Postnatal growth restriction augments oxygen-induced pulmonary hypertension in a neonatal rat model of bronchopulmonary dysplasia

Wedgwood, Stephen; Warford, Cris; Agvateesiri, Sharleen C.; Thai, Phung N.; Berkelhamer, Sara; Perez, Marta; Underwood, Mark A.; Steinhorn, Robin H.

doi:10.1038/pr.2016.164

Cited by 37 publications

(37 citation statements)

References 41 publications

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“…After birth, pups were pooled and randomly assigned to litters of 10 pups (normal litter size, N) or 17 pups (restricted litter size, R). Additionally, pups were randomly assigned to cages maintained in room air (A) or exposed to 75% oxygen (O) in a plexiglass chamber (Biospherix, Lacona, NY, United States) continuously, and dams were rotated with the appropriate control or PNGR dam every 24 h. As we have shown previously, the pups tolerate hyperoxia for 14 days without mortality (12). Some pups in each group were injected subcutaneously with the TLR4 inhibitor TAK-242 (Cayman Chemicals, Ann Arbor, MI, United States) (Resatorvid, 3 mg/kg/day from birth) or with vehicle alone (5% ethanol).…”

Section: Animalsmentioning

confidence: 99%

“…At day 14, echocardiography was performed on pups under light anesthesia with isoflurane using a VisualSonics VIVO 2100 in vivo ultrasound imaging system (VisualSonics, Toronto, ON, Canada) to determine the ratio of the pulmonary acceleration time (PAT) to the total ejection time (ET) a marker of PH as previously described (12).…”

Section: Echocardiographymentioning

confidence: 99%

“…Western blots were performed on lung tissue as previously described (12). Briefly, lung tissue was suspended in RIPA buffer containing protease and phosphatase inhibitors and sonicated on ice.…”

Section: Measurement Of Right Ventricular Hypertrophy (Rvh)mentioning

confidence: 99%

“…Neonatal rats exposed to hyperoxia (75-95% O 2 ) for 14 days develop PH, RVH, pulmonary vascular remodeling, and alveolar simplification characteristic of preterm infants with BPD (11). We have shown in a novel rodent model that PNGR, achieved by increasing litter size from 10 to 17 pups, triggers PH and amplifies the adverse effects of hyperoxia at 2 weeks of age (12,13). This age is roughly equivalent to a human infant at 6-12 months (14), a common time of death for premature infants with PH.…”

Section: Introductionmentioning

confidence: 99%

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Intestinal Dysbiosis and the Developing Lung: The Role of Toll-Like Receptor 4 in the Gut-Lung Axis

et al. 2020

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Background: In extremely premature infants, postnatal growth restriction (PNGR) is common and increases the risk of developing bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH). Mechanisms by which poor nutrition impacts lung development are unknown, but alterations in the gut microbiota appear to play a role. In a rodent model, PNGR plus hyperoxia causes BPD and PH and increases intestinal Enterobacteriaceae, Gram-negative organisms that stimulate Toll-like receptor 4 (TLR4). We hypothesized that intestinal dysbiosis activates intestinal TLR4 triggering systemic inflammation which impacts lung development. Methods: Rat pups were assigned to litters of 17 (PNGR) or 10 (normal growth) at birth and exposed to room air or 75% oxygen for 14 days. Half of the pups were treated with the TLR4 inhibitor TAK-242 from birth or beginning at day 3. After 14 days, pulmonary arterial pressure was evaluated by echocardiography and hearts were examined for right ventricular hypertrophy (RVH). Lungs and serum samples were analyzed by western blotting and immunohistochemistry. Results: Postnatal growth restriction + hyperoxia increased pulmonary arterial pressure and RVH with trends toward increased plasma IL1β and decreased IκBα, the inhibitor of NFκB, in lung tissue. Treatment with the TLR4 inhibitor attenuated PH and inflammation. Conclusion: Postnatal growth restriction induces an increase in intestinal Enterobacteriaceae leading to PH. Activation of the TLR4 pathway is a promising mechanism by which intestinal dysbiosis impacts the developing lung.

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Section: Animalsmentioning

confidence: 99%

Section: Echocardiographymentioning

confidence: 99%

Section: Measurement Of Right Ventricular Hypertrophy (Rvh)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Intestinal Dysbiosis and the Developing Lung: The Role of Toll-Like Receptor 4 in the Gut-Lung Axis

et al. 2020

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“…Further, the postnatal growth restriction resulting from insufficient total calories that is commonly observed in premature infants 98, 99 may represent an additional risk factor 100 , with evidence suggesting that adequate intake of protein 101 , fat 102 , and specific vitamins 103–106 are particularly important. Data from animals models 107–109 suggest that pre- and postnatal growth restriction alters antioxidant activity 110 , surfactant production 111 , pulmonary endothelial function 112 , and biologic pathways that regulate pulmonary vascular growth 113 . Despite these broad effects on key developmental pathways, recent clinical trials to optimize nutrition in preterm infants have demonstrated little or no impact on the incidence of BPD 114–117 , with the exception of Vitamin A supplementation, which is associated with a small decrease in the risk of developing BPD 118 .…”

Section: Injurious Stimuli That Disrupt Late Lung Developmentmentioning

confidence: 99%

Can We Understand the Pathobiology of Bronchopulmonary Dysplasia?

Alvira

Morty

2017

The Journal of Pediatrics

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Postnatal growth restriction impairs rat lung structure and function

Zhao

Ballard

Cohen

et al. 2023

The Anatomical Record

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The negative impact of nutritional deficits in the development of bronchopulmonary dysplasia is well recognized, yet mechanisms by which nutrition alters lung outcomes and nutritional strategies that optimize development and protect the lung remain elusive. Here, we use a rat model to assess the isolated effects of postnatal nutrition on lung structural development without concomitant lung injury. We hypothesize that postnatal growth restriction (PGR) impairs lung structure and function, critical mediators of lung development, and fatty acid profiles at postnatal day 21 in the rat. Rat pups were cross‐fostered at birth to rat dams with litter sizes of 8 (control) or 16 (PGR). Lung structure and function, as well as serum and lung tissue fatty acids, and lung molecular mediators of development, were measured. Male and female PGR rat pups had thicker airspace walls, decreased lung compliance, and increased tissue damping. Male rats also had increased lung elastance, increased lung elastin protein abundance, and lysol oxidase expression, and increased elastic fiber deposition. Female rat lungs had increased conducting airway resistance and reduced levels of docosahexaenoic acid in lung tissue. We conclude that PGR impairs lung structure and function in both male and female rats, with sex‐divergent changes in lung molecular mediators of development.

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Postnatal growth restriction augments oxygen-induced pulmonary hypertension in a neonatal rat model of bronchopulmonary dysplasia

Abstract: PNGR induces right ventricular and pulmonary vascular remodeling and augments the effects of oxygen in neonatal rats. This may be a powerful tool to investigate the mechanisms that induce PH in low-birth-weight preterm infants with BPD.

Cited by 37 publications

References 41 publications

Intestinal Dysbiosis and the Developing Lung: The Role of Toll-Like Receptor 4 in the Gut-Lung Axis

Intestinal Dysbiosis and the Developing Lung: The Role of Toll-Like Receptor 4 in the Gut-Lung Axis

Can We Understand the Pathobiology of Bronchopulmonary Dysplasia?

Postnatal growth restriction impairs rat lung structure and function

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