under the inverted microscope, the expressions CAV-1 and TGF-β1 were detected by double immunofluorescence staining technique, followed by laser scanning under the focus microscope. Results In the control group, there was high expression of CAV-1 associated with low expression of TGF-β1(44.25±3.23, 10.18±2.74). Compared with control group, the content of CAV-1 reduced continuously(12 h: 35.25±1.88, 24 h: 20.75±1.68, 48 h: 9.86±2.80) under prolonged hyperoxia exposure, but TGF-β1 increased gradually(12 h: 17.32±1.50, 24 h: 26.51±1.82, 48 h: 41.94±4.47), and the expression of CAV-1 had highly negative relation to TGF-β1 at the same time (r=-0.91, -0.62, -0.53, -0.88, all P<0.05) in the control group and the hyperoxia group in 12 h, 24 h, 48 h. Conclusions The reduction of CAV-1 expression can attenuate the inhibitory effect of TGF-β1 and activate TGF-β1 signaling pathway, which may result in hyperoxic lung injury. Key words: Hyperoxia; Lung injury; A549; Caveolin-1; Transforming growth factor-β1

Hyperoxia-induced alterations in the pulmonary proteome of juvenile rats

ABSTRACTHigh inspired concentrations of oxygen (hyperoxia) are often necessary to counteract tissue hypoxia during the treatment of ARDS. Reactive oxygen species generated by hyperoxic therapy may influence the expression of the pulmonary proteome and the application of discovery proteomics to the hyperoxic lung has the potential to divulge mechanisms regulating the expression of specific proteins integral to lung injury and repair. The present study examined the proteome derived from 30-day-old Sprague-Dawley rats exposed to room air (RA) and 95% O2 (Ox) for 24–72 hours using 2-dimensional difference in-gel electrophoresis (2D-DIGE) coupled with MALDI-ToF/ToF mass spectrometry. A total of 870 protein spots were visualized by 2D-DIGE across all gels. Mass spectral analysis identified 51 proteins representing 187 of the 214 significantly altered spots. Molecular and cellular function analysis grouped the identified proteins into free radical scavenging, cell death, cell-to-cell signaling, and cellular movement categories. The majority of the differences in the protein spots between RA and Ox occurred at 72 hours, with albumin, annexin A6 (AnxA6), and transferrin being increased, and mitochondrial Lon peptidase 1 being decreased by at least 20%. In Ox animals, AnxA6 protein expression increased three-fold without an increase in mRNA expression. Bioinformatic analysis of the AnxA6 transcript revealed the presence of a putative internal ribosome entry site within the 5′-untranslated region. These findings indicate that hyperoxia induces significant alterations in the pulmonary proteome which are temporally related. In addition, hyperoxia selectively enhances the expression of some proteins whose transcripts contain sequence motifs, which impart translational regulation.

Timing of umbilical cord blood derived mesenchymal stem cells transplantation determines therapeutic efficacy in the neonatal hyperoxic lung injury.

Intratracheal transplantation of human umbilical cord blood (UCB)-derived mesenchymal stem cells (MSCs) attenuates the hyperoxia-induced neonatal lung injury. The aim of this study was to optimize the timing of MSCs transplantation. Newborn Sprague-Dawley rats were randomly exposed to hyperoxia (90% for 2 weeks and 60% for 1 week) or normoxia after birth for 21 days. Human UCB-derived MSCs (5×105 cells) were delivered intratracheally early at postnatal day (P) 3 (HT3), late at P10 (HT10) or combined early+late at P3+10 (HT3+10). Hyperoxia-induced increase in mortality, TUNEL positive cells, ED1 positive alveolar macrophages, myeloperoxidase activity and collagen levels, retarded growth and reduced alveolarization as evidenced by increased mean linear intercept and mean alveolar volume were significantly better attenuated in both HT3 and HT3+10 than in HT10. Hyperoxia-induced up-regulation of both cytosolic and membrane p47phox indicative of oxidative stress, and increased inflammatory markers such as tumor necrosis factor-α, interleukin (IL) -1α, IL-1β, IL-6, and transforming growth factor-β measured by ELISA, and tissue inhibitor of metalloproteinase-1, CXCL7, RANTES, L-selectin and soluble intercellular adhesion molecule-1 measured by protein array were consistently more attenuated in both HT3 and HT3+10 than in HT10. Hyperoxia-induced decrease in hepatocyte growth factor and vascular endothelial growth factor was significantly up-regulated in both HT3 and HT3+10, but not in HT10. In summary, intratracheal transplantation of human UCB derived MSCs time-dependently attenuated hyperoxia-induced lung injury in neonatal rats, showing significant protection only in the early but not in the late phase of inflammation. There were no synergies with combined early+late MSCs transplantation.

Functional deficiency of aryl hydrocarbon receptor augments oxygen toxicity-induced alveolar simplification in newborn mice

Hyperoxia contributes to the development of bronchopulmonary dysplasia (BPD) in premature infants. New BPD is characterized as having alveolar simplification. We reported previously that aryl hydrocarbon receptor (AhR) deficiency increased susceptibility to hyperoxic lung injury in adult mice, and this was associated with decreased expression of cytochrome P450 1A enzymes and increased lung inflammation. Whether AhR protects newborn mice against hyperoxia-induced alveolar simplification is unknown. Thus, we tested the hypothesis that decreased activation of the pulmonary AhR augments hyperoxia-induced alveolar simplification and lung inflammation in newborn mice. Experimental groups included one-day old wild type (WT) and AhR dysfunctional (AhRd) mice exposed to 21% O2 (air) or 85% O2 (hyperoxia) for 14days. Exposure of newborn WT mice to hyperoxia resulted in increased protein, enzyme and mRNA expression of the AhR-regulated lung cytochrome P450 1A1, NAD(P)H quinone oxidoreductase-1, and microsomal glutathione S-transferase 1 enzymes, suggesting that hyperoxia increases activation of the pulmonary AhR. On the other hand, in the AhRd mice, hyperoxia induced the AhR-regulated enzymes to a lesser extent probably due to the dysfunctional AhR in these mice. Alveolar simplification and lung inflammation was increased in mice exposed to hyperoxia compared with those exposed to air, and AhRd mice were more susceptible to hyperoxia-induced alveolar simplification and lung inflammation compared with WT mice. These findings suggest that decreased activation of the pulmonary AhR in newborn AhRd mice augments hyperoxia-induced alveolar simplification and lung inflammation in these mice.

Ambrisentan reduces pulmonary arterial hypertension but does not stimulate alveolar and vascular development in neonatal rats with hyperoxic lung injury

Ambrisentan, an endothelin receptor type A antagonist, may be a novel therapeutic agent in neonatal chronic lung disease (CLD) by blocking the adverse effects of the vasoconstrictor endothelin-1, especially pulmonary arterial hypertension (PAH)-induced right ventricular hypertrophy (RVH). We determined the cardiopulmonary effects of ambrisentan treatment (1-20 mg·kg(-1)·day(-1)) in neonatal rats with CLD in 2 models: early treatment during continuous exposure to hyperoxia for 10 days and late treatment starting on day 6 in rat pups exposed postnatally to hyperoxia for 9 days, followed by a 9-day recovery period in room air. Parameters investigated included survival, lung and heart histopathology, right ventricular function, fibrin deposition, and differential mRNA expression in the lungs. In the early treatment model, we investigated the role of nitric oxide synthase (NOS) inhibition with N(ω)-nitro-L-arginine methyl ester (L-NAME; 25 mg·kg(-1)·day(-1)) during ambrisentan treatment. In the early treatment model, ambrisentan improved survival with reduced lung fibrin and collagen III deposition, arterial medial wall thickness, and RVH. These changes were not affected by L-NAME administration. Ambrisentan did not reduce the influx of macrophages and neutrophils or prevent reduced irregular elastin expression. In the late treatment model, ambrisentan diminished PAH, RVH, and right ventricular peak pressure, demonstrating that RVH is reversible in the neonatal period. Alveolarization and vascularization were not affected by ambrisentan. In conclusion, ambrisentan prolongs survival and reduces lung injury, PAH, and RVH via a NOS-independent mechanism but does not affect inflammation and alveolar and vascular development in neonatal rats with CLD.

Novel Flurometric Tool to Assess Mitochondrial Redox State of Isolated Perfused Rat Lungs after Exposure to Hyperoxia.

Recently, we demonstrated the utility of optical fluorometry to detect a change in the redox status of mitochondrial autofluorescent coenzymes nicotinamide adenine dinucleotide (NADH) and oxidized form of flavin adenine dinucleotide n}{}({rm FADH}_{2}) (FAD), as a measure of mitochondrial function in isolated perfused rat lungs (IPL). The objective of this paper was to utilize optical fluorometry to evaluate the effect of rat exposure to hyperoxia (n}{}{>}{95%}~{rm O}_{2} for 48 h) on lung tissue mitochondrial redox status of NADH and FAD in a nondestructive manner in IPL. Surface NADH and FAD signals were measured before and after lung perfusion with perfusate containing rotenone (ROT, complex I inhibitor), potassium cyanide (KCN, complex IV inhibitor), and/or pentachlorophenol (PCP, uncoupler). ROT- or KCN-induced increase in NADH signal is considered a measure of complex I activity, and KCN-induced decrease in FAD signal is considered a measure of complex II activity. The results show that hyperoxia decreased complex I and II activities by 63% and 55%, respectively, when compared to lungs of rats exposed to room air (normoxic rats). Mitochondrial complex I and II activities in lung homogenates were also lower (77% and 63%, respectively) for hyperoxic than for normoxic lungs. These results suggest that the mitochondrial matrix is more reduced in hyperoxic lungs than in normoxic lungs, and demonstrate the ability of optical fluorometry to detect a change in mitochondrial redox state of hyperoxic lungs prior to histological changes characteristic of hyperoxia.

Heme oxygenase-1 regulates postnatal lung repair after hyperoxia: Role of β-catenin/hnRNPK signaling

In the newborn, alveolarization continues postnatally and can be disrupted by hyperoxia, leading to long-lasting consequences on lung function. We wanted to better understand the role of heme oxygenase (HO)-1, the inducible form of the rate-limiting enzyme in heme degradation, in neonatal hyperoxic lung injury and repair. Although it was not observed after 3 days of hyperoxia alone, when exposed to hyperoxia and allowed to recover in air (O2/air recovered), neonatal HO-1 knockout (KO) mice had enlarged alveolar spaces and increased lung apoptosis as well as decreased lung protein translation and dysregulated gene expression in the recovery phase of the injury. Associated with these changes, KO had sustained low levels of active β-catenin and lesser lung nuclear heterogeneous nuclear ribonucleoprotein K (hnRNPK) protein levels, whereas lung nuclear hnRNPK was increased in transgenic mice over-expressing nuclear HO-1. Disruption of HO-1 may enhance hnRNPK-mediated inhibition of protein translation and subsequently impair the β-catenin/hnRNPK regulated gene expression required for coordinated lung repair and regeneration.

Long-Term (Postnatal Day 70) Outcome and Safety of Intratracheal Transplantation of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells in Neonatal Hyperoxic Lung Injury

PurposeThis study was performed to evaluate the long-term effects and safety of intratracheal (IT) transplantation of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) in neonatal hyperoxic lung injury at postnatal day (P)70 in a rat model.Materials and MethodsNewborn Sprague Dawley rat pups were subjected to 14 days of hyperoxia (90% oxygen) within 10 hours after birth and allowed to recover at room air until sacrificed at P70. In the transplantation groups, hUCB-MSCs (5×105) were administered intratracheally at P5. At P70, various organs including the heart, lung, liver, and spleen were histologically examined, and the harvested lungs were assessed for morphometric analyses of alveolarization. ED-1, von Willebrand factor, and human-specific nuclear mitotic apparatus protein (NuMA) staining in the lungs and the hematologic profile of blood were evaluated.ResultsImpaired alveolar and vascular growth, which evidenced by an increased mean linear intercept and decreased amount of von Willebrand factor, respectively, and the hyperoxia-induced inflammatory responses, as evidenced by inflammatory foci and ED-1 positive alveolar macrophages, were attenuated in the P70 rat lungs by IT transplantation of hUCB-MSCs. Although rare, donor cells with human specific NuMA staining were persistently present in the P70 rat lungs. There were no gross or microscopic abnormal findings in the heart, liver, or spleen, related to the MSCs transplantation.ConclusionThe protective and beneficial effects of IT transplantation of hUCB-MSCs in neonatal hyperoxic lung injuries were sustained for a prolonged recovery period without any long-term adverse effects up to P70.

Metallothionein-induced zinc partitioning exacerbates hyperoxic acute lung injury

Hypozincemia, with hepatic zinc accumulation at the expense of other organs, occurs in infection, inflammation, and aseptic lung injury. Mechanisms underlying zinc partitioning or its impact on extrahepatic organs are unclear. Here we show that the major zinc-binding protein, metallothionein (MT), is critical for zinc transmigration from lung to liver during hyperoxia and preservation of intrapulmonary zinc during hyperoxia is associated with an injury-resistant phenotype in MT-null mice. Particularly, lung-to-liver zinc ratios decreased in wild-type (WT) and increased significantly in MT-null mice breathing 95% oxygen for 72 h. Compared with female adult WT mice, MT-null mice were significantly protected against hyperoxic lung injury indicated by reduced inflammation and interstitial edema, fewer necrotic changes to distal airway epithelium, and sustained lung function at 72 h hyperoxia. Lungs of MT-null mice showed decreased levels of immunoreactive LC3, an autophagy marker, compared with WT mice. Analysis of superoxide dismutase (SOD) activity in the lungs revealed similar levels of manganese-SOD activity between strains under normoxia and hyperoxia. Lung extracellular SOD activity decreased significantly in both strains at 72 h of hyperoxia, although there was no difference between strains. Copper-zinc-SOD activity was ~4× higher under normoxic conditions in MT-null compared with WT mice but was not affected in either group by hyperoxia. Collectively the data suggest that genetic deletion of MT-I/II in mice is associated with compensatory increase in copper-zinc-SOD activity, prevention of hyperoxia-induced zinc transmigration from lung to liver, and hyperoxia-resistant phenotype strongly associated with differences in zinc homeostasis during hyperoxic acute lung injury.

Hyperoxic acute lung injury.

Prolonged breathing of very high F(IO(2)) (F(IO(2)) ≥ 0.9) uniformly causes severe hyperoxic acute lung injury (HALI) and, without a reduction of F(IO(2)), is usually fatal. The severity of HALI is directly proportional to P(O(2)) (particularly above 450 mm Hg, or an F(IO(2)) of 0.6) and exposure duration. Hyperoxia produces extraordinary amounts of reactive O(2) species that overwhelms natural anti-oxidant defenses and destroys cellular structures through several pathways. Genetic predisposition has been shown to play an important role in HALI among animals, and some genetics-based epidemiologic research suggests that this may be true for humans as well. Clinically, the risk of HALI likely occurs when F(IO(2)) exceeds 0.7, and may become problematic when F(IO(2)) exceeds 0.8 for an extended period of time. Both high-stretch mechanical ventilation and hyperoxia potentiate lung injury and may promote pulmonary infection. During the 1960s, confusion regarding the incidence and relevance of HALI largely reflected such issues as the primitive control of F(IO(2)), the absence of PEEP, and the fact that at the time both ALI and ventilator-induced lung injury were unknown. The advent of PEEP and precise control over F(IO(2)), as well as lung-protective ventilation, and other adjunctive therapies for severe hypoxemia, has greatly reduced the risk of HALI for the vast majority of patients requiring mechanical ventilation in the 21st century. However, a subset of patients with very severe ARDS requiring hyperoxic therapy is at substantial risk for developing HALI, therefore justifying the use of such adjunctive therapies.

Mitochondrial DNA Damage Mediates Hyperoxic Dysmorphogenesis in Rat Fetal Lung Explants

Background: Numerous studies in cultured cells indicate that damage to mitochondrial DNA (mtDNA) dictates cellular responses to oxidant stress, yet the consequences of mtDNA damage have not been studied directly in the preterm lung. Objective: We sought to determine whether hyperoxia-induced fetal lung dysmorphogenesis is linked to mtDNA damage and establish mtDNA repair as a potential therapeutic approach for treating lung dysplasia in the preterm neonate. Methods: Hyperoxia-induced mtDNA damage was assessed by quantitative alkaline gel electrophoresis in normoxic (3% O₂) and hyperoxic (21% O₂) fetal rat lung explants. A fusion protein construct targeting the DNA repair enzyme endonuclease III (Endo III) to the mitochondria was used to augment mtDNA repair. Fetal lung branching and surfactant protein C (SFPTC) were assessed in these tissues. Results: Hyperoxia induced mtDNA damage in lung explants and was accompanied by impaired branching morphogenesis and decreased SFPTC mRNA expression. Treatment of lung explants with Endo III fusion protein prevented hyperoxia-induced mtDNA damage and restored normal branching morphogenesis and SFPTC mRNA expression. Conclusion: These findings support the concept that mtDNA governs cellular responses to oxidant stress in the fetal lung and suggest that modulation of mtDNA repair is a potential pharmacologic strategy in the prevention of hyperoxic lung injury.

Parametric proportional hazards model for mapping genomic imprinting of survival traits

A number of imprinted genes have been observed in plants, animals and humans. They not only control growth and developmental traits, but may also be responsible for survival traits. Based on the Cox proportional hazards (PH) model, we constructed a general parametric model for dissecting genomic imprinting, in which a baseline hazard function is selectable for fitting the effects of imprinted quantitative trait loci (iQTL) genotypes on the survival curve. The expectation-maximisation (EM) algorithm is derived for solving the maximum likelihood estimates of iQTL parameters. The imprinting patterns of the detected iQTL are statistically tested under a series of null hypotheses. The Bayesian information criterion (BIC) model selection criterion is employed to choose an optimal baseline hazard function with maximum likelihood and parsimonious parameterisation. We applied the proposed approach to analyse the published data in an F(2) population of mice and concluded that, among five commonly used survival distributions, the log-logistic distribution is the optimal baseline hazard function for the survival time of hyperoxic acute lung injury (HALI). Under this optimal model, five QTL were detected, among which four are imprinted in different imprinting patterns.

Inhibition of Cox-2 Decreases Macrophage Infiltration in Newborn Hyperoxic Lung Injury

Inhibition of Cox-2 Decreases Macrophage Infiltration in Newborn Hyperoxic Lung Injury

Surfactant metabolism and anti-oxidative capacity in hyperoxic neonatal rat lungs: effects of keratinocyte growth factor on gene expression in vivo

Development of preterm infant lungs is frequently impaired resulting in bronchopulmoary dysplasia (BPD). BPD results from interruption of physiologic anabolic intrauterine conditions, the inflammatory basis and therapeutic consequences of premature delivery, including increased oxygen supply for air breathing. The latter requires surfactant, produced by alveolar type II (AT II) cells to lower surface tension at the pulmonary air:liquid interface. Its main components are specific phosphatidylcholine (PC) species including dipalmitoyl-PC, anionic phospholipids and surfactant proteins. Local antioxidative enzymes are essential to cope with the pro-inflammatory side effects of normal alveolar oxygen pressures. However, respiratory insufficiency frequently requires increased oxygen supply. To cope with the injurious effects of hyperoxia to epithelia, recombinant human keratinocyte growth factor (rhKGF) was proposed as a surfactant stimulating, non-catabolic and epithelial-protective therapeutic. The aim of the present study was to examine the qualification of rhKGF to improve expression parameters of lung maturity in newborn rats under hyperoxic conditions (85% O(2) for 7 days). In response to rhKGF proliferating cell nuclear antigen mRNA, as a feature of stimulated proliferation, was elevated. Similarly, the expressions of ATP-binding cassette protein A3 gene, a differentiation marker of AT II cells and of peroxiredoxin 6, thioredoxin and thioredoxin reductase, three genes involved in oxygen radical protection were increased. Furthermore, mRNA levels of acyl-coA:lysophosphatidylcholine acyltransferase 1, catalyzing dipalmitoyl-PC synthesis by acyl remodeling, and adipose triglyceride lipase, considered as responsible for fatty acid supply for surfactant PC synthesis, were elevated. These results, together with a considerable body of other confirmative evidence, suggest that rhKGF should be developed into a therapeutic option to treat preterm infants at risk for impaired lung development.

Arginyl-glutamine dipeptide or docosahexaenoic acid attenuate hyperoxia-induced lung injury in neonatal mice

ObjectivesSupplementation studies of glutamine, arginine, and docosahexaenoic acid (DHA) have established the safety of each of these nutrients in neonates. However, the potential for a more stable and soluble dipeptide, arginyl-glutamine (Arg-Gln) or DHA, a long-chain ω-3 fatty acid with anti-inflammatory properties, to exert benefits on hyperoxia-induced lung injury has not to our knowledge been investigated. The aim of this study was to investigate whether Arg-Gln dipeptide or DHA could attenuate markers of injury and inflammation in neonatal mouse lungs exposed to hyperoxia. MethodsSeven-day-old mouse pups were placed with their dams in 75% oxygen for 5 d. After 5 d of hyperoxic exposure (postnatal days 7–12), pups were removed from hyperoxia and allowed to recover in atmospheric conditions for 5 d (postnatal days 12–17). Mouse pups received Arg-Gln (5 g · kg−1 · d−1) or DHA (5 g · kg−1 · d−1) or saline orally from postnatal days 12 through 17. Histologic changes, myeloperoxidase, lactate dehydrogenase, inflammatory cytokines, and nuclear factor-κB inhibitor levels were checked in each group. ResultsThe Arg-Gln and DHA prevented the development of key markers of injury, including histologic changes, myeloperoxidase, lactate dehydrogenase, and inflammatory cytokines interleukin-6 and C-X-C motif ligand 1 (CXCL1)/keratinocyte-derived chemokine (KC). The highly beneficial effects of Arg-Gln on the reversal of oxygen-induced lung damage was associated with restoration of levels of nuclear factor-κB inhibitor. ConclusionThe Arg-Gln and DHA, with protective effects on hyperoxic lung injury in neonatal mice, are promising nutritional adjuncts that may prevent lung damage owing to oxygen toxicity in infants.

128 Intraperitoneal Administration of Cytidine 5’-Diphosphocholine (CDP-Choline) Reduces Hyperoxic Lung Injury in a Neonatal Rat Model of Bronchopulmonary Dysplasia

PurposeThe purpose of this study was to evaluate the preventive effect of CDP-choline treatment on hyperoxic lung injury, inflammation and apoptosis in a neonatal rat model of bronchopulmonary dysplasia BPD.MethodsA...

597 Valproic Acid-Mediated Protection Against Hyperoxic Lung Injury Via Histone Deacetylase Inhibition in a Neonatal Rat Model

Epigenetic mechanisms might play an important role in development of BPD. The aim of this study was to evaluate the protective effect of valproic acid (VPA), an histon deacetylase inhibitor,...

Colchicine Protects against Hyperoxic Lung Injury in Neonatal Rats

Background: Bronchopulmonary dysplasia (BPD) is characterized by inflammation, fibrosis and mucosal necrosis, which leads to emphysematous coalescence of alveoli. Objective: We tested whether prophylaxis with colchicine , an anti-inflammatory, antioxidant and antifibrotic drug, would decrease the severity of lung injury in an animal model of BPD. Methods: Twenty-five rat pups were divided into three groups: control (n = 8), hyperoxia (n = 7), and hyperoxia + colchicine (n = 10). The hyperoxia groups were exposed to >95% oxygen from day 1 to 10 of life. On day 10, the animals were sacrificed and the lungs were processed for histology and biochemical analysis. Lung morphology was assessed by the mean linear intercept (MLI), a measure of alveolar size. The degree of lung inflammation and antioxidant capacity were assessed by quantifying lung homogenate tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels. Results: Colchicine significantly decreased lung damage as determined by the MLI in the hyperoxia groups (p < 0.01). The median level of lung MDA was significantly higher in the hyperoxia group compared with the control group (p < 0.05) and the colchicine-treated group (p < 0.05). Lung homogenate SOD and GSH-Px activities in the colchicine-treated group were significantly higher than in the hyperoxia group (p < 0.05). Furthermore, colchicine-treated pups had lower lung homogenate TNF-α and IL-1β levels compared with the hyperoxia group (p < 0.05). Conclusions: Colchicine has favorable effects on alveolarization as well as inflammation and oxidative stress markers in an animal model of BPD.

Citrulline: pharmacological perspectives and its role as an emerging biomarker in future

L-Citrulline is a naturally occurring non-essential amino acid, an intermediate in urea cycle and conditionally essential in intestinal pathology. It is a potent hydroxyl radical scavenger and much more effective precursor of arginine and nitric oxide (NO) than arginine itself so exploited in therapeutics. Plasma citrulline concentration is used by clinicians to assess functional enterocyte mass in various chronic and acute small bowel pathologies like short bowel syndrome that has become an indication in clinical practice. Its supplementation is likely to be used in conditions like erectile dysfunction, sickle cell anemia, short bowel syndrome (to restore nitrogen balance), hyperlipidemia, cancer chemotherapy, hypercholestremia, in hyperoxic lung damage, urea cycle disorders, Alzheimers disease, multi-infarct dementia and as an immunomodulator. Its emerging role as a biomarker in intestinal pathology and early diagnosis of Rheumatoid arthritis has spread considerable interest. Antibody detection to Anti-cyclic citrullinated peptide (ACCP) antibodies can be recommended for early detection of RA decreasing joint damage and deformity, because these are detected well before the onset of disease manifestations of RA. The test is highly specific than RF (Rheumatoid factor), with moderate sensitivity, but much useful in differentiating RA from other disorders. Further studies and exploration is required in these areas.