Effects of Pharmacological Inhibition and Genetic Deficiency of Plasminogen Activator Inhibitor-1 in Radiation-Induced Intestinal Injury

Abderrahmani, Rym; François, Agnès; Buard, Valérie; Benderitter, Marc; Sabourin, Jean‐Christophe; Crandall, David L.; Milliat, Fabien

doi:10.1016/j.ijrobp.2009.01.077

Cited by 25 publications

(16 citation statements)

References 36 publications

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“…These results suggest that PAI-1 is the most probably part of the plasminogen activation system involved in radiation-induced enteropathy. Radiation injury scoring revealed that PAI-1 −/− mice are protected against radiation damage in both the late and acute phases, confirming previous results [12], [31] (Figure 1A). Detailed analyses performed at 3 and 14 days showed that differences in radiation injury between Wt and PAI-1 −/− mice are strongly associated with protection of the mucosae (Figure 1B–C).…”

Section: Resultssupporting

confidence: 90%

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PAI-1-Dependent Endothelial Cell Death Determines Severity of Radiation-Induced Intestinal Injury

Abderrahmani¹,

François²,

Buard³

et al. 2012

PLoS ONE

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Normal tissue toxicity still remains a dose-limiting factor in clinical radiation therapy. Recently, plasminogen activator inhibitor type 1 (SERPINE1/PAI-1) was reported as an essential mediator of late radiation-induced intestinal injury. However, it is not clear whether PAI-1 plays a role in acute radiation-induced intestinal damage and we hypothesized that PAI-1 may play a role in the endothelium radiosensitivity. In vivo, in a model of radiation enteropathy in PAI-1 −/− mice, apoptosis of radiosensitive compartments, epithelial and microvascular endothelium was quantified. In vitro, the role of PAI-1 in the radiation-induced endothelial cells (ECs) death was investigated. The level of apoptotic ECs is lower in PAI-1 −/− compared with Wt mice after irradiation. This is associated with a conserved microvascular density and consequently with a better mucosal integrity in PAI-1 −/− mice. In vitro, irradiation rapidly stimulates PAI-1 expression in ECs and radiation sensitivity is increased in ECs that stably overexpress PAI-1, whereas PAI-1 knockdown increases EC survival after irradiation. Moreover, ECs prepared from PAI-1 −/− mice are more resistant to radiation-induced cell death than Wt ECs and this is associated with activation of the Akt pathway. This study demonstrates that PAI-1 plays a key role in radiation-induced EC death in the intestine and suggests that this contributes strongly to the progression of radiation-induced intestinal injury.

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Section: Resultssupporting

confidence: 90%

“…In this model we recently showed that PAI-1 pharmacological inhibition conferred temporary protection against early lethality and that PAI-1 genetic deficiency conferred complete protection [31]. These results suggested that PAI-1 could be involved in radiosensitivity of the microvascular and stem cell compartments.…”

Section: Discussionmentioning

confidence: 86%

PAI-1-Dependent Endothelial Cell Death Determines Severity of Radiation-Induced Intestinal Injury

Abderrahmani¹,

François²,

Buard³

et al. 2012

PLoS ONE

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“…To date, there is limited information on this topic. One study administered PAI-039 for 42 days through addition to the rodent chow and found an acute protection against radiation-induced intestinal injury but noted no adverse effects of drug treatment (45), whereas a second study provided a 2-month administration of PAI-039 to AngII/salt–treated mice (46). In the latter study, PAI-039 was effective in decreasing aortic remodeling with no effect of PAI-039 alone on serum amyloid A levels (an index of systemic inflammation).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Plasminogen Activator Inhibitor-1 Restores Skeletal Muscle Regeneration in Untreated Type 1 Diabetic Mice

et al. 2011

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OBJECTIVEType 1 diabetes leads to impairments in growth, function, and regenerative capacity of skeletal muscle; however, the underlying mechanisms have not been clearly defined.RESEARCH DESIGN AND METHODSWith the use of Ins2WT/C96Y mice (model of adolescent-onset type 1 diabetes), muscle regeneration was characterized in terms of muscle mass, myofiber size (cross-sectional area), and protein expression. Blood plasma was analyzed for glucose, nonesterified fatty acids, insulin, and plasminogen activator inhibitor-1 (PAI-1). PAI-039, an effective inhibitor of PAI-1, was orally administered to determine if PAI-1 was attenuating muscle regeneration in Ins2WT/C96Y mice.RESULTSIns2WT/C96Y mice exposed to 1 or 8 weeks of untreated type 1 diabetes before chemically induced muscle injury display significant impairments in their regenerative capacity as demonstrated by decreased muscle mass, myofiber cross-sectional area, myogenin, and Myh3 expression. PAI-1, a physiologic inhibitor of the fibrinolytic system and primary contributor to other diabetes complications, was more than twofold increased within 2 weeks of diabetes onset and remained elevated throughout the experimental period. Consistent with increased circulating PAI-1, regenerating muscles of diabetic mice exhibited excessive collagen levels at 5 and 10 days postinjury with concomitant decreases in active urokinase plasminogen activator and matrix metalloproteinase-9. Pharmacologic inhibition of PAI-1 with orally administered PAI-039 rescued the early regenerative impairments in noninsulin-treated Ins2WT/C96Y mice.CONCLUSIONSTaken together, these data illustrate that the pharmacologic inhibition of elevated PAI-1 restores the early impairments in skeletal muscle repair observed in type 1 diabetes and suggests that early interventional studies targeting PAI-1 may be warranted to ensure optimal growth and repair in adolescent diabetic skeletal muscle.

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“…All cell types are sensitive to ionizing radiations, and tissue scaring process initiates immediately after radiation exposure, involving all cell types and compartments of the tissue. Reduction of endothelial cells radiation-induced apottosis by basic fibroblast growth factor protects mice from gastrointestinal syndrome [10], and reduced small intestinal tissue damage following localized radiation exposure in PAI-1 −/− mice is associated with less endothelial cells apoptosis [11]. Tissue response to radiation exposure is considered as a continuum between very acute events and late tissue fibrosis.…”

Section: Radiation-induced Breakdown Of the Fragile Balance Governmentioning

confidence: 99%

Inflammation and Immunity in Radiation Damage to the Gut Mucosa

François

Milliat

Guipaud

et al. 2013

BioMed Research International

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107

104

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Erythema was observed on the skin of the first patients treated with radiation therapy. It is in particular to reduce this erythema, one feature of tissue inflammation, that prescribed dose to the tumor site started to be fractionated. It is now well known that radiation exposure of normal tissues generates a sustained and apparently uncontrolled inflammatory process. Radiation-induced inflammation is always observed, often described, sometimes partly explained, but still today far from being completely understood. The thing with the gut and especially the gut mucosa is that it is at the frontier between the external milieu and the organism, is in contact with a plethora of commensal and foreign antigens, possesses a dense-associated lymphoid tissue, and is particularly radiation sensitive because of a high mucosal turnover rate. All these characteristics make the gut mucosa a strong responsive organ in terms of radiation-induced immunoinflammation. This paper will focus on what has been observed in the normal gut and what remains to be done concerning the immunoinflammatory response following localized radiation exposure.

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Effects of Pharmacological Inhibition and Genetic Deficiency of Plasminogen Activator Inhibitor-1 in Radiation-Induced Intestinal Injury

Cited by 25 publications

References 36 publications

PAI-1-Dependent Endothelial Cell Death Determines Severity of Radiation-Induced Intestinal Injury

PAI-1-Dependent Endothelial Cell Death Determines Severity of Radiation-Induced Intestinal Injury

Inhibition of Plasminogen Activator Inhibitor-1 Restores Skeletal Muscle Regeneration in Untreated Type 1 Diabetic Mice

Inflammation and Immunity in Radiation Damage to the Gut Mucosa

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