Serial Review: Redox Signaling in Immune Function and Cellular Responses in Lung Injury and Diseases Serial Review Editors: Victor Darley-Usmar, Lin MantellHyperoxia-induced signal transduction pathways in pulmonary epithelial cells☆
Introduction
Oxygen is required to sustain aerobic life. Supraphysiological concentrations of O2 (hyperoxia) are routinely used to prevent or treat hypoxemia and acute respiratory failure [1], [2]. However, prolonged exposure to hyperoxia can result in tissue damage in many organs, including lungs, and lead to the development of both acute and chronic lung injury [3], [4]. The lung is particularly vulnerable to exogenous oxidative inhalants because of its large epithelial surface and anatomic location. Hyperoxia-induced damage is characterized by an extensive inflammatory response, destruction of the alveolar-capillary barrier, impaired gas exchange, and pulmonary edema [5].
Significant progress has been made in delineating the regulatory and functional elements of hyperoxic lung injury. Pulmonary epithelial cells are essential in maintaining the integrity of the alveolar-capillary barrier and serve as a first line of defense against a variety of insults, including excessive oxygen. In hyperoxic animals, however, injury and death of pulmonary epithelium are prominent [6].
The molecular mechanisms leading to pulmonary cell death in hyperoxia are regulated at several levels. First, oxygen toxicity is believed to be mediated by the production and accumulation of excessive ROS, such as superoxide (O2−), hydrogen peroxide (H2O2), and hydroxyl radical (HO) at levels exceeding the capacity of the lung antioxidant defense mechanisms [7], [8], [9]. The nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system, in conjunction with mitochondria, is a major site of ROS generation during hyperoxia [10], [11], [12], [13].
Excessive ROS can directly damage cellular macromolecules, resulting in cell cycle arrest and/or cell death [14], [15], [16]. In addition, exposure to hyperoxia triggers an inflammatory response, which exacerbates oxidative toxicity [17]. On exposure to hyperoxia, ROS evoke pulmonary cells to increase the secretion of chemoattractants and other proinflammatory cytokines that leads to leukocyte recruitment to the lung. Recruited leukocytes, including neutrophils and monocytes, accumulate within the pulmonary circulation, interstitium, and air spaces, and are significant sources of additional ROS, as well as proteinases, and antimicrobial peptides [18], [19], [20], [21]. Therefore, the interactions between ROS and leukocytes establish a vicious cycle that initiates and/or exacerbates lung injury. In this series of reviews, Dr. Downey and colleagues discuss the role of ROS in neutrophil functions and the effects of inflammation on lung injury. In this review, we focus on the recent advances on signaling pathways that modulate epithelial responses to hyperoxia and their implications in inflammatory responses in hyperoxic lungs.
Section snippets
Pulmonary epithelial cell death in hyperoxia
Pulmonary epithelial cells are essential in maintaining the homeostasis of pulmonary functions. Damage to these cells can lead to dysfunction and injury of the lung [22], [23]. Under physiological conditions, proliferation and death of lung epithelial cells are under stringent control. However, the production of excessive ROS during exposure to prolonged hyperoxia can trigger the injury and death of epithelial cells in hyperoxic animal lungs and in cell culture model systems [10], [11], [24],
Expression of regulatory genes in hyperoxic cell death
With the hope that one can mitigate injury by specifically blocking deleterious pathways that lead to hyperoxic epithelial cell death, a significant effort has been made in the identification of these biochemical pathways and cell death mediators. It is becoming clear that hyperoxia-induced epithelial cell death can be regulated by a variety of factors. The major subfamily members of mitogen-activated protein kinases (MAPKs) include extracellular signal regulated kinase (ERK1/2), c-Jun
Redox transcription factors in pulmonary hyperoxic cell death
Hyperoxic lung injury is associated with the activation of a number of transcription factors, including NF-κB, AP-1, and signal transducers and activators of transcription (STAT) [56]. Emerging evidence has demonstrated that these transcription factors play important roles in regulating pulmonary responses, including pulmonary cell death following hyperoxic exposure [16], [68]. Understanding the roles of these transcriptional factors in modulating the death of pulmonary epithelial cells may
Proinflammatory responses in hyperoxic lung injury
Hyperoxia-induced lung injury is the product of direct toxicity of ROS and indirect effects of the properties and products of activated resident and recruited inflammatory cells. The accumulation of leukocytes in lung tissues of patients with severe inflammatory lung injury is thought to significantly contribute to the development of acute lung injury [110]. It is believed that hyperoxia-induced acute lung injury is initiated by ROS. However, the more severe injury is associated with extensive
Transcription factors and proinflammatory cytokines in hyperoxia
Under normal physiological conditions, a highly intricate network of transcription factors regulates the balance of the gene expression of proinflammatory and anti-inflammatory cytokines. However, this balance is perturbed under pathological conditions, resulting in an overwhelming proinflammatory activity [134]. Among the transcription factors involved in modulating proinflammatory responses, NF-κB is the most important one under hyperoxic conditions, although recent data have also implicated
Conclusions
In summary, hyperoxia-induced epithelial cell death and leukocyte infiltration play essential roles in the pathogenesis of hyperoxic lung injury. Both events are consequences of many complicated and overlapping signaling pathways, including those that are mediated by MAPKs and redox transcription factors, especially NF-κB (Fig. 1). Hyperoxia-induced damage to pulmonary epithelial cells involves multimodal cell death via both apoptotic and nonapoptotic mechanisms. Despite extensive studies
Acknowledgments
We thank Dr. Charles R. Ashby Jr., Thi Le, and Nicole Palma for insightful discussion and invaluable suggestions on this manuscript. The authors are supported by grants from ALANYS, NIH, St. John’s University College of Pharmacy, and the Feinstein Institute for Medical Research at North Shore-Long Island Jewish Health System.
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This article is part of a series of reviews on “Redox signaling in immune function and cellular responses in lung injury and diseases.” The full list of papers may be found on the home page of the journal.