Regular article
The role of hyperoxia in the pathogenesis of experimental BPD

https://doi.org/10.1053/j.semperi.2013.01.002Get rights and content

Abstract

Supplemental oxygen is often used as a life-saving therapy in the treatment of preterm infants. However, its protracted use can lead to the development of bronchopulmonary dysplasia (BPD), and more recently, has been associated with adversely affecting the general health of children and adolescents who were born preterm. Efforts to understand how exposure to excess oxygen can disrupt lung development have historically focused on the interplay between oxidative stress and antioxidant defense mechanisms. However, there has been a growing appreciation for how changes in gene–environment interactions occurring during critically important periods of organ development can profoundly affect human health and disease later in life. Here, we review the concept that oxygen is an environmental stressor that may play an important role at birth to control normal lung development via its interactions with genes and cells. Understanding how changes in the oxygen environment have the potential to alter the developmental programing of the lung, such that it now proceeds along a different developmental trajectory, could lead to novel therapies in the prevention and treatment of respiratory diseases, such as BPD.

Section snippets

Evolution of the lung in response to changing atmospheric levels of oxygen

The geological record indicates that until the present atmospheric level of oxygen was reached, specifically 21%, there were cyclical episodes of low and high oxygen, ranging from as low as 15% to as high as 35%.20 These fluctuating oxygen conditions have been suggested to play a substantial role in the development and evolution of cellular and organismal respiration.20., 21. In fact, the transition from aquatic to terrestrial habitation by vertebrates likely occurred during a time when

Lung development and the undefined use of oxygen in neonatal care

At birth, sufficient development and function of the cardio-respiratory system, the digestive system, and the brain are required for survival. The lung, in particular, is an essential organ in this context, as the developmental maturity of the respiratory system is critical for surviving the transition into air at birth.

Human lung development is typically divided into five stages, including the embryonic (0–6 weeks gestation), pseudoglandular (6–16 weeks gestation), canalicular (16–24 weeks

Vulnerability of the lung to oxygen toxicity

Due to its anatomical location, the respiratory tract epithelium is one of the three tissues (including the cornea and skin) that are exposed to 21% oxygen (a partial pressure of about 160 mmHg), while other tissues of the body are exposed to much lower oxygen tensions.59 As a result, the cells that constitute the lung are primary targets for oxygen-induced injury. In vivo models of hyperoxia have demonstrated in several adult animal species that exposure to high levels of oxygen initially leads

Suitable animal models

Much of what is currently understood about lung development and the pathogenesis of BPD has arisen from animal models of oxidant-mediated lung injury.2 Such models, some better than others, include the rodent, rabbit, lamb and non-human primate. Large-animal models, such as the non-human primate, have been extensively studied since postnatal lung development in non-human primates parallels human lung development. Preterm ventilated baboons delivered at 75% completion of gestation, approximately

Gene–cell–environment interactions

As mentioned earlier, there has been an increased appreciation for the impact of environmental change during development on the occurrence of disease later in life.19 In the context of the lung, orderly development, beginning during embryogenesis and continuing through adolescence, requires the timely expression of key genes and their interaction with specific cell types, as represented in Figure 2. Understanding how the oxygen environment influences these complex developmental interactions has

Summary

Lung development is a complex process that has evolved over time and has been optimized to ensure compatibility with postnatal survival. The purposeful orchestration, or programing, of transcription factors, morphogens, and extracellular matrix molecules in both space and time ensure the formation of a properly functioning lung that will be capable of performing the critical task of gas exchange upon the transition to newborn life. However, factors that interfere with the developmental

Disclosures

The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article.

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    This work was supported by National Institutes of Health Grants HL-067392, HL-091968, and HL-097141 (M.A. O’Reilly). NIH Training Grants ES-07026 and HL-66988 supported B.W. Buczynski, and HD-057821 and Bradford Fellowship Grant supported E.T. Maduekwe.

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