Antioxidant Therapeutic Approaches Toward Amelioration of the Pulmonary Pathophysiological Damaging Effects of Ionizing Irradiation

Abstract

There is increasing evidence that lung irradiation damage is mediated by oxidative stress responses of pulmonary vascular and parenchymal cells. The acute irradiation response involves strand breaks in nuclear DNA, then stress activated protein kinase (SAP-Kinase) transport to mitochondria where lipid peroxidation changes lead to cytochrome-c release and apoptosis. However, secondary cytokine elevations lead to a second wave of apoptosis both directly and indirectly mediated through inflammatory cell infiltrates. A recovery phase and latent period follows wherein little structural or physiological evidence of lung damage is detectable in animal models or in humans. The late effects of irradiation pulmonary fibrosis initiate by unknown triggering events thought to involve not only resident pulmonary endothelial cells, but also recruited bone marrow origin macrophages and progenitors of myofibroblasts, which contribute to the lesion of organizing alveolitis in the mouse model or pulmonary irradiation fibrosis in humans. Oxidative stress markers are elevated during formation of the late lesion in a pattern, which is reminiscent of the acute lesion. The amelioration of both the acute and late pulmonary pathophysiologic changes by administration of antioxidant therapies suggests that similar molecular mechanisms may be involved. This article reviews several bodies of evidence concerning the cause and possible therapeutic strategies, which may be of value in treating ionizing irradiation, induced lung damage.

Research progress in the radioprotective effect of superoxide dismutase

“…This explains the signifi cant role of water in the indirect effects of IR (18). Moreover, it has been demonstrated that the radiationexposed organisms perpetuate elevated levels of ROS (19)(20)(21) (23), which is the most toxic of all ROS responsible for the majority of IR-mediated adverse reactions. Depending on the photochemical reaction between radiation and some endogenous photosensitizers localized in the cellular or mitochondrial membrane, such as nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and xanthine oxidase (24), huge doses of ROS are generated, overwhelming the antioxidant defense system in organisms, which result in a series of serious adverse effects.…”

Antioxidant Approaches to Management of Ionizing Irradiation Injury

“…The mechanism of total body irradiation protection and mitigation by both gene therapy (MnSOD-PL), and small molecule antioxidants (GS-nitroxides) [ 16 , 42 , 57 , 58 , 77 , 79 , 83 , 94 , 95 , 96 , 97 , 104 , 105 , 106 , 107 , 108 ] may not be attributable solely to direct cellular effects. The bystander effect of both radiation injury and amelioration of irradiation damage by radiation mitigator drugs has been well documented in the radiobiology literature [ 76 ].…”

“…Oxidative stress has been shown to be a chronic component of irradiation damage to tissues and organs. These oxidative stress events are detected in the lung years after therapeutic lung irradiation [ 57 ]. In animal models, markers of antioxidant stress are detected in irradiated lungs months after irradiation[ 54 ].…”

“…Initial experiments using free radical scavengers include N -Acetyl-Cysteine (NAC) or the supplement/replenishing of antioxidant stores by delivering glutathione. These methods demonstrated some success in tissue culture and animal models [ 57 , 58 , 59 , 60 , 61 , 62 ]. However, true breakthroughs occurred with the molecular cloning and expression of transgenes for antioxidant enzymes, prominently the superoxide dismutases [ 63 , 64 , 65 , 66 , 67 ].…”

Thioredoxin mitigates radiation-induced hematopoietic stem cell injury in mice

“…Hematopoietic stem cells (HSCs) and hematopoiesis are among the tissues/organs most sensitive to radiation injury and contribute to many of the manifestations of acute radiation injury, including bleeding, infection, and bone marrow failure. Evidence has emerged that excessive reactive oxygen species (ROS) following radiation injury cause HSC apoptosis and senescence and the loss of long-term repopulating capacity [ 6 – 9 ]. However, what remains poorly understood is how to harness the redox pathway for the mitigation of radiation-induced HSC injury.…”