Anti-neutrophil chemokine preserves alveolar development in hyperoxia-exposed newborn rats

Inflammation may contribute to lung injury and impaired alveolar development in bronchopulmonary dysplasia. We treated hyperoxia-exposed newborn rats with antibodies to the neutrophil chemokine cytokine-induced neutrophil chemoattractant-1 (CINC-1) during 95% O2exposure to reduce adverse effects of hyperoxia-induced inflammation on lung development. Rats were exposed at birth to air, 95% O2, or 95% O2+ anti-CINC-1 (injected on days 3 and 4). Bromodeoxyuridine (BrdU) was injected 6 h before death. Anti-CINC-1 treatment improved weight gain but not survival at day 8. Anti-CINC-1 reduced bronchoalveolar lavage neutrophils at day 8 to levels equal to air controls. Total detectable lung CINC-1 was reduced to air control levels. Lung compliance was improved by anti-CINC-1, achieving air control levels in the 10-μg anti-CINC-1 group. Anti-CINC-1 preserved proliferating cell nuclear antigen expression in airway epithelium despite 95% O2exposure. BrdU incorporation was depressed by hyperoxia but preserved by anti-CINC-1 to levels similar to air control. Alveolar volume and surface density were decreased by hyperoxia but preserved by anti-CINC-1 to levels equal to air control. Blockade of neutrophil influx in newborns may avert early lung injury and avoid alveolar developmental arrest that contributes to bronchopulmonary dysplasia.

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Effects of Lycopene in Hyperoxia-Induced Lung Injury in Newborn Rats

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000238 ◽

2018 ◽

Vol 88 (5-6) ◽

pp. 270-280

Author(s):

Osman Bastug ◽

Mehmet Fatih Sonmez ◽

Mehmet Adnan Ozturk ◽

Levent Korkmaz ◽

Hakan Kesici ◽

...

Keyword(s):

Body Weight ◽

Lung Injury ◽

Ambient Air ◽

Nuclear Antigen ◽

Newborn Rats ◽

Negative Effects ◽

Rat Pups ◽

Injury Model ◽

Lung Injury Model ◽

Proliferating Cell

Abstract. The aim of this study was to evaluate the therapeutic effect of lycopene on a hyperoxia-induced lung injury model in rat pups. Full-term rat pups were included in the study 12–24 h after delivery. The pups were separated into 4 groups: normoxia control (NC), hyperoxia control (HC), hyperoxia + lycopene (HL), and normoxia lycopene (NL). The normoxia groups were housed in ambient air, and the hyperoxia groups in > 85% O2. HL and NL groups received 50 mg lycopene in oil/kg body weight/day delivered intraperitoneally (i.p.), the other groups received oil alone. On day 11, the rat pups were sacrificed and their lungs removed. Statistically significant injury was observed in all histological parameters measured (MLI, proliferating cell nuclear antigen (PCNA), and apoptosis) in the HC group (HC vs NC, p = 0.001). This injury could not be reversed with lycopene treatment (HC vs HL, 0.05; NC vs HL, p = 0.001). With hyperoxia, statistically significant decreases were observed in biochemical parameters in terms of SOD, MDA, and IL-6 values (HC vs NC: SOD, p = 0.02; MDA, p = 0.043; IL-6, p = 0.001). The use of lycopene did not provide any improvement in these values (HC vs HL, p > 0.05). Hyperoxia or lycopene had no effect on IL-1β and GPx (p > 0.05). When comparing NC and NL groups, negative effects were observed in the group given lycopene in terms of MLI, PCNA, apoptosis, and IL-6 (all parameters, p = 0.001). We observed that 50 mg lycopene in oil/kg body weight/day given via i.p. had no curative effect on the hyperoxia-induced lung injury in newborn rats and may even induce adverse effects.

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Endothelial Adenosine Monophosphate-Activated Protein Kinase-Alpha1 Deficiency Potentiates Hyperoxia-Induced Experimental Bronchopulmonary Dysplasia and Pulmonary Hypertension

Antioxidants ◽

10.3390/antiox10121913 ◽

2021 ◽

Vol 10 (12) ◽

pp. 1913

Author(s):

Ahmed Elsaie ◽

Renuka T. Menon ◽

Amrit K. Shrestha ◽

Sharada H. Gowda ◽

Nidhy P. Varghese ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Protein Kinase ◽

Lung Injury ◽

Bronchopulmonary Dysplasia ◽

Adenosine Monophosphate ◽

Causative Factor ◽

Nuclear Antigen ◽

Tubule Formation ◽

Neonatal Mice ◽

Deficient Mice

Bronchopulmonary dysplasia and pulmonary hypertension, or BPD-PH, are serious chronic lung disorders of prematurity, without curative therapies. Hyperoxia, a known causative factor of BPD-PH, activates adenosine monophosphate-activated protein kinase (AMPK) α1 in neonatal murine lungs; however, whether this phenomenon potentiates or mitigates lung injury is unclear. Thus, we hypothesized that (1) endothelial AMPKα1 is necessary to protect neonatal mice against hyperoxia-induced BPD-PH, and (2) AMPKα1 knockdown decreases angiogenesis in hyperoxia-exposed neonatal human pulmonary microvascular endothelial cells (HPMECs). We performed lung morphometric and echocardiographic studies on postnatal day (P) 28 on endothelial AMPKα1-sufficient and -deficient mice exposed to 21% O2 (normoxia) or 70% O2 (hyperoxia) from P1–P14. We also performed tubule formation assays on control- or AMPKα1-siRNA transfected HPMECs, exposed to 21% O2 or 70% O2 for 48 h. Hyperoxia-mediated alveolar and pulmonary vascular simplification, pulmonary vascular remodeling, and PH were significantly amplified in endothelial AMPKα1-deficient mice. AMPKα1 siRNA knocked down AMPKα1 expression in HPMECs, and decreased their ability to form tubules in normoxia and hyperoxia. Furthermore, AMPKα1 knockdown decreased proliferating cell nuclear antigen expression in hyperoxic conditions. Our results indicate that AMPKα1 is required to reduce hyperoxia-induced BPD-PH burden in neonatal mice, and promotes angiogenesis in HPMECs to limit lung injury.

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K2P2.1 (TREK-1) potassium channel activation protects against hyperoxia-induced lung injury

Scientific Reports ◽

10.1038/s41598-020-78886-y ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Tatiana Zyrianova ◽

Benjamin Lopez ◽

Riccardo Olcese ◽

John Belperio ◽

Christopher M. Waters ◽

...

Keyword(s):

Lung Injury ◽

Lung Compliance ◽

Alveolar Epithelial Cells ◽

Pharmacological Intervention ◽

Alveolar Epithelial ◽

Protein Levels ◽

Cell Counts ◽

Novel Approach ◽

Intracellular Ca ◽

Cell Depolarization

AbstractNo targeted therapies exist to counteract Hyperoxia (HO)-induced Acute Lung Injury (HALI). We previously found that HO downregulates alveolar K2P2.1 (TREK-1) K+ channels, which results in worsening lung injury. This decrease in TREK-1 levels leaves a subset of channels amendable to pharmacological intervention. Therefore, we hypothesized that TREK-1 activation protects against HALI. We treated HO-exposed mice and primary alveolar epithelial cells (AECs) with the novel TREK-1 activators ML335 and BL1249, and quantified physiological, histological, and biochemical lung injury markers. We determined the effects of these drugs on epithelial TREK-1 currents, plasma membrane potential (Em), and intracellular Ca2+ (iCa) concentrations using fluorometric assays, and blocked voltage-gated Ca2+ channels (CaV) as a downstream mechanism of cytokine secretion. Once-daily, intra-tracheal injections of HO-exposed mice with ML335 or BL1249 improved lung compliance, histological lung injury scores, broncho-alveolar lavage protein levels and cell counts, and IL-6 and IP-10 concentrations. TREK-1 activation also decreased IL-6, IP-10, and CCL-2 secretion from primary AECs. Mechanistically, ML335 and BL1249 induced TREK-1 currents in AECs, counteracted HO-induced cell depolarization, and lowered iCa2+ concentrations. In addition, CCL-2 secretion was decreased after L-type CaV inhibition. Therefore, Em stabilization with TREK-1 activators may represent a novel approach to counteract HALI.

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Non-Invasive Ventilatory Strategies to Decrease Bronchopulmonary Dysplasia—Where Are We in 2021?

Children ◽

10.3390/children8020132 ◽

2021 ◽

Vol 8 (2) ◽

pp. 132

Author(s):

Vikramaditya Dumpa ◽

Vineet Bhandari

Keyword(s):

Lung Injury ◽

Bronchopulmonary Dysplasia ◽

Premature Infants ◽

Extremely Low Birth Weight ◽

Positive Pressure ◽

Invasive Ventilation ◽

Clinical Practices ◽

Non Invasive ◽

Non Invasive Ventilation ◽

Increased Risk

Recent advances in neonatology have led to the increased survival of extremely low-birth weight infants. However, the incidence of bronchopulmonary dysplasia (BPD) has not improved proportionally, partly due to increased survival of extremely premature infants born at the late-canalicular stage of lung development. Due to minimal surfactant production at this stage, these infants are at risk for severe respiratory distress syndrome, needing prolonged ventilation. While the etiology of BPD is multifactorial with antenatal, postnatal, and genetic factors playing a role, ventilator-induced lung injury is a major, potentially modifiable, risk factor implicated in its causation. Infants with BPD are at a higher risk of developing complications including sepsis, pulmonary arterial hypertension, respiratory failure, and death. Long-term problems include increased risk of hospital readmissions, respiratory infections, and asthma-like symptoms during infancy and childhood. Survivors who have BPD are also at increased risk of poor neurodevelopmental outcomes. While the ultimate solution for avoiding BPD lies in the prevention of preterm births, strategies to decrease its incidence are the need of the hour. It is time to focus on gentler modes of ventilation and the use of less invasive surfactant administration techniques to mitigate lung injury, thereby potentially decreasing the burden of BPD. In this article, we discuss the use of non-invasive ventilation in premature infants, with an emphasis on studies showing an effect on BPD with different modes of non-invasive ventilation. Practical considerations in the use of nasal intermittent positive pressure ventilation are also discussed, considering the significant heterogeneity in clinical practices and management strategies in its use.

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Oral Maternal Administration of the Cytochrome P450 (CYP)1A/1B Inducer, Beta-Napthoflavone (BNF), Attenuates Oxygen-Mediated Lung Injury in Newborn Mice: Implications for Bronchopulmonary Dysplasia (BPD)

10.1164/ajrccm-conference.2019.199.1_meetingabstracts.a5313 ◽

2019 ◽

Author(s):

X. Couroucli ◽

Y.W. Liang ◽

K. Lingappan ◽

P. Maturu ◽

W. Jiang ◽

...

Keyword(s):

Cytochrome P450 ◽

Lung Injury ◽

Bronchopulmonary Dysplasia ◽

Newborn Mice ◽

Maternal Administration

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Postnatal alveolar development of the rabbit

Journal of Applied Physiology ◽

10.1152/japplphysiol.01044.2001 ◽

2002 ◽

Vol 93 (2) ◽

pp. 629-635 ◽

Cited By ~ 40

Author(s):

Jana Kovar ◽

Peter D. Sly ◽

Karen E. Willet

Keyword(s):

Wall Thickness ◽

Alveolar Wall ◽

Alveolar Volume ◽

Surface Fraction ◽

Alveolar Development ◽

The Right ◽

Timing Of Onset ◽

Alveolar Formation ◽

Tissue Fraction

Previous studies of alveolarization have used rats or lambs; however, neither closely reflects human alveolar development. We characterized alveolar development in rabbits ( n = 3–7 /group) at 28 days gestation (dg) to 9 mo to determine whether they followed the human pattern more closely. The right lung was made up of 30% alveolar and 50% duct space at 28 dg to 3 days and of 50 and 30%, respectively, at 14 days to 9 mo. Tissue fraction and alveolar wall thickness decreased by 40% 28 dg to birth. At birth, ∼4.5% of the number of alveoli seen at 9 mo were present, with alveolar number increasing progressively well into adulthood. The rate of alveolar formation was high around birth, decreasing progressively with age. Alveolar volume increased more than twofold (28 dg to birth) and continued to increase postnatally to 16 wk. Surface fraction decreased by 17% (28 dg to 3 days), after which it remained uniform. Our findings suggest that the timing of onset of alveolarization in humans and rabbits is similar and that rabbits may be used to model postnatal influences on alveolar development.

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Animal models of bronchopulmonary dysplasia. The term mouse models

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00159.2014 ◽

2014 ◽

Vol 307 (12) ◽

pp. L936-L947 ◽

Cited By ~ 131

Author(s):

Jessica Berger ◽

Vineet Bhandari

Keyword(s):

Animal Models ◽

Lung Injury ◽

Mouse Models ◽

Bronchopulmonary Dysplasia ◽

Lung Development ◽

Invasive Mechanical Ventilation ◽

Therapeutic Interventions ◽

Contributing Factors ◽

Short Term ◽

Injury Models

The etiology of bronchopulmonary dysplasia (BPD) is multifactorial, with genetics, ante- and postnatal sepsis, invasive mechanical ventilation, and exposure to hyperoxia being well described as contributing factors. Much of what is known about the pathogenesis of BPD is derived from animal models being exposed to the environmental factors noted above. This review will briefly cover the various mouse models of BPD, focusing mainly on the hyperoxia-induced lung injury models. We will also include hypoxia, hypoxia/hyperoxia, inflammation-induced, and transgenic models in room air. Attention to the stage of lung development at the timing of the initiation of the environmental insult and the duration of lung injury is critical to attempt to mimic the human disease pulmonary phenotype, both in the short term and in outcomes extending into childhood, adolescence, and adulthood. The various indexes of alveolar and vascular development as well as pulmonary function including pulmonary hypertension will be highlighted. The advantages (and limitations) of using such approaches will be discussed in the context of understanding the pathogenesis of and targeting therapeutic interventions to ameliorate human BPD.

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Cell proliferation in the gastrulating chick embryo: a study using BrdU incorporation and PCNA localization

Development ◽

10.1242/dev.118.2.389 ◽

1993 ◽

Vol 118 (2) ◽

pp. 389-399 ◽

Cited By ~ 2

Author(s):

E.J. Sanders ◽

M. Varedi ◽

A.S. French

Keyword(s):

Cell Proliferation ◽

Chick Embryo ◽

Cell Density ◽

Generation Time ◽

Primitive Streak ◽

S Phase ◽

Nuclear Antigen ◽

Brdu Incorporation ◽

Similar Proportion ◽

Differential Growth

Cell proliferation in the gastrulating chick embryo was assessed using two independent techniques which mark cells in S phase of the mitotic cycle: nuclear incorporation of bromodeoxyuridine (BrdU) detected immunocytochemically and immunolocalization of proliferating cell nuclear antigen (PCNA). Computer-reconstructed maps were produced showing the distribution of labelled nuclei in the primitive streak and the cell layers. These distributions were also normalized to take into account regional differences in cell density across the embryo. Results from a 2 hour pulse of BrdU indicated that although cells at caudal levels of the primitive streak showed the highest incorporation, this region showed a similar proportion of labelled cells to the surrounding caudal regions of the epiblast and mesoderm when normalized for cell density. The entire caudal third of the embryo showed the highest proportion of cells in S phase. Cells of Hensen's node showed a relatively low rate of incorporation and, although the chordamesoderm cells showed many labelled nuclei, this appeared to be a reflection of a high cell density in this region. Combining this result with results from a 4 hour pulse of BrdU permitted mapping of cell generation time across the entire embryo. Generation times ranged from a low value of approximately 2 hours at caudal levels of both the epiblast and mesoderm, to an upper value of approximately 10 hours in the rostral regions of the primitive streak, in the mid-lateral levels of the epiblast and in the chordamesoderm rostral to Hensen's node. Cells at caudal regions of the primitive streak showed a generation time of approximately 5 hours. Taking into account that cells are generally considered to be continuously moving through the primitive streak, we conclude that cell division, as judged by generation time, is greatly reduced during transit through this region, despite the presence there of cells in S phase and M phase. Immunocytochemical localization of PCNA-positive nuclei gave generally similar distributions to those obtained with BrdU incorporation, confirming that this endogenous molecule is a useful S-phase marker during early embryogenesis. Mid-levels and caudal levels of the primitive streak showed the highest numbers of positive nuclei, and the highest proportion of labelling after cell density was accounted for. As with BrdU incorporation, the highest proportions of PCNA-positive nuclei were found towards the caudal regions of the epiblast and mesoderm. These results suggest that the differential growth of the caudal region of the embryo at this time is a direct consequence of elevated levels of cell proliferation in this region.(ABSTRACT TRUNCATED AT 400 WORDS)

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