Pharmacological models and approaches for pathophysiological conditions associated with hypoxia and oxidative stress

Abstract

Hypoxia is the failure of oxygenation at the tissue level, where the reduced oxygen delivered is not enough to satisfy tissue demands. Metabolic depression is the physiological adaptation associated with reduced oxygen consumption, which evidently does not cause any harm to organs that are exposed to acute and short hypoxic insults. Oxidative stress (OS) refers to the imbalance between the generation of reactive oxygen species (ROS) and the ability of endogenous antioxidant systems to scavenge ROS, where ROS overwhelms the antioxidant capacity. Oxidative stress plays a crucial role in the pathogenesis of diseases related to hypoxia during intrauterine development and postnatal life. Thus, excessive ROS are implicated in the irreversible damage to cell membranes, DNA, and other cellular structures by oxidizing lipids, proteins, and nucleic acids. Here, we describe several pathophysiological conditions and in vivo and ex vivo models developed for the study of hypoxic and oxidative stress injury. We reviewed existing literature on the responses to hypoxia and oxidative stress of the cardiovascular, renal, reproductive, and central nervous systems, and discussed paradigms of chronic and intermittent hypobaric hypoxia. This systematic review is a critical analysis of the advantages in the application of some experimental strategies and their contributions leading to novel pharmacological therapies.

Introduction

Disorders characterized by hypoxia, such as myocardial infarction, stroke, peripheral vascular disease, and renal ischemia, are among the most frequent causes of morbidity and mortality (Foltynie & Kahan, 2013). Moreover, during development, chronic hypoxia may cause intrauterine growth restriction (IUGR) and markedly affect the functions of the newly developed organs (Fowden et al., 2006). Hypoxia is defined as the threshold where the oxygen concentration is a limiting factor for normal cellular processes since oxygen is an essential component for metabolism, including ATP synthesis. Furthermore, the integration of local responses defines hypoxia as a paradigm of reactions affecting the whole organism (Kwasiborski et al., 2012). Subsequently, an oxygen gradient arises between affected and non-affected tissues, stimulating the migration and proliferation of endothelial cells and fibroblasts, which intend to reconstitute normal oxygen supply by increasing perfusion (Nauta et al., 2014). If this process fails, a prolonged inadequate vascular supply of oxygen leads to chronic hypoxia and can cause chronic diseases. Further, intrauterine chronic hypoxia may increase the risk of developing cardiovascular disease later in life, with cardiovascular impairment and endothelial dysfunction (Giussani & Davidge, 2013).

Several difficulties exist in translating basic science findings into clinical practice. For instance, patients usually have marked differences in hypoxia or ischemia duration, concomitant disease, age diversity, co-morbidities, and the medications used. Therefore, accurately representing the clinical situation when establishing an animal model, is a challenge. Moreover, animal models need to account for the differences in response and species-specific reactions in relation to hypoxia (Garcia-Dorado et al., 2009). Despite these limitations, results from animal studies have allowed us to gain considerable insight into the mechanisms of specific phenomena, aiding the design of clinical trials using new pharmacological approaches. The major advantages of hypoxic animal models include highly reliable mechanistic experimental data and the conservation of responses among mammalians.

The findings from animal-based research can establish a cause–effect relationship between a hypoxic protocol and endpoints, such as, reduction in cell death, function improvement, and tissue structure maintenance. This review describes some models for mechanistic studies in pathophysiological states, where the main means of damage are the induction of hypoxia and oxidative stress (OS).