-
[show abstract]
[hide abstract]
ABSTRACT: The intestinal mucosa is the compartment that sustains the most severe injury in response to radiation and is therefore of primary interest. The use of whole gut extracts for analysis of gene expression may confound important changes in the mucosa. On the other hand, laser capture microdissection (LCM) is hampered by the unstable nature of RNA and by a more complicated collection process. This study assessed, in parallel samples from a validated radiation model, the indications for use of LCM for intestinal gene expression analysis.
RNA was extracted from mouse whole intestine and from mucosa by LCM at baseline and 4 h, 24 h, and 3.5 d after total body irradiation and subjected to microarray analysis. Among mucosal genes that were altered > = 2-fold, less than 7% were present in the whole gut at 4 and 24 h, and 25% at 3.5 d. As expected, pathway analysis of mucosal LCM samples showed that radiation activated the coagulation system, lymphocyte apoptosis, and tight junction signaling, and caused extensive up-regulation of cell cycle and DNA damage repair pathways. Using similar stringent criteria, regulation of these pathways, with exception of the p53 pathway, was undetectable in the whole gut. Radiation induced a dramatic increase of caspase14 and ectodysplasin A2 receptor (Eda2r), a TNFα receptor, in both types of samples.
LCM-isolated mucosal specimens should be used to study cellular injury, cell cycle control, and DNA damage repair pathways. The remarkable increase of caspase14 and Eda2r suggests a novel role for these genes in regulating intestinal radiation injury. Comparative gene expression data from complex tissues should be interpreted with caution.
PLoS ONE 01/2013; 8(1):e53711. · 4.09 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Our study was to elucidate the mechanisms whereby BMS-345541 (BMS, a specific IκB kinase β inhibitor) inhibits the repair of DNA double-strand breaks (DSBs) and evaluate whether BMS can sensitize MCF-7 breast cancer cells (MCF-7 cells) to ionizing radiation (IR) in an apoptosis-independent manner. In this study, MCF-7 cells were exposed to IR in vitro and in vivo with or without pretreatment of BMS. The effects of BMS on the repair of IR-induced DSBs by homologous recombination (HR) and non-homologous end-joining (NHEJ) were analyzed by the DR-GFP and EJ5-GFP reporter assays and IR-induced γ-H2AX, 53BP1, Brca1 and Rad51 foci assays. The mechanisms by which BMS inhibits HR were examined by microarray analysis and quantitative reverse transcription PCR. The effects of BMS on the sensitivity of MCF-7 cells to IR were determined by MTT and clonogenic assays in vitro and tumor growth inhibition in vivo in a xenograft mouse model. The results showed that BMS selectively inhibited HR repair of DSBs in MCF-7 cells, most likely by down-regulation of several genes that participate in HR. This resulted in a significant increase in the DNA damage response that sensitizes MCF-7 cells to IR-induced cell death in an apoptosis-independent manner. Furthermore, BMS treatment sensitized MCF-7 xenograft tumors to radiation therapy in vivo in an association with a significant delay in the repair of IR-induced DSBs. These data suggest that BMS is a novel HR inhibitor that has the potential to be used as a radiosensitizer to increase the responsiveness of cancer to radiotherapy. © 2013 by Radiation Research Society.
Radiation Research 12/2012; · 2.68 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: PURPOSE: To determine, using a specific small-molecule inhibitor of protease-activated receptor 1 (PAR1) signaling, whether the beneficial effect of thrombin inhibition on radiation enteropathy development is due to inhibition of blood clotting or to cellular (PAR1-mediated) thrombin effects. METHODS AND MATERIALS: Rats underwent fractionated X-irradiation (5 Gy × 9) of a 4-cm small-bowel segment. Early radiation toxicity was evaluated in rats receiving PAR1 inhibitor (SCH602539, 0, 10, or 15 mg/kg/d) from 1 day before to 2 weeks after the end of irradiation. The effect of PAR1 inhibition on development of chronic intestinal radiation fibrosis was evaluated in animals receiving SCH602539 (0, 15, or 30 mg/kg/d) until 2 weeks after irradiation, or continuously until termination of the experiment 26 weeks after irradiation. RESULTS: Blockade of PAR1 ameliorated early intestinal toxicity, with reduced overall intestinal radiation injury (P=.002), number of myeloperoxidase-positive (P=.03) and proliferating cell nuclear antigen-positive (P=.04) cells, and collagen III accumulation (P=.005). In contrast, there was no difference in delayed radiation enteropathy in either the 2- or 26-week administration groups. CONCLUSION: Pharmacological blockade of PAR1 seems to reduce early radiation mucositis but does not affect the level of delayed intestinal radiation fibrosis. Early radiation enteropathy is related to activation of cellular thrombin receptors, whereas platelet activation or fibrin formation may play a greater role in the development of delayed toxicity. Because of the favorable side-effect profile, PAR1 blockade should be further explored as a method to ameliorate acute intestinal radiation toxicity in patients undergoing radiotherapy for cancer and to protect first responders and rescue personnel in radiologic/nuclear emergencies.
International journal of radiation oncology, biology, physics 05/2012; · 4.59 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The somatostatin analog SOM230 has potent radioprophylactic and radiation mitigating properties that are unrelated to cytoprotection but appear to be due to suppression of secretion of pancreatic enzymes into the intestinal lumen. To determine the maximal postirradiation time window for administration, male CD2F1 mice were exposed to 8.5-11 Gy total-body radiation; SOM230 (0.5, 2 or 5 mg/kg) or vehicle was given by twice daily subcutaneous injections for 14 days, beginning 24-72 h after irradiation, and 30-day animal survival was recorded. The contribution of the gut to systemic cytokine levels was estimated by analyzing plasma samples obtained simultaneously from the portal vein and carotid artery. The effect of SOM230 on cell trypsin secretion was assessed in vitro and intestinal proteolytic activity was measured in vivo. SOM230 was associated with a 40-60% absolute improvement in overall postirradiation survival when treatment was started 48 h after irradiation and even exhibited a statistically significant survival benefit when started at 72 h. SOM230 ameliorated the radiation-induced decrease in chemokine (C-X-C motif) ligand 9 (CXCL9). SOM230 inhibited pancreatic acinar cell trypsin secretion in vitro in a dose-dependent fashion and reduced intraluminal and intestinal tissue proteolytic activity in vivo. SOM230 is an excellent radiation mitigator with a postirradiation time window in excess of 48 h. The mechanism likely involves preservation of intestinal barrier function due to decreased secretion of pancreatic enzymes into the bowel lumen.
Radiation Research 06/2011; 175(6):728-35. · 2.68 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Activation of the IKK-NFκB pathway increases the resistance of cancer cells to ionizing radiation (IR). This effect has been largely attributed to the induction of anti-apoptotic proteins by NFκB. Since efficient repair of DNA double strand breaks (DSBs) is required for the clonogenic survival of irradiated cells, we investigated if activation of the IKK-NFκB pathway also regulates DSB repair to promote cell survival after IR. We found that inhibition of the IKK-NFκB pathway with a specific IKKβ inhibitor significantly reduced the repair of IR-induced DSBs in MCF-7 cells. The repair of DSBs was also significantly inhibited by silencing IKKβ expression with IKKβ shRNA. However, down-regulation of IKKα expression with IKKα shRNA had no significant effect on the repair of IR-induced DSBs. Similar findings were also observed in IKKα and/or IKKβ knockout mouse embryonic fibroblasts (MEFs). More importantly, inhibition of IKKβ with an inhibitor or down-regulation of IKKβ with IKKβ shRNA sensitized MCF-7 cells to IR-induced clonogenic cell death. DSB repair function and resistance to IR were completely restored by IKKβ reconstitution in IKKβ-knockdown MCF-7 cells. These findings demonstrate that IKKβ can regulate the repair of DSBs, a previously undescribed and important IKKβ kinase function; and inhibition of DSB repair may contribute to cance cell radiosensitization induced by IKKβ inhibition. As such, specific inhibition of IKKβ may represents a more effective approach to sensitize cancer cells to radiotherapy.
PLoS ONE 01/2011; 6(4):e18447. · 4.09 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Protease-activated receptor-2 (PAR(2)) is highly expressed throughout the gut and regulates the inflammatory, mitogenic, fibroproliferative, and nociceptive responses to injury. PAR(2) is strikingly upregulated and exhibits increased activation in response to intestinal irradiation. We examined the mechanistic significance of radiation enteropathy development by assessing the effect of exogenous PAR(2) activation.
Rat small bowel was exposed to localized single-dose radiation (16.5 Gy). The PAR(2) agonist (2-furoyl-LIGRLO-NH(2)) or vehicle was injected intraperitoneally daily for 3 days before irradiation (before), for 7 days after irradiation (after), or both 3 days before and 7 days after irradiation (before-after). Early and delayed radiation enteropathy was assessed at 2 and 26 weeks after irradiation using quantitative histologic examination, morphometry, and immunohistochemical analysis.
The PAR(2) agonist did not elicit changes in the unirradiated (shielded) intestine. In contrast, in the irradiated intestine procured 2 weeks after irradiation, administration of the PAR(2) agonist was associated with more severe mucosal injury and increased intestinal wall thickness in all three treatment groups (p <.05) compared with the vehicle-treated controls. The PAR(2) agonist also exacerbated the radiation injury score, serosal thickening, and mucosal inflammation (p <.05) in the before and before-after groups. The short-term exogenous activation of PAR(2) did not affect radiation-induced intestinal injury at 26 weeks.
The results of the present study support a role for PAR(2) activation in the pathogenesis of early radiation-induced intestinal injury. Pharmacologic PAR(2) antagonists might have the potential to reduce the intestinal side effects of radiotherapy and/or as countermeasures in radiologic accidents or terrorism scenarios.
International journal of radiation oncology, biology, physics 07/2010; 77(4):1206-12. · 4.59 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The intestinal immune system is the largest in the body. This study analyzed changes in intestinal immune cell populations, cytokine protein levels, and transcript profiles after total-body irradiation (TBI) in CD2F1 mice. A single dose of 8.0 Gy gamma radiation caused negligible 30-day lethality but induced significant histological damage in jejunal mucosa that was maximal at 3.5 days and that had seemingly recovered by day 21 after irradiation. These changes were accompanied by decreased numbers of mucosal macrophages, neutrophils, and B and T lymphocytes, mostly coinciding with similar reductions in peripheral blood cell counts. Recovery of mucosal macrophages occurred within 1 week, whereas mucosal granulocytes and lymphocytes remained low until 3 weeks after TBI. Maximal suppression of T-helper cell (T(H))-related transcripts occurred at 3.5 days, but there was no obvious T(H)1 or T(H)2 bias. Genome-wide transcriptional profiling revealed a preponderance of differentially regulated genes involved in cell cycle control, cell death and DNA repair between 4 h and 3.5 days after irradiation. Genes involved in tissue recovery predominated from day 7 onward. We conclude that the intestinal immune system undergoes profound changes after sublethal TBI and that these changes likely contribute to postirradiation pathophysiological manifestations.
Radiation Research 04/2010; 173(4):469-78. · 2.68 Impact Factor
-
Vesta Valuckaite,
Olga Zaborina,
Jason Long,
Martin Hauer-Jensen, Junru Wang,
Christopher Holbrook,
Alexander Zaborin,
Kenneth Drabik,
Mukta Katdare,
Helena Mauceri,
Ralph Weichselbaum,
Millicent A Firestone,
Ka Yee Lee,
Eugene B Chang,
Jeffrey Matthews,
John C Alverdy
[show abstract]
[hide abstract]
ABSTRACT: Intestinal injury following abdominal radiation therapy or accidental exposure remains a significant clinical problem that can result in varying degrees of mucosal destruction such as ulceration, vascular sclerosis, intestinal wall fibrosis, loss of barrier function, and even lethal gut-derived sepsis. We determined the ability of a high-molecular-weight polyethylene glycol-based copolymer, PEG 15-20, to protect the intestine against the early and late effects of radiation in mice and rats and to determine its mechanism of action by examining cultured rat intestinal epithelia. Rats were exposed to fractionated radiation in an established model of intestinal injury, whereby an intestinal segment is surgically placed into the scrotum and radiated daily. Radiation injury score was decreased in a dose-dependent manner in rats gavaged with 0.5 or 2.0 g/kg per day of PEG 15-20 (n = 9-13/group, P < 0.005). Complementary studies were performed in a novel mouse model of abdominal radiation followed by intestinal inoculation with Pseudomonas aeruginosa (P. aeruginosa), a common pathogen that causes lethal gut-derived sepsis following radiation. Mice mortality was decreased by 40% in mice drinking 1% PEG 15-20 (n = 10/group, P < 0.001). Parallel studies were performed in cultured rat intestinal epithelial cells treated with PEG 15-20 before radiation. Results demonstrated that PEG 15-20 prevented radiation-induced intestinal injury in rats, prevented apoptosis and lethal sepsis attributable to P. aeruginosa in mice, and protected cultured intestinal epithelial cells from apoptosis and microbial adherence and possible invasion. PEG 15-20 appeared to exert its protective effect via its binding to lipid rafts by preventing their coalescence, a hallmark feature in intestinal epithelial cells exposed to radiation.
AJP Gastrointestinal and Liver Physiology 10/2009; 297(6):G1041-52. · 3.43 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Somatostatin analogs ameliorate intestinal injury after localized irradiation. This study investigated whether SOM230, a novel, metabolically stable analog with broad receptor affinity, reduces intestinal injury and lethality in mice exposed to total-body irradiation (TBI). Male CD2F1 mice were exposed to 7-15 Gy TBI. Twice-daily administration of SOM230 (1, 4 or 10 mg/kg per day) or vehicle was started either 2 days before or 4 h after TBI and continued for either 14 or 21 days. Parameters of intestinal and hematopoietic radiation injury, bacterial translocation, and circulating cytokine levels were assessed. Animal survival was monitored for up to 30 days. SOM230 increased survival (P < 0.001) and prolonged survival time (P < 0.001) whether administration was initiated before or after TBI. There was no benefit from administration for 21 compared to 14 days. The survival benefit of SOM230 was completely reversed by co-administration of pancreatic enzymes (P = 0.009). Consistent with the presumed non-cytoprotective mechanism of action, SOM230 did not influence hematopoietic injury or intestinal crypt lethality. However, SOM230 preserved mucosal surface area (P < 0.001) and reduced bacterial translocation in a dose-dependent manner (P < 0.001). Circulating IL-12 levels were reduced in SOM230-treated mice (P = 0.007). No toxicity from SOM230 was observed. SOM230 enhances animal survival whether administration begins before or after TBI; i.e., it is effective both as a protector and as a mitigator. The mechanism likely involves reduction of intraluminal pancreatic enzymes. Because of its efficacy and favorable safety profile, SOM230 is a promising countermeasure against radiation and should undergo further development.
Radiation Research 07/2009; 171(6):698-707. · 2.68 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Analogs of vitamin E (tocols) are under development as radioprophylactic agents because of their high efficacy and lack of toxicity. Gamma-tocotrienol (GT3) is of particular interest because, in addition to being an antioxidant, it also inhibits 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and accumulates to greater extent in endothelial cells than other tocols. We addressed in vivo whether HMG-CoA reductase inhibition contributes to the radioprotection conferred by GT3. Groups of mice were treated with vehicle, mevalonate (the product of the reaction catalyzed by HMG-CoA reductase), GT3 alone or GT3 in combination with mevalonate. Lethality and standard parameters of injury to the hematopoietic, intestinal and vascular/endothelial systems were assessed after exposure to total-body irradiation. GT3 improved postirradiation survival and decreased radiation-induced vascular oxidative stress, an effect that was reversible by mevalonate. GT3 also enhanced hematopoietic recovery, reduced intestinal radiation injury, and accelerated the recovery of soluble markers of endothelial function. These parameters were not reversed by mevalonate co-administration. Our data confirm GT3's radioprophylactic properties against hematopoietic injury and, for the first time, demonstrate benefits in terms of protection against gastrointestinal and vascular injury. The radioprotective efficacy of GT3 against vascular injury is related to its properties as an HMG-CoA reductase inhibitor.
Radiation Research 06/2009; 171(5):596-605. · 2.68 Impact Factor
-
Marjan Boerma,
Qiang Fu, Junru Wang,
David S Loose,
Alessandra Bartolozzi,
James L Ellis,
Sharon McGonigle,
Elsa Paradise,
Paul Sweetnam,
Louis M Fink,
Marie-Catherine Vozenin-Brotons,
Martin Hauer-Jensen
[show abstract]
[hide abstract]
ABSTRACT: Inhibitors of Rho kinase (ROCK) are a relatively new class of drugs with potential benefits in oncology, neurology, and fibrotic and cardiovascular diseases. ROCK inhibitors modulate many cellular functions, some of which are similar to the pleiotropic effects of statins, suggesting additive or synergistic properties. Studies to date have used compounds that inhibit both isoforms of ROCK, ROCK1 and ROCK2. This study was designed to compare gene expression profiles of atorvastatin with the newly developed ROCK2 inhibitor SLx-2119 in primary cultures of normal human endothelial cells, smooth muscle cells, and fibroblasts. Cells were treated with each compound for 24 h, after which total RNA was isolated and genome-wide gene-expression profiles were obtained with Illumina arrays. Because of the known effect of statins on the actin cytoskeleton and on connective tissue growth factor, a prominent growth factor involved in tissue fibrosis, the effects of SLx-2119 and atorvastatin on the actin cytoskeleton and connective tissue growth factor mRNA were also examined in cultures of smooth muscle cells with a fibrotic phenotype, isolated from biopsies of human intestine with radiation-induced fibrosis. Although SLx-2119 and atorvastatin affected expression of genes belonging to the same biological processes, individual genes were mostly different, consistent with synergistic or additive properties. Both SLx-2119 and atorvastatin reduced connective tissue growth factor mRNA and remodeled the actin cytoskeleton in fibrosis-derived smooth muscle cells, suggesting that both compounds have antifibrotic properties. These results form the basis for further studies to assess the possible therapeutic benefit of combined treatments.
Blood Coagulation and Fibrinolysis 11/2008; 19(7):709-18. · 1.24 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Radiation-induced heart disease is a severe side effect of thoracic radiotherapy. Studies suggest that mast cells play a protective role in radiation-induced heart disease and that the endothelin (ET) system mediates protective effects of mast cells in other disorders. This study examined whether mast cells modulate the cardiac ET system and examined the effects of ET receptor inhibition in a rat model of radiation-induced heart disease. Mast cell-deficient (Ws/Ws), mast cell-competent (+/+) and Sprague-Dawley rats received 18 Gy irradiation to the heart. Left ventricular mRNA of ET1 and its receptors (ETA and ETB) was measured in Ws/Ws and +/+ rats at 1 week and 3 months. Sprague-Dawley rats were treated with the ETA/ETB antagonist bosentan, and at 6 months cardiac changes were assessed using the Langendorff perfused rat heart preparation, immunohistochemistry and real-time PCR. Ws/Ws and +/+ rat hearts did not differ in baseline mRNA. In contrast, +/+ rats hearts exhibited up-regulation of ET1 after irradiation, whereas Ws/Ws rats hearts did not, suggesting the possibility of interactions between mast cells and the cardiac ET system. Bosentan induced reductions in left ventricular systolic pressure, developed pressure and +dP/dtmax but did not affect fibrosis. Because of the known opposing effects of ETA and ETB, studies with selective antagonists may clarify the role of each receptor.
Radiation Research 10/2008; 170(3):275-83. · 2.68 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Statins upregulate endothelial thrombomodulin (TM) by mechanisms that involve members of the Kruppel-like factor family. Although Kruppel-like factors are unequivocally implicated in this process, experimental evidence points to additional mechanisms. Deletion/mutation analysis of reporter constructs was used to demonstrate that mutation of the SP1/Kruppel-like factor element in the TM promoter only partially abolishes statin-induced TM upregulation, whereas simultaneous mutation of relevant heat shock elements and SP1/Kruppel-like factor element completely prevents statin-induced TM upregulation, thus demonstrating a role for heat shock factors (HSFs). We further identified the pathway by which statins increase binding of HSF1 to heat shock elements in the TM promoter. Specifically, statins caused NO-dependent dissociation of HSF1 from heat shock protein 90, nuclear translocation of HSF1, and binding to heat shock elements in the TM promoter. Statins also decreased nuclear content of the HSF1 chaperone 14-3-3beta. In addition to reducing TM upregulation, inhibition of HSF1 reduced statin-induced upregulation of tissue plasminogen activator, whereas downregulation of thrombomospondin, plasminogen activator inhibitor 1, or connective tissue growth factor was unaffected. Knockdown of 14-3-3beta or inhibition of HSF1 phosphorylation enhanced the effect of statins on TM and tissue plasminogen activator, but did not influence thrombomospondin, plasminogen activator inhibitor 1, or connective tissue growth factor. These data demonstrate that HSF1 is involved in statin-induced regulation of TM. They also suggest that analogous mechanisms may apply to genes that are upregulated by statins, but not to downregulated genes. These results may have broad implications and suggest the use of heat shock protein modulators to selectively regulate pleiotropic statin effects.
Circulation Research 08/2008; 103(4):369-77. · 9.49 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Normal tissue radiation injury is associated with loss of vascular thromboresistance, notably because of deficient levels of endothelial thrombomodulin (TM). TM is located on the luminal surface of most endothelial cells and has critical anticoagulant and anti-inflammatory functions. Chemical oxidation of a specific methionine residue (Met388) at the thrombin-binding site in TM reduces its main functional activity, i.e., the ability to activate protein C. We examined whether exposure to ionizing radiation affects TM in a similar manner. Full-length recombinant human TM, a construct of epidermal growth factor-like domains 4-6, which are involved in protein C activation, and a synthetic peptide containing the methionine of interest were exposed to gamma radiation in a cell-free system, i.e., a system not confounded by TM turnover or ectodomain shedding. The influence of radiation on functional activity was assessed with the protein C activation assay; formation of a TM-thrombin complex was assessed with surface plasmon resonance (Biacore), and oxidation of Met388 was assessed by HPLC and confirmed by mass spectroscopy. Exposure to radiation caused a dose-dependent reduction in protein C activation, impaired TM-thrombin complex formation, and oxidation of Met388. These results demonstrate that ionizing radiation adversely affects the TM molecule. Our findings may have relevance to normal tissue toxicity in clinical radiation therapy as well as to the development of radiation syndromes in the non-therapeutic radiation exposure setting.
Radiation Research 05/2008; 169(4):408-16. · 2.68 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Intestinal radiation injury is dose limiting during abdominal and pelvic radiotherapy and critical for the outcome after accidental whole-body radiation exposure. The multifunctional cytokine, interleukin-11 (IL-11), ameliorates the intestinal radiation response, but its clinical use is hampered by severe toxicity after systemic administration. This study addressed whether protection against intestinal radiation injury can be achieved by intraluminal administration of IL-11. Male rats underwent surgical transposition of a 4-cm small bowel loop to the scrotum. For repeated intraluminal drug administration, an ileostomy, proximal to the bowel loop in the scrotum, was created. The transposed intestinal loop was exposed to 5 Gy fractions on 9 consecutive days. Recombinant human IL-11 (rhIL-11; 2 mg/kg/d) or vehicle was given through the ileostomy from 2 days before until 2 weeks after irradiation. At 2 weeks, structural, cellular, and molecular aspects of intestinal radiation injury were assessed. rhIL-11 ameliorated structural manifestations of radiation enteropathy, including radiation injury score (6.5 +/- 0.6 in the vehicle group versus 4.0 +/- 0.3 in the IL-11 group; P = 0.001), mucosal surface area loss (0.2 +/- 0.1 versus 0.5 +/- 0.03; P < 0.0001), and intestinal wall thickening (842 +/- 66 microm versus 643 +/- 54 microm; P = 0.02), reduced postradiation transforming growth factor-beta overexpression, and reduced numbers of ED2-positive cells. Postirradiation mucosal mast cell numbers were partially restored by rhIL-11. These data show that local administration of rhIL-11 ameliorates early intestinal radiation injury and support further development of rhIL-11 to reduce manifestations of intestinal radiation injury in the clinic.
Cancer Research 11/2007; 67(19):9501-6. · 7.86 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Microvascular injury plays a key role in normal tissue radiation responses. Statins, in addition to their lipid-lowering effects, have vasculoprotective properties that may counteract some effects of radiation on normal tissues. We examined whether administration of simvastatin ameliorates intestinal radiation injury, and whether the effect depends on protein C activation.
Rats received localized, fractionated small bowel irradiation. The animals were fed either regular chow or chow containing simvastatin from 2 weeks before irradiation until termination of the experiment. Groups of rats were euthanized at 2 weeks and 26 weeks for assessment of early and delayed radiation injury by quantitative histology, morphometry, and quantitative immunohistochemistry. Dependency on protein C activation was examined in thrombomodulin (TM) mutant mice with deficient ability to activate protein C.
Simvastatin administration was associated with lower radiation injury scores (p < 0.0001), improved mucosal preservation (p = 0.0009), and reduced thickening of the intestinal wall and subserosa (p = 0.008 and p = 0.004), neutrophil infiltration (p = 0.04), and accumulation of collagen I (p = 0.0003). The effect of simvastatin was consistently more pronounced for delayed than for early injury. Surprisingly, simvastatin reduced intestinal radiation injury in TM mutant mice, indicating that the enteroprotective effect of simvastatin after localized irradiation is unrelated to protein C activation.
Simvastatin ameliorates the intestinal radiation response. The radioprotective effect of simvastatin after localized small bowel irradiation does not appear to be related to protein C activation. Statins should undergo clinical testing as a strategy to minimize side effects of radiation on the intestine and other normal tissues.
International Journal of Radiation OncologyBiologyPhysics 08/2007; 68(5):1483-90. · 4.11 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: This review summarizes the current state of knowledge regarding the role of endothelial dysfunction in the pathogenesis of early and delayed intestinal radiation toxicity and discusses various endothelial-oriented interventions aimed at reducing the risk of radiation enteropathy. Studies published in the biomedical literature during the past four decades and cited in PubMed, as well as clinical and laboratory data from our own research program are reviewed. The risk of injury to normal tissues limits the cancer cure rates that can be achieved with radiation therapy. During treatment of abdominal and pelvic tumors, the intestine is frequently a major dose-limiting factor. Microvascular injury is a prominent feature of both early (inflammatory), as well as delayed (fibroproliferative) radiation injuries in the intestine and in many other normal tissues. Evidence from our and other laboratories suggests that endothelial dysfunction, notably a deficiency of endothelial thrombomodulin, plays a key role in the pathogenesis of these radiation responses. Deficient levels of thrombomodulin cause loss of vascular thromboresistance, excessive activation of cellular thrombin receptors by thrombin, and insufficient activation of protein C, a plasma protein with anticoagulant, anti-inflammatory, and cytoprotective properties. These changes are presumed to be critically involved in many aspects of early intestinal radiation toxicity and may sustain the fibroproliferative processes that lead to delayed intestinal dysfunction, fibrosis, and clinical complications. In conclusion, injury of vascular endothelium is important in the pathogenesis of the intestinal radiation response. Endothelial-oriented interventions are appealing strategies to prevent or treat normal tissue toxicity associated with radiation treatment of cancer.
World Journal of Gastroenterology 07/2007; 13(22):3047-55. · 2.47 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Correlative data suggest that mast cells adversely affect cardiac transplantation. This study uses a mast cell-deficient rat model to directly address the role of mast cells in cardiac allotransplantation. Standardized cardiac heterotopic transplantation with cyclosporine immunosuppression was performed in mast cell-deficient and mast cell-competent rats. Rejection, ischemia, fibrosis, fibrin deposition, numbers of T-cell receptor alpha/beta positive cells, expression of transforming growth factor-beta (TGF-beta), and of endothelin-1 (ET-1) and its receptors ETA and ETB were assessed. Differences in baseline cardiac gene expression were quantified by real-time PCR in a separate group of untransplanted animals. Baseline cardiac gene expression levels of all investigated growth factors, cytokines, ET-1, ETA, and ETB were similar in mast cell-deficient and mast cell-competent rats. Surprisingly, upon heterotopic transplantation, donor heart survival was significantly reduced in mast cell-deficient rats. Moreover, in mast cell-deficient donor hearts rejection was more severe, although nonsignificant, and extracellular matrix associated TGF-beta immunoreactivity was significantly lower than in mast cell-competent donor hearts. Fibrin immunoreactive area, on the other hand, was only increased in mast cell-deficient donor hearts, but not in mast cell-competent donor hearts. Histopathological changes in all donor hearts were accompanied by increased immunoreactivity for ET-1. In conclusion, this study shows that mast cells play a protective role after cardiac transplantation.
Transplant International 04/2007; 20(3):256-65. · 2.92 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To summarize current knowledge about gastrointestinal radiation toxicity, with emphasis on mechanisms and clinical diagnosis and management.
While there has been only modest change in cancer incidence and cancer mortality rates during the past 30 years, the number of cancer survivors has more than doubled. Moreover, the recognition of uncomplicated cancer cure as the ultimate goal in oncology has intensified efforts to prevent, diagnose, and manage side effects of radiation therapy. These efforts have been facilitated by recent insight into the underlying pathophysiology.
The risk of injury to the intestine is dose limiting during abdominal and pelvic radiation therapy. Delayed bowel toxicity is difficult to manage and adversely impacts the quality of life of cancer survivors. More than 200,000 patients per year receive abdominal or pelvic radiation therapy, and the estimated number of cancer survivors with postradiation intestinal dysfunction is 1.5-2 million. Worthwhile progress towards reducing toxicity of radiation therapy has been made by dose-sculpting treatment techniques. Approaches derived from an improved understanding of the pathophysiology of bowel injury, however, will result in further advances. This article discusses the mechanisms of radiation-induced bowel toxicity and reviews current principles in diagnosis and management.
Current opinion in supportive and palliative care 04/2007; 1(1):23-9.
-
[show abstract]
[hide abstract]
ABSTRACT: Radiation therapy, either alone or in combination with other types of treatment, is responsible for 40% of cancer cures and 70% of all cancer patients receive radiation therapy at some point during the course of their disease. Radiation therapy has profound effects, both acute and long-term, on skin and connective tissues. Radiation therapy also affects the time course and end result of wound healing, and the risk of postoperative complications. For example, radiation therapy of tumors in the abdomen or in the abdominal wall inevitably affects the integrity of abdominal wall structures and may adversely affect the outcome of operations on the abdominal wall, for example hernia surgery. All surgeons will encounter patients who have undergone or will receive radiation therapy. In these situations, it is important to carefully consider the optimum timing of surgery relative to radiation therapy, to decide which perioperative precautions are needed to minimize the risk of complications, to estimate and inform the patient about the increased risk of complications, and, if surgery is done before a planned course of radiation therapy, to consider how soon after surgery it is safe to commence the radiation treatment. This review will (1) describe features of acute and long term radiation-induced changes in skin and connective tissues; (2) provide a brief overview of the biological mechanisms underlying these changes; and (3) discuss practical considerations that have direct relevance to surgical decision making and postoperative outcome.
Hernia 01/2007; 10(6):502-6. · 1.84 Impact Factor
