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This issue of the Journal of Applied Physiology marks the beginning of the second of the Highlighted Topics series, "Hypoxia Influence on Gene Expression." As with the previous series on "Molecular and Cellular Basis of Exercise Adaptations," we are hoping to shape the overall scope of the Journal and define areas of emphasis. Accordingly, our call for papers in this area has attracted the submission of a number of outstanding manuscripts. Some of these manuscripts have been selected early in the review process to be highlighted because of the potential impact in this area of investigation. Commentaries on two of these articles are included in this issue. Also included in this series is a Historical Perspectives article by Dr. Sukhamay Lahiri that examines the foundations of research in cellular oxygen sensing and responses to hypoxia.

Hypoxia is a life-threatening stress that must be dealt with at both the cellular and systemic level. Whereas hypoxia is the natural consequence of some environments (e.g., high altitude, diving), it is also a common feature of many clinical diseases or syndromes ranging from inadequate respiration (e.g., sleep apnea syndrome, chronic obstructive pulmonary disease) to inadequate delivery of oxygen (e.g., heart failure, vascular diseases, stroke) and to inadequate oxygen extraction or utilization by tissues (e.g., sepsis, metabolic myopathies).

Many species live with hypoxia as an everyday occurrence, and they express a multitude of adaptive responses at the cellular, molecular, and systemic levels as strategies to minimize the injurious effects of hypoxia. The more successful the adaptation, the more hypoxia tolerant the animal and the less successful, the more hypoxia sensitive. Of particular importance to humans is a relatively high incidence of obstructive sleep apnea syndrome, which in the United States alone affects more than 15 million people, with an incidence of ~9% in women and ~24% in men. There are also about 5.5 million people in the United States with chronic obstructive pulmonary disease, which is the fifth most common cause of death in people over 55. Therefore, an understanding of the adaptive strategies to hypoxia could provide useful clues for developing therapeutic interventions.

Although the adaptive strategies of animals to hypoxia may alter physiological functions at many levels, we have specifically focused on the hypoxia-induced up- or downregulation of specific gene products. The first issue of this Highlighted Topics series on hypoxia features two mini-reviews that focus on the adaptive response to hypoxia at the gene level. In the first mini-review, Dr. Gregg L. Semenza focuses on hypoxia-inducible factor-1, known to be responsible for orchestrating a large number of hypoxia-sensitive responses by binding to upstream elements on a number of genes to regulate their transcription. The induction of these gene products is critical for eliciting the functional adaptations to hypoxia (e.g., erythropoietin, heme oxygenase-1). Future questions in this area would relate to what other genes are sensitive to hypoxia and how would we find them. A number of exciting new approaches are being developed to identify hypoxia-sensitive elements both in terms of technology (e.g., gene chip and differential arrays) and unique animal models (e.g., genetically engineered mice, C. elegans, and Drosophila). In the second mini-review, Dr. Gabriel G. Haddad focuses on one of these new, exciting experimental approaches by addressing how Drosophila genetics can be used to identify genes that render hypoxia tolerance and by discussing how this genetic approach can be further exploited to dissect the mechanisms for adaptive responses to hypoxia.

A direct effect of hypoxia on gene regulation is not the only determinant of hypoxia-adaptive responses. Cellular metabolism is critically dependent on aerobic pathways for energy production and scavenger pathways to eliminate the destructive oxygen species that are generated as by-products of aerobic metabolism. The oxygen sensitivity of these mitochondrial pathways and their ability to prevent or cause cell injury and/or cell death are fundamental parts of the ultimate strategy to survive the deleterious effects of hypoxia. This raises important questions: How do these pathways sense hypoxia and what adaptive processes are initiated? In the second issue of this Highlighted Topics series, we will feature two mini-reviews that explore how mitochondrial pathways sense and adapt to changes in oxygenation.

In the third and final issue of this Highlighted Topics series, we will feature two mini-reviews that explore integrative and systemic adaptive responses to hypoxia, which require specialized chemosensitive elements that detect changes in the level of oxygenation and provide feedback via mechanisms that include changes in ion channel activation, the production of oxygen sensing proteins, and changes in metabolic pathways involving cytochrome oxidase. One of the mini-reviews will address a current view of the oxygen-sensing mechanism of the carotid body, and the second will focus on the developmental consequences of oxygen sensitivity of the carotid body.

The next three issues of the Journal will begin to explore a fundamentally important area of applied physiology: adaptive responses to the macro- and microenvironment of hypoxia. The mini-reviews and highlighted articles in this series only scratch the surface of this important area of investigation. The Associate Editors and I hope that this Highlighted Topics series on hypoxia will provide a stimulus for the submission of more manuscripts that explore the genetic, cellular, and integrative responses to hypoxia.