Hypoxic Preconditioning with Cobalt Attenuates Hypobaric Hypoxia-Induced Oxidative Damage in Rat Lungs

Abstract

Shukla, Dhananjay, Saurabh Saxena, Purushotman Jayamurthy, Mustoori Sairam, Mrinalini, Singh, Swatantra Kumar Jain, Anju Bansal, and Govindaswamy Ilavazaghan. High Alt. Med. Biol. 10:57-69, 2009.-Hypoxic preco759nditioning (HPC) provides robust protection against injury from subsequent prolonged hypobaric hypoxia, which is a characteristic of high altitude and is known to induce oxidative injury in lung by increasing the generation of reactive oxygen species (ROS) and decreasing the effectiveness of the antioxidant defense system. We hypothesize that HPC with cobalt might protect the lung from subsequent hypobaric hypoxia-induced lung injury. HPC with cobalt can be achieved by oral feeding of CoCl(2) (12.5 mg kg(-1)) in rats for 7 days. Nonpreconditioned rats responded to hypobaric hypoxia (7619 m) by increased reactive oxygen species (ROS) generation and a decreased GSH/GSSG ratio. They also showed a marked increase in lipid peroxidation, heat-shock proteins (HSP32, HSP70), metallothionins (MT), levels of inflammatory cytokines (TNF-alpha, IFN-gamma, MCP-1), and SOD, GPx, and GST enzyme activity. In contrast, rats preconditioned with cobalt were far less impaired by severe hypobaric hypoxia, as observed by decreased ROS generation, lipid peroxidation, and inflammatory cytokine release and an inceased GSH/GSSG ratio. Increased expression of antioxidative proeins Nrf-1, HSP-32, and MT was also observed in cobalt- preconditioned animals. A marked increase in the protein expression and DNA binding activity of hypoxia-inducible transcriptional factor (HIF-1alpha) and its regulated genes, such as erythropoietin (EPO) and glucose transporter-1 (glut-1), was observed after HPC with cobalt. We conclude that HPC with cobalt enhances antioxidant status in the lung and protects from subsequent hypobaric hypoxia-induced oxidative stress.

Radioprotective effect on HepG2 cells of low concentrations of cobalt chloride: induction of hypoxia-inducible factor-1 alpha and clearance of reactive oxygen species

“…Surprisingly, when combined with irradiation at low or moderate doses, CoCl 2 could reduce the levels of ROS generated by IR, which was confirmed by an increase in cell viability. Toxicological experiments have shown that CoCl 2 protects cells against chemical insults and blocks injury to biological systems, and that induction of the expression of HIF-1α plays an important role in this effect [30, 31]. Similarly, our results show that like hypoxia, CoCl 2 increases levels of HIF-1α and enhances cellular radio-resistance.…”

Tetramethylpyrazine Inhibits Hypoxia-Induced Pulmonary Vascular Leakage in Rats via the ROS-HIF-VEGF Pathway

“…In addition to the protective effect in cell culture, in vivo studies were also performed. We exposed rats to a simulated altitude of 8,000 m for 48 h for the following reasons: (1) smaller animals have higher capillary density in tissue, which makes them more resistant to hypoxia than humans [32] , and (2) most high-altitude-induced problems, such as high-altitude pulmonary edema, generally develop within 2-4 days after arriving at high altitude [33] . Our observation of an increase in lung water content following exposure to hypobaric hypoxia coincided with the reports of earlier investigators [34,35] .…”

Oxidative stress and metal carcinogenesis

“…There are also contrasting findings showing the beneficial roles of Co. Shukla et al [145] revealed that hypoxic preconditioning with Co diminishes hypobaric hypoxia-induced oxidative damage in rat lungs. Co(II) b-ketoaminato complexes exhibited a prospective pharmacological benefit as novel inhibitors of neuroinflammatory processes [146].…”