Respiratory Effects of Gestational Intermittent Hypoxia in the Developing Rat

Gozal, David; Reeves, Stephen R.; Row, Barry W.; Neville, Jennifer J.; Guo, Song; Lipton, Andrew J.

doi:10.1164/rccm.200208-963oc

Cited by 119 publications

(74 citation statements)

References 66 publications

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“…Chronic intermittent hypoxia (CIH) is present in obstructive sleep apnea (OSA), sickle cell anemia and asthma. [1][2][3][4][5][6][7] These various paradigms of hypoxia often result in different consequences on growth and development. Hypoxia leads to many consequences but one that affects individual subjects early in life is growth and development causing growth deficits or cognitive and behavioral abnormalities.…”

Section: Introductionmentioning

confidence: 99%

Differential effects of chronic intermittent and chronic constant hypoxia on postnatal growth and development

Farahani

Kanaan

Gavrialov

et al. 2007

Pediatric Pulmonology

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Summary. Exposure to chronic constant or intermittent hypoxia (CCH or CIH) may have different effects on growth and development in early life. In this work, we exposed postnatal day 2 (P2) CD1 mice to CCH or CIH (11% O 2 ) for 4 weeks and examined the effect of hypoxia on body and organ growth until P30. Regression analysis showed that weight increased in control, CCH and CIH cohorts with age with r 2 values of 0.99, 0.97, and 0.94, respectively. Between days 2 and 30, slopes were 0.93 AE 0.057, 0.76 AE 0.108, and 0.63 AE 0.061 (g/day, means AE SEM) for control, CIH, and CCH, respectively and significantly different from each other (P < 0.001). The slopes between P2 and P16 were 0.78 AE 0.012, 0.46 AE 0.002, and 0.47 AE 0.019 for control, CCH and CIH, respectively. From P16 to 30, slopes were 1.12 AE 0.033, 1.09 AE 0.143, and 0.82 AE 0.08 for control, CIH, and CCH, respectively with no significant difference from each other, suggesting a catch-up growth in the latter part of the hypoxic period. Slower weight gain resulted in a 12% and 23% lower body weight in CIH and CCH mice (P < 0.001) by P30. Lung/body ratios were 0.010, 0.015, 0.015 for control, CIH, and CCH at P30, respectively. The decrease in liver, kidney, and brain weight were greater in CCH than CIH. Smaller liver weight was shown to be due to a reduction in cell size and cell number. Liver in CIH and CCH mice showed a 5% and 10% reduction in cell size (P < 0.05) and a reduction of 28% in cell number (P < 0.001) at P30. In contrast, CCH and CIH heart weight was 13% and 33% greater than control at P30 (P < 0.05), respectively. This increase in the heart weight was due to an increase in the size of cardiomyocytes which showed an increase of 12% and 14% (P < 0.001) for CIH and CCH, respectively as compared to control. Brain weight was 0.48 and 0.46 g for CIH and CCH, respectively (95% and 92% of normal). We concluded that (a) CIH and CCH follow different body and organ growth patterns; (b) mostly with CCH, the liver and kidneys are reduced in size in a proportionate way to body size but heart, lung, and brain are either spared or increased in size compared to body weight; and (c) the decrease in liver is secondary mostly to a decrease in cell number.

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Section: Introductionmentioning

confidence: 99%

Differential effects of chronic intermittent and chronic constant hypoxia on postnatal growth and development

Farahani

Kanaan

Gavrialov

et al. 2007

Pediatric Pulmonology

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“…In rats, the most striking effect of neonatal CIH (10 and 21% O 2 alternating at 90-s intervals, 12 h/day for 30 days beginning on the first postnatal day) is an increase in normoxic ventilation that persists into adulthood, and it may be permanent (84,85); similar effects on normoxic ventilation have been reported following prenatal CIH (40). The magnitude of these effects, and their persistence, decreases with age at onset of exposure and are most pronounced when CIH commences during the first 2 postnatal wk (83,84).…”

Section: Developmental Plasticity In Respiratory Control: Examplesmentioning

confidence: 63%

Long-term effects of the perinatal environment on respiratory control

Bavis¹,

Mitchell²

2008

Journal of Applied Physiology

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The respiratory control system exhibits considerable plasticity, similar to other regions of the nervous system. Plasticity is a persistent change in system behavior triggered by experiences such as changes in neural activity, hypoxia, and/or disease/injury. Although plasticity is observed in animals of all ages, some forms of plasticity appear to be unique to development (i.e., “developmental plasticity”). Developmental plasticity is an alteration in respiratory control induced by experiences during “critical” developmental periods; similar experiences outside the critical period will have little or no lasting effect. Thus complementary experiments on both mature and developing animals are generally needed to verify that the observed plasticity is unique to development. Frequently studied models of developmental plasticity in respiratory control include developmental manipulations of respiratory gas concentrations (O2 and CO2). Environmental factors not specifically associated with breathing may also trigger developmental plasticity, however, including psychological stress or chemicals associated with maternal habits (e.g., nicotine, cocaine). Despite rapid advances in describing models of developmental plasticity in breathing, our understanding of fundamental mechanisms giving rise to such plasticity is poor; mechanistic studies of developmental plasticity are of considerable importance. Developmental plasticity may enable organisms to “fine tune” their phenotype to optimize the performance of this critical homeostatic regulatory system. On the other hand, developmental plasticity could also increase the risk of disease later in life. Future directions for studies concerning the mechanisms and functional implications of developmental plasticity in respiratory motor control are discussed.

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“…Direct comparison of responses to acute intermittent versus continuous hypoxic challenge in piglets showed that the intermittent pattern produced greater decline in respiratory indices (20). In addition, gestational intermittent hypoxia in rats resulted in a decrease of ventilatory responses to subsequent acute hypoxia on p5 (21). One might therefore expect that intermittent recurrent hypoxia in rats throughout the developmental age used in this study would further enhance the decline in ventilatory responses to subsequent acute hypoxia in later life.…”

Section: Discussionmentioning

confidence: 80%

Long-Term Recurrent Hypoxia in Developing Rat Attenuates Respiratory Responses to Subsequent Acute Hypoxia

2006

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Whereas definitive treatment of pediatric conditions associated with hypoxemia reverses many pathologic symptoms, some physiologic dysfunctions appear to persist. These abnormalities are attributed to long-lasting central effects of prior hypoxia. To investigate such effects in an animal model, male rats were exposed to FiO 2 ϭ 0.12 continuously for 7 h daily from postnatal day (p) 17 (representing early childhood) through p33 (representing adolescence), defined as recurrent hypoxia. Respiratory responses during and following 20 min FiO 2 ϭ 0.12 were measured on p35 and p47. To control for early weaning on p15 (normal weaning ϭ p21), male rats were weaned on either p15 or p21, raised in normoxia, and also tested for respiratory responsiveness to acute hypoxia. To assess sex differences, female rats were assigned to similar groups and protocols. Minute ventilation, respiratory frequency, tidal volume, and respiratory drive were measured in unsedated animals using whole-body plethysmography. After recurrent hypoxia, male rats displayed an attenuation of ventilation, frequency, and drive during hypoxia, and of all functions after hypoxia on both p35 and p47. There were no differences between test days during hypoxia, and greater attenuation of tidal volume and respiratory drive on p47 during recovery from hypoxia. Respiratory responses displayed no effect of sex on p35, and occasional effects of early weaning on p35 and p47. Thus, recurrent hypoxia produces long-lasting attenuation in respiratory responsiveness to subsequent acute hypoxia. Such long-lasting attenuation, if present in humans, may diminish the protection of children with a history of recurrent hypoxemia against future hypoxic events. H ypoxemia of varying duration, pattern, and timing is an important feature in many clinical conditions in pediatrics. A strong association or causality between hypoxemia and developmental, behavioral, and/or cognitive dysfunctions has been documented, primarily for sleep-disordered breathing and congenital heart disease (1). With regard to sleepdisordered breathing, the dysfunctions also include sleep fragmentation, diminished arousability, diminished responsiveness to respiratory chemical stimuli, fatigue, failure to thrive, hypertension, and cor pulmonale (2-6).Whereas adenotonsillectomy, a definitive treatment for sleep-disordered breathing associated with enlarged adenoids and/or tonsils, reverses the upper airway obstruction and many sleep-related symptoms in children, recent studies suggest that abnormalities in cardiorespiratory control, arousability, learning, and behavior can persist beyond the relief of such obstruction (4,7-9). These studies have attributed the lingering dysfunctions to long-term central effects of prior hypoxemia associated with more severe obstructive sleep apnea.It is important to establish in controlled animal studies whether there indeed are long-lasting effects of an antecedent hypoxia. It is also important to determine whether such effects, if present, are particular to a spe...

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Respiratory Effects of Gestational Intermittent Hypoxia in the Developing Rat

Cited by 119 publications

References 66 publications

Differential effects of chronic intermittent and chronic constant hypoxia on postnatal growth and development

Differential effects of chronic intermittent and chronic constant hypoxia on postnatal growth and development

Long-term effects of the perinatal environment on respiratory control

Long-Term Recurrent Hypoxia in Developing Rat Attenuates Respiratory Responses to Subsequent Acute Hypoxia

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