Chest
Laboratory and Animal InvestigationsNeonatal Exposure to 65% Oxygen Durably Impairs Lung Architecture and Breathing Pattern in Adult Mice*
Section snippets
Mice
Six Swiss female mice (IFFA-CREDO; L’Arbresle, France) were housed at 24°C with a 12 h/12h light/dark cycle and food and water ad libitum. These female mice were mated with Swiss male mice. Three pregnant females were randomly assigned to the hyperoxic group, and three pregnant females were assigned to the normoxic group. The hyperoxic female mice gave birth to 24 pups (10 males and 14 females), and the normoxia female mice gave birth to 19 pups (10 males and 9 females). Experimental protocols
Weight
The hyperoxic mice showed normal aspect and behavior. Neither weight, which increased normally with PNA (Fig 1), nor rectal temperature, which remained steady throughout the study period, was significantly different in hyperoxic and normoxic mice (37.5 ± 0.6°C vs 37.4 ± 0.3°C).
Breathing Pattern
Baseline Vt and Ttot were slightly but significantly larger in hyperoxic mice than in normoxic mice at all PNAs (Fig 2). The longer Ttot values in hyperoxic mice were caused by significantly longer Ti and expiratory
Discussion
This study shows that 28-day postnatal exposure to 65% O2 in mice causes long-term changes in pulmonary structure and breathing pattern. Seven months after 65% O2 hyperoxic exposure, the mice had reduced alveolarization, enlarged alveolar spaces, fibrotic lesions, increased Crs, lower baseline breathing frequency, and larger Vt than normoxic control mice. In contrast, hyperoxic exposure did not cause major impairments of respiratory homeostasis, as suggested by blood gas values, baseline
Conclusion
Hyperoxic exposure during lung septation in mice may cause irreversible lung injury and breathing pattern abnormalities in adulthood at O2 concentrations lower than previously thought. However, ventilatory function and body growth were preserved, and ventilatory function showed no major abnormalities, at least at rest, despite early oxygen-induced injuries.
ACKNOWLEDGMENT
We thank Dr. Caroline Rambaud (Service d’Anatomo-Pathologie, Hôpital Antoine-Béclère, Université Paris XI) for her careful reading of a previous version of the article.
REFERENCES (58)
- et al.
A theoretical analysis of the barometric method for measurement of tidal volume
Respir Physiol
(1978) - et al.
The effects of restraint on ventilatory responses to hypercapnia and hypoxia in adult mice
Respir Physiol
(1998) - et al.
The postnatal development and growth of the human lung: II. Morphology
Respir Physiol
(1987) - et al.
The senile lung: comparison with normal and emphysematous lungs; 2. Functional aspects
Chest
(1992) - et al.
The senile lung: comparison with normal and emphysematous lungs; 1. Structural aspects
Chest
(1992) - et al.
Neonatal conditioning for adult respiratory behavior
Respir Physiol
(1997) - et al.
Pathology of arrested acinar development in postsurfactant bronchopulmonary dysplasia
Hum Pathol
(1998) - et al.
Differential effects of inhaled nitric oxide and hyperoxia on pulmonary dysfunction in newborn guinea pigs
Am J Physiol Regul Integr Comp Physiol
(2000) - et al.
Functional and pathological effects of prolonged hyperoxia in neonatal mice
Am J Physiol
(1998) - et al.
The formation of alveoli in rat lung during the third and fourth postnatal weeks: effect of hyperoxia, dexamethasone, and deferoxamine
Pediatr Res
(1993)
Development of gas-exchange surface area in rat lung: the effect of alveolar shape
Am J Respir Crit Care Med
Protection against acute and chronic hyperoxic inhibition of neonatal rat lung development with the 21-aminosteroid drug U74389F
Pediatr Res
Effects of retinoic acid on airspace development and lung collagen in hyperoxia-exposed newborn rats
Pediatr Res
The development of the newborn rat lung in hyperoxia: a dose-response study of lung growth, maturation, and changes in antioxidant enzyme activities
Pediatr Res
Pulmonary injury in rats following continuous exposure to 60% O2 for 7 days
J Appl Physiol
Leukotrienes are indicated as mediators of hyperoxia-inhibited alveolarization in newborn rats
Am J Physiol
Extracellular superoxide dismutase in the airways of transgenic mice reduces inflammation and attenuates lung toxicity following hyperoxia
J Clin Invest
The effect of 60% oxygen on air-space enlargement and cross-linked elastin synthesis in hamsters with elastase-induced emphysema
Am Rev Respir Dis
Blunted peripheral chemoreceptor response to hyperoxia in a group of infants with bronchopulmonary dysplasia
Pediatr Pulmonol
Development of peripheral chemoreceptor function in infants with chronic lung disease and initially lacking hyperoxic response
Arch Dis Child Fetal Neonatal Ed
Pulmonary function until two years of life in infants with bronchopulmonary dysplasia
Am J Respir Crit Care Med
Retinoic acid receptor-β: an endogenous inhibitor of the perinatal formation of pulmonary alveoli
Physiol Genomics
Genetic control of differential baseline breathing pattern
J Appl Physiol
Pulmonary fibrosis and chronic lung inflammation in ET-1 transgenic mice
Am J Respir Cell Mol Biol
Blood ammonia concentration in mice: normal reference values and changes during growth
Lab Anim Sci
Extracellular matrix and oscillatory mechanics of rat lung parenchyma in bleomycin-induced fibrosis
Am J Respir Crit Care Med
The radial alveolar count method of Emery and Mithal: a reappraisal 1; postnatal lung growth
Thorax
Postnatal development of alveoli: regulation and evidence for a critical period in rats
J Clin Invest
Postnatal treatment with retinoic acid increases the number of pulmonary alveoli in rats
Am J Physiol
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Neonatal hyperoxia promotes asthma-like features through IL-33–dependent ILC2 responses
2018, Journal of Allergy and Clinical ImmunologyLong-term pulmonary and cardiovascular morbidities of neonatal hyperoxia exposure in mice
2018, International Journal of Biochemistry and Cell BiologyCitation Excerpt :Excessive supplemental oxygen (O2) use or hyperoxia leads to BPD and PH by disrupting growth factor signaling, extracellular matrix assembly, cell proliferation, and vasculogenesis (Madurga et al., 2013). Several studies (Aslam et al., 2009; Chen et al., 2011; Lee et al., 2013), including ours (Reynolds et al., 2016), have demonstrated that hyperoxia-induced lung parenchymal and vascular injury in neonatal mice leads to a phenotype similar to that of human BPD with PH. Moreover, preclinical studies have consistently shown that neonatal hyperoxia exposure causes decreased alveolarization and lung vascularization that persists into adulthood (Dauger et al., 2003; Mankouski et al., 2017; O'Reilly et al., 2014; Wilson et al., 1985; Yee et al., 2011). However, whether this exposure similarly causes PH and RV dysfunction in adulthood is not well studied.
Ventilatory and chemoreceptor responses to hypercapnia in neonatal rats chronically exposed to moderate hyperoxia
2017, Respiratory Physiology and NeurobiologyAltered lung function at mid-adulthood in mice following neonatal exposure to hyperoxia
2015, Respiratory Physiology and NeurobiologyCitation Excerpt :In addition, neonatal hyperoxia can increase airway smooth muscle (ASM) deposition and increase airway reactivity (Belik et al., 2003; Denis et al., 2001; O'Reilly et al., 2014b). Long-term studies in rodents suggest that, not only do these structural alterations remain evident in early adulthood, but that neonatal hyperoxia also affects lung function at this age, as evidenced by altered lung compliance (Dauger et al., 2003; O'Reilly et al., 2014a; Yee et al., 2009). We have recently shown that changes in lung structure in mice exposed to neonatal hyperoxia not only persist with advancing age, but actually appear to worsen (O'Reilly et al., 2014b).
Effects of hyperoxic exposure on signal transduction pathways in the lung
2015, Respiratory Physiology and NeurobiologyCitation Excerpt :Moreover, most animal models of BPD involve hyperoxic exposure, such as with premature baboons, or newborn rats or mice in the early postnatal period. From a histopathological point of view, hyperoxia disrupts postnatal alveolar development, which leads to smaller numbers of enlarged and simplified alveoli, thicker septa, and an increase in alveolar macrophages (e.g., Dauger et al., 2003; Balasubramaniam et al., 2007; Porzionato et al., 2012a, 2013a; Grisafi et al., 2012, 2013). Experimental hyperoxic models of BPD also result in changes in microvascular development and thickening of the medial muscle layer of arteries, with pulmonary hypertension (e.g., Jones et al., 1984; Koppel et al., 1994; Porzionato et al., 2012a, 2013a; Grisafi et al., 2012, 2013).
This study was supported by the Institut National de la Santé et de la Recherche Médicale (grant awarded to Dr. Dauger), and the Université Paris VII (Legs Poix).