Effects of Chronic Hypercapnia in the Neonatal Mouse Lung and Brain

Das, Sumon Kumar; Du, Zhongfang; Bassly, Shira; Singer, Lewis P.; Vicencio, Alfin G.

doi:10.1002/ppul.20971

Cited by 8 publications

(4 citation statements)

References 30 publications

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“…In neonatal mice, chronic exposure to 8% CO 2 from birth has been reported to induce changes in lung morphology consistent with accelerated maturation, including thinning of alveolar walls and increased secondary septation (13). Taken together, these observations sound a note of caution that the risks vs. benefits of chronic hypercapnia for long-term lung development, function, and susceptibility to lung injury remain unclear and require further study.…”

Section: Discussionmentioning

confidence: 77%

Therapeutic hypercapnia prevents bleomycin-induced pulmonary hypertension in neonatal rats by limiting macrophage-derived tumor necrosis factor-α

Sewing

Kantores

Ivanovska

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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Sewing AC, Kantores C, Ivanovska J, Lee AH, Masood A, Jain A, McNamara PJ, Tanswell AK, Jankov RP. Therapeutic hypercapnia prevents bleomycin-induced pulmonary hypertension in neonatal rats by limiting macrophage-derived tumor necrosis factor-␣. Am J Physiol Lung Cell Mol Physiol 303: L75-L87, 2012. First published May 11, 2012; doi:10.1152/ajplung.00072.2012.-Bleomycin-induced lung injury is characterized in the neonatal rat by inflammation, arrested lung growth, and pulmonary hypertension (PHT), as observed in human infants with severe bronchopulmonary dysplasia. Inhalation of CO2 (therapeutic hypercapnia) has been described to limit cytokine production and to have anti-inflammatory effects on the injured lung; we therefore hypothesized that therapeutic hypercapnia would prevent bleomycin-induced lung injury. Spontaneously breathing rat pups were treated with bleomycin (1 mg/kg/d ip) or saline vehicle from postnatal days 1-14 while being continuously exposed to 5% CO2 (PaCO 2 elevated by 15-20 mmHg), 7% CO2 (PaCO 2 elevated by 35 mmHg), or normocapnia. Bleomycin-treated animals exposed to 7%, but not 5%, CO2, had significantly attenuated lung tissue macrophage influx and PHT, as evidenced by normalized pulmonary vascular resistance and right ventricular systolic function, decreased right ventricular hypertrophy, and attenuated remodeling of pulmonary resistance arteries. The level of CO2 neither prevented increased tissue neutrophil influx nor led to improvements in decreased lung weight, septal thinning, impaired alveolarization, or decreased numbers of peripheral arteries. Bleomycin led to increased expression and content of lung tumor necrosis factor (TNF)-␣, which was found to colocalize with tissue macrophages and to be attenuated by exposure to 7% CO2. Inhibition of TNF-␣ signaling with the soluble TNF-2 receptor etanercept (0.4 mg/kg ip from days 1-14 on alternate days) prevented bleomycin-induced PHT without decreasing tissue macrophages and, similar to CO2, had no effect on arrested alveolar development. Our findings are consistent with a preventive effect of therapeutic hypercapnia with 7% CO2 on bleomycin-induced PHT via attenuation of macrophage-derived TNF-␣. Neither tissue macrophages nor TNF-␣ appeared to contribute to arrested lung development induced by bleomycin. That 7% CO2 normalized pulmonary vascular resistance and right ventricular function without improving inhibited airway and vascular development suggests that vascular hypoplasia does not contribute significantly to functional changes of PHT in this model. carbon dioxide; inflammation; neonatal lung injury BRONCHOPULMONARY DYSPLASIA (BPD) is a chronic pneumopathy affecting extremely premature infants who frequently require supplemental oxygen and/or mechanical ventilation. The incidence of BPD is inversely proportional to the gestational age at which infants are born, with an incidence approaching 60% in the smallest survivors (4). The cardinal feature of BPD, as observed in the current era, is an inhibition or arrest of alveolar and ...

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Section: Discussionmentioning

confidence: 77%

Therapeutic hypercapnia prevents bleomycin-induced pulmonary hypertension in neonatal rats by limiting macrophage-derived tumor necrosis factor-α

Sewing

Kantores

Ivanovska

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Increased cortical neuronal nuclei apoptosis was described in hypercapnic (PaCO 2 > 65 mm Hg) newborn pigs ( 33 ). Das et al ( 34 ) demonstrated increased TUNEL-positive cells in developing brain of neonatal mouse pups exposed to chronic hypercapnia (6 days exposed to 8% CO 2 ).…”

Section: Discussionmentioning

confidence: 99%

Does prolonged severe hypercapnia interfere with normal cerebrovascular function in piglets?

et al. 2018

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Background Hypercapnia causes cerebral vasodilation and increased cerebral blood flow (CBF). During prolonged hypercapnia it is unknown whether cerebral vasodilation persists and whether cerebrovascular function is preserved. We investigated the effects of prolonged severe hypercapnia on pial arteriolar diameters (PAD) and cerebrovascular reactivity to vasodilators and vasoconstrictors. Methods Piglets were anesthetized, intubated and ventilated. Closed cranial windows were implanted to measure PAD. Changes in PAD were documented during hypercapnia (PaCO2 75–80 mm Hg). Cerebrovascular reactivity was documented during normocapnia and at 30, 60 and 120 min of hypercapnia. Results Cerebral vasodilation to hypercapnia was sustained over 120 min. Cerebrovascular responses to vasodilators and vasoconstrictors were preserved during hypercapnia. During hypercapnia, vasodilatory responses to second vasodilators were similar to normocapnia, while exposure to vasoconstrictors caused significant vasoconstriction. Conclusions Prolonged severe hypercapnia causes sustained vasodilation of pial arteriolar diameters indicative of hyperperfusion. During hypercapnia, cerebral vascular responses to vasodilators and vasoconstrictors were preserved, suggesting that cerebral vascular function remained intact. Of note, cerebral vessels during hypercapnia were capable of further dilation when exposed to additional cerebral vasodilators and, significant vasoconstriction when exposed to vasoconstrictors. Extrapolating these findings to infants, we suggest that severe hypercapnia should be avoided, because it could cause/increase cerebrovascular injury.

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“…Increased arterial carbon dioxide levels have been associated with beneficial effects after experimental brain injury in the past. [2][3][4] The effects of mild respiratory acidosis in prevention as well as recovery from organ system damage have previously been studied in the heart, lung, and immune systems, [5][6][7][8][9] and permissive hypercapnia is part of today's clinical practice of low tidal volume ventilation to improve the outcome of patients with acute lung injury. 10 Interestingly, the current American Heart Association Guidelines recommend 12-15 breaths/min during cardiopulmonary resuscitation and stress the potential negative role of inadvertent hyperventilation on survival.…”

Section: "Therapeutic Hypercapnia" After Ischemic Brain Injurymentioning

confidence: 99%

“Therapeutic Hypercapnia” after Ischemic Brain Injury

Brambrink¹,

Orfanakis²

2010

Anesthesiology

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Effects of Chronic Hypercapnia in the Neonatal Mouse Lung and Brain

Abstract: Exposure to chronic hypercapnia may lead to early initiation of alveolar budding in the neonatal mouse, but may also lead to increased TUNEL-positive cells in the developing brain.

Cited by 8 publications

References 30 publications

Therapeutic hypercapnia prevents bleomycin-induced pulmonary hypertension in neonatal rats by limiting macrophage-derived tumor necrosis factor-α

Therapeutic hypercapnia prevents bleomycin-induced pulmonary hypertension in neonatal rats by limiting macrophage-derived tumor necrosis factor-α

Does prolonged severe hypercapnia interfere with normal cerebrovascular function in piglets?

“Therapeutic Hypercapnia” after Ischemic Brain Injury

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