Radiation pneumonitis in mice. Some effects of corticosteroids on mortality and pulmonary physiology.

Gross, Nicholas J.

doi:10.1172/jci109881

Cited by 51 publications

(17 citation statements)

References 19 publications

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“…Medical management has been demonstrated to increase the MST for ARS (Jackson et al 1959; MacVittie et al 1991; Perman et al 1962;Bagdasarov et al 1959; Thomas et al 1962;MacVittie et al 2005; Conard et al 1956; Taketa 1962). Similarly, corticosteroid treatment was used in murine models of radiation-induced lung injury to influence survival and has been estimated to have a protection factor of 1.2 (Gross 1980; Gross et al 1988; Libshitz and Shuman 1984). Comparable studies have not been performed in the NHP; therefore, the effect of corticosteroid treatment on survival and MST are unknown at this time.…”

Section: Discussionmentioning

confidence: 99%

The Prolonged Gastrointestinal Syndrome in Rhesus Macaques

MacVittie¹,

Bennett²,

Booth³

et al. 2012

Health Physics

110

126

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The dose response relationship for the acute gastrointestinal syndrome following total-body irradiation prevents analysis of the full recovery and damage to the gastrointestinal system, since all animals succumb to the subsequent 100% lethal hematopoietic syndrome. A partial-body irradiation model with 5% bone marrow sparing was established to investigate the prolonged effects of high-dose radiation on the gastrointestinal system, as well as the concomitant hematopoietic syndrome and other multi-organ injury including the lung. Herein, cellular and clinical parameters link acute and delayed coincident sequelae to radiation dose and time course post-exposure. Male rhesus Macaca mulatta were exposed to partial-body irradiation with 5% bone marrow (tibiae, ankles, feet) sparing using 6 MV linear accelerator photons at a dose rate of 0.80 Gy min−1 to midline tissue (thorax) doses in the exposure range of 9.0 to 12.5 Gy. Following irradiation, all animals were monitored for multiple organ-specific parameters for 180 d. Animals were administered medical management including administration of intravenous fluids, antiemetics, prophylactic antibiotics, blood transfusions, antidiarrheals, supplemental nutrition, and analgesics. The primary endpoint was survival at 15, 60, or 180 d post-exposure. Secondary endpoints included evaluation of dehydration, diarrhea, hematologic parameters, respiratory distress, histology of small and large intestine, lung radiographs, and mean survival time of decedents. Dose- and time-dependent mortality defined several organ-specific sequelae, with LD50/15 of 11.95 Gy, LD50/60 of 11.01 Gy, and LD50/180 of 9.73 Gy for respective acute gastrointestinal, combined hematopoietic and gastrointestinal, and multi-organ delayed injury to include the lung. This model allows analysis of concomitant multi-organ sequelae, thus providing a link between acute and delayed radiation effects. Specific and multi-organ medical countermeasures can be assessed for efficacy and interaction during the concomitant evolution of acute and delayed key organ-specific subsyndromes.

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Section: Discussionmentioning

confidence: 99%

The Prolonged Gastrointestinal Syndrome in Rhesus Macaques

MacVittie¹,

Bennett²,

Booth³

et al. 2012

Health Physics

110

126

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“…Because TNF-a induction is associated with acute and subacute complications of therapeutic radiation, inhibition of phospholipase A2 represents a means of abating these sequelae. Indeed, pharmacologic agents used to ameliorate the acute and subacute sequelae of radiotherapy include glucocorticoids and pentoxifylline (22,23,53). For example, acute effects ofradiation, such as pneumonitis and the central nervous system syndrome, have been abated by these drugs (23).…”

Section: Discussionmentioning

confidence: 99%

Membrane-derived second messenger regulates x-ray-mediated tumor necrosis factor alpha gene induction.

Hallahan

Virudachalam

Kuchibhotla

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

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Cells adapt to adverse environmental conditions through a wide range of responses that are conserved throughout evolution. Physical agents such as Ionizing radiation are known to initiate a stress response that is triggered by the recognition of DNA damage. We have identified a sgnlIng pathway involving the activation of phospholipase A2 and protein kinase C in human cells that confers x-ray induction of the tumor necrosis factor a gene. Treatment of human cells with ionizing radiation or H202 was associated with the production of arachidonic acid. Inhibition of phospholipase A2 abolished radiation-mediated arachidonate production as well as the subsequent activation of protein kinase C and tumor necrosis factor a gene expression. These findings demonstrate that ionizing radiation-mediated gene expression in human cells is regulated in part by extranuclear signal transduction. One practical application of phospholipase A2 inhibitors is to ameliorate the adverse effects of radiotherapy associated with tumor necrosis factor a production.Signaling pathways activated by DNA (4,5). The complexity ofthis signaling pathway is demonstrated by the number of genes involved in sensing DNA damage and transmitting the signal (5). DNA damage is presumed to be the initiating event in mammalian cell induction of stress response genes following x-ray or UV exposure (6, 7). However, the mechanisms of DNA damage recognition have not been identified in mammalian cells.Signal transduction pathways activated by ionizing radiation include increased phosphotransferase activity of cytoplasmic protein kinases (8-10). Moreover, inhibition of protein kinases blocks radiation-mediated gene induction and effects diverse biological endpoints such as apoptosis (10), radiation survival (11), and induction of the cytokine tumor necrosis factor a (TNF-a) (9). The calcium/phospholipiddependent protein kinase (protein kinase C; PKC) is activated within 15 sec of ionizing radiation exposure and is extinguished by 90 sec in human leukemia HL-60 cells (9). Second messengers that participate in PKC activation following exposure to external stimuli include free fatty acids such as arachidonic acid (12) (16,17). To determine whether arachadonic acid production was associated with radiationmediated signal transduction, we quantified arachidonic acid production in irradiated HL-60 cells and found an increase in arachidonate within 30 min following irradiation.Since phospholipase A2 hydrolyzes phosphatidylcholine to arachidonic acid, we studied the effects of the phospholipase A2 inhibitors mepacrine (18) and bromphenylbromide (BPB) (19). In addition, we studied the effects of dexamethasone and pentoxifylline on radiation-induced fatty acid hydrolysis, as these agents have been shown to inhibit phospholipase A2, reduce the production of cellular mediators of inflammation and tissue injury, and inhibit lipopolysaccharide-induced TNF-a production in monocytes (20, 21). Moreover, glucocorticoids and pentoxifylline are employed clinically to prevent ...

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“…Steroids have demonstrated potential to mitigate lung injury in irradiated animals ( 37 – 40 ). Survival of mice treated with prednisolone 80 days after 2,800 rads in two fractions was better in mice that were irradiated only, but the survival rate dropped sharply when the treatment was discontinued ( 38 ). Of these drugs, genistein and EUK compounds mitigated injury to more than one organ ( 8 , 31 , 41 , 42 ).…”

Section: Discussionmentioning

confidence: 99%

Model Development and Use of ACE Inhibitors for Preclinical Mitigation of Radiation-Induced Injury to Multiple Organs

Medhora

Gao²,

Wu³

et al. 2014

Radiation Research

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The NIH/NIAID initiated a countermeasure program to develop mitigators for radiation-induced injuries from a radiological attack or nuclear accident. We have previously characterized and demonstrated mitigation of single organ injuries, such as radiation pneumonitis, pulmonary fibrosis or nephropathy by angiotensin converting enzyme (ACE) inhibitors. Our current work extends this research to examine the potential for mitigating multiple organ dysfunctions occurring in the same irradiated rats. Using total body irradiation (TBI) followed by bone marrow transplant, we tested four doses of X radiation (11, 11.25, 11.5 and 12 Gy) to develop lethal late effects. We identified three of these doses (11, 11.25 and 11.5 Gy TBI) that were lethal to all irradiated rats by 160 days to test mitigation by ACE inhibitors of injury to the lungs and kidneys. In this study we tested three ACE inhibitors at doses: captopril (88 and 176 mg/m2/day), enalapril (18, 24 and 36 mg/m2/day) and fosinopril (60 mg/m2/day) for mitigation. Our primary end point was survival or criteria for euthanization of morbid animals. Secondary end points included breathing intervals, other assays for lung structure and function and blood urea nitrogen (BUN) to assess renal damage. We found that captopril at 176 mg/m2/day increased survival after 11 or 11.5 Gy TBI. Enalapril at 18–36 mg/m2/day improved survival at all three doses (TBI). Fosinopril at 60 mg/m2/day enhanced survival at a dose of 11 Gy, although no improvement was observed for pneumonitis. These results demonstrate the use of a single countermeasure to mitigate the lethal late effects in the same animal after TBI.

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Radiation pneumonitis in mice. Some effects of corticosteroids on mortality and pulmonary physiology.

Cited by 51 publications

References 19 publications

The Prolonged Gastrointestinal Syndrome in Rhesus Macaques

The Prolonged Gastrointestinal Syndrome in Rhesus Macaques

Membrane-derived second messenger regulates x-ray-mediated tumor necrosis factor alpha gene induction.

Model Development and Use of ACE Inhibitors for Preclinical Mitigation of Radiation-Induced Injury to Multiple Organs

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