scholarly journals Disruption of NO-cGMP signaling by neonatal hyperoxia impairs relaxation of lung parenchyma

2007 ◽  
Vol 293 (4) ◽  
pp. L1029-L1036 ◽  
Author(s):  
Ramadan B. Sopi ◽  
Musa A. Haxhiu ◽  
Richard J. Martin ◽  
Ismail A. Dreshaj ◽  
Suneel Kamath ◽  
...  
Keyword(s):  
Electrical Field Stimulation ◽  
Lung Parenchyma ◽  
Airway Hyperreactivity ◽  
Neonatal Rat ◽  
Air Exposure ◽  
Rat Pups ◽  
Hyperoxic Exposure ◽  
Cgmp Signaling ◽  
Neonatal Lung ◽  
Neonatal Hyperoxia

Exposure of immature lungs to hyperoxia for prolonged periods contributes to neonatal lung injury and airway hyperreactivity. We studied the role of disrupted nitric oxide-guanosine 3′,5′-cyclic monophosphate (NO-cGMP) signaling in impairing the relaxant responses of lung tissue from hyperoxia-exposed rat pups. Pups were exposed to ≥95% O2 or room air for 7 days starting from days 1, 5, or 14. The animals were killed, lungs were removed, and 1-mm-thick lung parenchymal strips were prepared. Lung parenchymal strips of room air or hyperoxic pups were preconstricted using bethanechol and then graded electrical field stimulation (EFS) was applied to induce relaxation. EFS-induced relaxation of lung parenchymal strips was greater at 7 and 12 days than at 21 days in room air-exposed rat pups. Hyperoxic exposure significantly reduced relaxation at 7 and 12 days but not 21 days compared with room air exposure. NO synthase blockade with Nω-nitro-l-arginine methyl ester diminished relaxant responses in room air but not in hyperoxic pups at 12 days. After incubation with supplemental l-arginine, the relaxation response of hyperoxic strips was restored. cGMP, a key mediator of the NO signaling pathway, also decreased in strips from hyperoxic vs. room air pups and cGMP levels were restored after incubation with supplemental l-arginine. In addition, arginase activity was significantly increased in hyperoxic lung parenchymal strips compared with room air lung parenchymal strips. These data demonstrate disruption of NO-cGMP signaling in neonatal rat pups exposed to hyperoxia and show that bioavailability of the substrate l-arginine is implicated in the predisposition of this model to airway hyperreactivity.

Hyperoxia impairs airway relaxation in immature rats via a cAMP-mediated mechanism

2004 ◽  
Vol 96 (5) ◽  
pp. 1854-1860 ◽  
Author(s):  
Maroun J. Mhanna ◽  
Musa A. Haxhiu ◽  
Marwan A. Jaber ◽  
Ronald W. Walenga ◽  
Chang-Ho Chang ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Electrical Field Stimulation ◽  
Prostaglandin E ◽  
Nitric Oxide Synthase Inhibitor ◽  
Cgmp Production ◽  
Rat Pups ◽  
Hyperoxic Exposure ◽  
Camp Signaling Pathway ◽  
Synthase Inhibitor ◽  
Oxide Synthase

Hyperoxic exposure enhances airway reactivity in newborn animals, possibly due to altered relaxation. We sought to define the role of prostaglandinand nitric oxide-mediated mechanisms in impaired airway relaxation induced by hyperoxic stress. We exposed 7-day-old rat pups to either room air or hyperoxia (>95% O2) for 7 days to assess airway relaxation and cAMP and cGMP production after electrical field stimulation (EFS). EFS-induced relaxation of preconstricted trachea was diminished in hyperoxic vs. normoxic animals ( P < 0.05). Indomethacin (a cyclooxygenase inhibitor) reduced EFS-induced airway relaxation in tracheae from normoxic ( P < 0.05), but not hyperoxic, rat pups; however, in the presence of NG-nitro-l-arginine methyl ester (a nitric oxide synthase inhibitor) EFS-induced airway relaxation was similarly decreased in tracheae from both normoxic and hyperoxic animals. After EFS, the increase from baseline in the production of cAMP was significantly higher in tracheae from normoxic than hyperoxic rat pups, and this was accompanied by greater prostaglandin E2 release only in the normoxic group. cGMP production after EFS stimulation did not differ between normoxic and hyperoxic groups. We conclude that hyperoxia impairs airway relaxation in immature animals via a mechanism primarily involving the prostaglandin-cAMP signaling pathway with an impairment of prostaglandin E2 release and cAMP accumulation.

Hyperoxia enhances brain-derived neurotrophic factor and tyrosine kinase B receptor expression in peribronchial smooth muscle of neonatal rats

2005 ◽  
Vol 289 (2) ◽  
pp. L307-L314 ◽  
Author(s):  
Qin Yao ◽  
Musa A. Haxhiu ◽  
Syed I. Zaidi ◽  
Shijian Liu ◽  
Anjum Jafri ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Neurotrophic Factor ◽  
Brain Derived Neurotrophic Factor ◽  
Airway Hyperreactivity ◽  
Receptor Expression ◽  
Postnatal Life ◽  
Bdnf Mrna ◽  
Protein Levels ◽  
Rat Pups ◽  
Hyperoxic Exposure

Airway hyperreactivity is one of the hallmarks of hyperoxic lung injury in early life. As neurotrophins such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are potent mediators of neuronal plasticity, we hypothesized that neurotrophin levels in the pulmonary system may be disturbed by hyperoxic exposure. We therefore evaluated the effects of hyperoxia on the expression of BDNF, NGF, and their corresponding high-affinity receptors, TrkB and TrkA, respectively, in the lung of rat pups. Five-day-old Sprague-Dawley rat pups were randomized to hyperoxic or control groups and then continuously exposed to hyperoxia (>95% oxygen) or normoxia over 7 days. At both mRNA and protein levels, BDNF was detected in lung but not in trachea; its level was substantially enhanced in lungs from the hyperoxia-exposed rat pups. Distribution of BDNF mRNA by in situ hybridization indicates that peribronchial smooth muscle was the major source of increased BDNF production in response to hyperoxic exposure. Interestingly, hyperoxia-induced elevation of BDNF was not accompanied by any changes of NGF levels in lung. Furthermore, hyperoxic exposure increased the expression of TrkB in peribronchial smooth muscle but had no effect on the distribution of the specific NGF receptor TrkA. These findings indicate that hyperoxic stress not only upregulates BDNF at mRNA and protein levels but also enhances TrkB within peribronchial smooth muscle. However, there was no corresponding effect on NGF and TrkA receptors. We speculate that the increased level of BDNF may contribute to hyperoxia-induced airway hyperresponsiveness in early postnatal life.

Leukotrienes are indicated as mediators of hyperoxia-inhibited alveolarization in newborn rats

1997 ◽  
Vol 272 (3) ◽  
pp. L433-L441 ◽  
Author(s):  
V. Boros ◽  
J. S. Burghardt ◽  
C. J. Morgan ◽  
D. M. Olson
Keyword(s):  
Internal Surface ◽  
Lung Parenchyma ◽  
Lavage Fluid ◽  
Neonatal Rat ◽  
Lung Water ◽  
Internal Surface Area ◽  
Rat Pups ◽  
Septal Thickness ◽  
Mean Linear Intercept ◽  
Induced Changes

We investigated the role of leukotrienes (LT) in hyperoxia-induced changes in lung parenchyma in neonatal rat pups. Rat pups were exposed to 21% O(2) (air) or >95% O(2) from days 4 to 14 after birth and were administered the 5-lipoxygenase (5-LO) inhibitor and LTD4 receptor antagonist Wy-50295, 5-LO-activating protein inhibitor MK-0591, or vehicle from days 3 to 14. All measurements were done on days 12-14. There was a significant (P < 0.05) increase in peptido-LT output from lung slices of animals exposed to O(2) compared with air-exposed animals. Both Wy-50295 and MK-0591 significantly lowered (P < 0.05) peptido-LT output in O(2)-exposed animals. The 6-ketoprostaglandin F(1alpha) output was increased similarly in both vehicle- and drug-treated O(2)-exposed animals. O(2) exposure also caused a significant increase in bronchoalveolar lavage fluid protein and extravascular lung water that could not be ameliorated by Wy-50295 or MK-0591. Hyperoxia-induced inhibition of alveolarization, indicated by a significantly (P < 0.05) lower parenchymal tissue density, specific internal surface area, and airspace perimeter-to-area ratio, and a significantly (P < 0.05) higher mean linear intercept and airspace unit volume than air-exposed animals, was prevented by both Wy-50295 and MK-0591. Although hyperoxia had no effect on septal thickness, Wy-50295 caused significant thickening in both air- and O(2)-exposed pups. Our studies provide evidence that hyperoxia-induced peptido-LT may mediate O(2)-induced inhibition of alveolarization and that this is not caused by an arachidonic acid shunt to cyclooxygenase.

scholarly journals Role of brain-derived neurotrophic factor in hyperoxia-induced enhancement of contractility and impairment of relaxation in lung parenchyma

2008 ◽  
Vol 295 (2) ◽  
pp. L348-L355 ◽  
Author(s):  
Ramadan B. Sopi ◽  
Richard J. Martin ◽  
Musa A. Haxhiu ◽  
Ismail A. Dreshaj ◽  
Qin Yao ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Tyrosine Kinase ◽  
Airway Smooth Muscle ◽  
Neurotrophic Factor ◽  
Critical Role ◽  
Lung Parenchyma ◽  
Brain Derived Neurotrophic Factor ◽  
Airway Hyperreactivity ◽  
Rat Pups

Prolonged hyperoxic exposure contributes to neonatal lung injury, and airway hyperreactivity is characterized by enhanced contraction and impaired relaxation of airway smooth muscle. Our previous data demonstrate that hyperoxia in rat pups upregulates expression of brain-derived neurotrophic factor (BDNF) mRNA and protein, disrupts NO-cGMP signaling, and impairs cAMP production in airway smooth muscle. We hypothesized that BDNF-tyrosine kinase B (TrkB) signaling plays a functional role in airway hyperreactivity via upregulation of cholinergic mechanisms in hyperoxia-exposed lungs. Five-day-old rat pups were exposed to ≥95% oxygen or room air for 7 days and administered daily tyrosine kinase inhibitor K-252a (50 μg·kg−1·day−1 ip) to block BDNF-TrkB signaling or vehicle. Lungs were removed for HPLC measurement of ACh or for in vitro force measurement of lung parenchymal strips. ACh content doubled in hyperoxic compared with room air-exposed lungs. K-252a treatment of hyperoxic pups restored ACh content to room air levels. Hyperoxia increased contraction and impaired relaxation of lung strips in response to incremental electrical field stimulation. K-252a administration to hyperoxic pups reversed this increase in contraction and decrease in relaxation. K-252a or TrkB-Fc was used to block the effect of exogenous BDNF in vitro. Both K-252a and TrkB-Fc blocked the effects of exogenous BDNF. Hyperoxia decreased cAMP and cGMP levels in lung strips, and blockade of BDNF-TrkB signaling restored cAMP but not cGMP to control levels. Therefore, hyperoxia-induced increase in activity of BDNF-TrkB receptor signaling appears to play a critical role in enhancing cholinergically mediated contractile responses of lung parenchyma.

Hyperoxic exposure of developing rat lung decreases tropoelastin mRNA levels that rebound postexposure

1993 ◽  
Vol 265 (3) ◽  
pp. L293-L300 ◽  
Author(s):  
M. C. Bruce ◽  
E. N. Bruce ◽  
K. Janiga ◽  
A. Chetty
Keyword(s):  
Elastic Fiber ◽  
Lung Parenchyma ◽  
Regulatory Control ◽  
Separate Experiment ◽  
Elastic Fibers ◽  
Mrna Levels ◽  
Fiber Assembly ◽  
Total Length ◽  
Rat Pups ◽  
Hyperoxic Exposure

These studies were undertaken to determine whether tropoelastin message expression in lung parenchymal tissue is altered in rats reared in an hyperoxic environment during the period of time that alveolar septation normally occurs. Rat pups were exposed to > 95% oxygen from days 4 to 14 and killed during the exposure and recovery periods. Results of in situ hybridizations indicated a delay in peak tropoelastin (TE) message levels in oxygen-exposed rats vs. controls, day 16 vs. day 11, respectively. In addition, lung parenchymal TE mRNA levels in the oxygen-exposed pups remained elevated through day 23, 1 wk after TE mRNA levels had decreased in controls. These observations suggest that the regulatory control of elastin synthesis during lung alveolar septation is altered by hyperoxic exposure. In a separate experiment, rat pups were exposed to > 95% oxygen during the period of alveolarization and followed for 4 wk postexposure. Pulmonary function measurements were conducted to determine whether lung function was altered postexposure and, if so, whether recovery occurred. We also used stereological techniques to quantitate the total length of lung parenchymal elastic fibers to determine whether elastic fiber content in the oxygen-exposed pups was restored to normal levels during the month postexposure. Although the total length of elastic fibers in lung parenchyma was found to be greater in oxygen-exposed than control pups from postnatal days 22 to 41, pressure-volume curves indicated that lungs of the oxygen-exposed pups tended to be more compliant than controls, suggesting that abnormal elastic fiber assembly might have been a contributing factor.

Role of endogenous nitric oxide in hyperoxia-induced airway hyperreactivity in maturing rats

2000 ◽  
Vol 89 (3) ◽  
pp. 1205-1212 ◽  
Author(s):  
Sabine C. Iben ◽  
Ismail A. Dreshaj ◽  
Carol F. Farver ◽  
Musa A. Haxhiu ◽  
Richard J. Martin
Keyword(s):  
Nitric Oxide ◽  
Vagal Stimulation ◽  
Muscle Thickness ◽  
Nerve Fibers ◽  
Airway Hyperreactivity ◽  
Contractile Responses ◽  
Rat Pups ◽  
Hyperoxic Exposure ◽  
Release Of Acetylcholine ◽  
Stimulation Of

We sought to define the effects of maturation and hyperoxic stress on nitric oxide (NO)-induced modulation of bronchopulmonary responses to stimulation of vagal preganglionic nerve fibers. Experiments were performed on decerebrate, paralyzed, and ventilated rat pups at 6–7 days ( n = 21) and 13–15 days of age ( n= 23) breathing room air and on rat pups 13–15 days of age ( n = 19) after exposure to hyperoxia (≥95% inspired O2 fraction for 4–6 days). Total lung resistance (Rl) and lung elastance (El) were measured by body plethysmograph. Vagal stimulation and release of acetylcholine caused a frequency-dependent increase in Rl and El in all animals. The Rl response was significantly potentiated in normoxic animals by prior blockade of nitric oxide synthase (NOS) ( P < 0.05). Hyperoxic exposure increased responses of Rl to vagal stimulation ( P < 0.05); however, after hyperoxic exposure, the potentiation of contractile responses by NOS blockade was abolished. The response of El was potentiated by NOS blockade in the 13- to 15-day-old animals after both normoxic and hyperoxic exposure ( P < 0.01). Morphometry revealed no effect of hyperoxic exposure on airway smooth muscle thickness. We conclude that NO released by stimulation of vagal preganglionic fibers modulates bronchopulmonary contractile responses to endogenously released acetylcholine in rat pups. Loss of this modulatory effect of NO could contribute to airway hyperreactivity after prolonged hyperoxic exposure, as may occur in bronchopulmonary dysplasia.

scholarly journals Perinatal hyperoxic exposure reconfigures the central respiratory network contributing to intolerance to anoxia in newborn rat pups

2014 ◽  
Vol 116 (1) ◽  
pp. 47-53 ◽  
Author(s):  
Alexis M. Bierman ◽  
Clarke G. Tankersley ◽  
Christopher G. Wilson ◽  
Raul Chavez-Valdez ◽  
Estelle B. Gauda
Keyword(s):  
Ventilatory Response ◽  
Ex Vivo ◽  
Respiratory Control ◽  
Neonatal Rat ◽  
Central Component ◽  
Burst Frequency ◽  
Rat Pups ◽  
Respiratory Network ◽  
Hyperoxic Exposure

Perinatal exposure to hyperoxia (30–60% O2) alters the respiratory control system via modulation of peripheral arterial chemoreceptor development and function. Furthermore, hyperoxic exposure during the first two postnatal weeks of life can alternatively modulate the different phases of the hypoxic ventilatory response. Given the effects of perinatal hyperoxia, the aims of our study were 1) to determine the effect on survival time in response to lethal anoxic stimuli in rat pups and 2) to characterize the output of the isolated central respiratory network in response to acute hypoxic stimuli. We hypothesized that perinatal hyperoxic exposure would modify the neonatal rat ventilatory response to anoxia by affecting a central component of the respiratory network in addition to the maturation of the carotid body chemoreceptors. We found that animals continuously exposed to 60% oxygen up to age 5 days after parturition (P5) have reduced breathing frequency at baseline and within the first 10 min of a fatal anoxic challenge. Hyperoxic rat pups also have a shortened time to last gasp in response to anoxia that is not associated with lung injury or inflammation. This study is the first to demonstrate that these in vivo findings correlate with reduced phrenic burst frequency from the isolated brainstem ex vivo. Thus hyperoxic exposure reduced the phrenic burst frequency at baseline and in response to ex vivo anoxia. Importantly, our data suggest that perinatal hyperoxia alters ventilation and the response to anoxia at P5 in part by altering the frequency of phrenic bursts generated by the central respiratory network.

Effect of prenatal isoxsuprine on pulmonary oxygen toxicity in the newborn rat

1980 ◽  
Vol 48 (3) ◽  
pp. 505-510 ◽  
Author(s):  
L. Frank ◽  
J. Summerville ◽  
D. Massaro
Keyword(s):  
Enzyme Activities ◽  
Oxygen Toxicity ◽  
Fetal Lung ◽  
Antioxidant Enzyme Activities ◽  
Newborn Rats ◽  
Lung Maturation ◽  
Lung Weight ◽  
Pregnant Rats ◽  
Rat Pups ◽  
Hyperoxic Exposure

Isoxsuprine, a beta-sympathomimetic agent used clinically to delay premature parturition and to possibly accelerate fetal lung maturation, was administered to pregnant rats at 48 and 24 h prior to delivery. Newborn rats were placed in 96-98% O2 (or room air) to determine if the prenatal isoxsuprine treatment compromised their tolerance to prolonged hyperoxic exposure. (Exogenous catecholamines are known to exacerbate O2 toxicity in adult animals). Survival of the isoxsuprine-treated pups in O2 (52%) was no different than for control neonates exposed to hyperoxia for 7 days (57%) (P = 0.22). Body weight, lung weight, lung protein, and DNA content of the newborns were also not altered by the prenatal isoxsuprine treatment. Lung antioxidant enzyme activities for superoxide dismutase, catalase, and glutathione peroxidase were the same at birth in the isoxsuprine-treated and control rat pups, and the enzyme activities increased in response to hyperoxic exposure in each group to an equivalent degree. Thus, in utero treatment with isoxsuprine had no apparent adverse effect on newborn rats exposed to a prolonged O2 challenge.

Behavioral Components of Milk-Induced Activation in Neonatal Rat Pups

1996 ◽  
Vol 82 (3) ◽  
pp. 903-911 ◽  
Author(s):  
Steven M. Specht ◽  
Richard G. Burright ◽  
Linda Patia Spear
Keyword(s):  
Brain Stimulation ◽  
Principal Components ◽  
Behavioral Activation ◽  
Neural Substrates ◽  
Neonatal Rat ◽  
Exact Nature ◽  
Electrical Brain Stimulation ◽  
Global Pattern ◽  
Rat Pups ◽  
Components Analysis

Neonatal rat pups exhibit a complex constellation of behaviors in response to a variety of salient stimuli such as the odor of milk or maternal saliva, stroking with a soft brush, electrical brain stimulation, and intraoral infusions of milk. Although psychobiologists have used the term “behavioral activation” to refer to such behavioral displays, the exact nature of “behavioral activation” and its underlying neural substrates have yet to be elucidated. This study was undertaken to characterize “behavioral activation” quantitatively to describe and define this apparently global pattern of response in terms of possible underlying components. Principal components analysis suggested that “behavioral activation” may be comprised of separable ingestive, exploratory, and locomotor behavioral “assemblies.”

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