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Radiation-induced impairment in lung lymphatic vasculature.

ABSTRACT: The lymphatic vasculature has been shown to play important roles in lung injury and repair, particularly in lung fibrosis. The effects of ionizing radiation on lung lymphatic vasculature have not been previously reported.C57Bl/6 mice were immobilized in a lead shield exposing only the thoracic cavity, and were irradiated with a single dose of 14 Gy. Animals were sacrificed and lungs collected at different time points (1, 4, 8, and 16 weeks) following radiation. To identify lymphatic vessels in lung tissue sections, we used antibodies that are specific for lymphatic vessel endothelial receptor 1 (LYVE-1), a marker of lymphatic endothelial cells (LEC). To evaluate LEC cell death and oxidative damage, lung tissue sections were stained for LYVE-1 and with TUNEL staining, or 8-oxo-dG respectively. Images were imported into ImageJ v1.36b and analyzed. Compared to a non-irradiated control group, we observed a durable and progressive decrease in the density, perimeter, and area of lymphatic vessels over the study period. The decline in the density of lymphatic vessels was observed in both subpleural and interstitial lymphatics. Histopathologically discernible pulmonary fibrosis was not apparent until 16 weeks after irradiation. Furthermore, there was significantly increased LEC apoptosis and oxidative damage at one week post-irradiation that persisted at 16 weeks.There is impairment of lymphatic vasculature after a single dose of ionizing radiation that precedes architectural distortion and fibrosis, suggesting important roles for the lymphatic circulation in the pathogenesis of the radiation-induced lung injury.

SUBMITTER: Cui Y

PROVIDER: S-EPMC4267131 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Radiation-induced impairment in lung lymphatic vasculature.

Cui Ye Y Wilder Julie J Rietz Cecilia C Gigliotti Andrew A Tang Xiaomeng X Shi Yuanyuan Y Guilmette Raymond R Wang Hao H George Gautam G Nilo de Magaldi Eduarda E Chu Sarah G SG Doyle-Eisele Melanie M McDonald Jacob D JD Rosas Ivan O IO El-Chemaly Souheil S

Lymphatic research and biology 20141201 4

<h4>Background</h4>The lymphatic vasculature has been shown to play important roles in lung injury and repair, particularly in lung fibrosis. The effects of ionizing radiation on lung lymphatic vasculature have not been previously reported.<h4>Methods and results</h4>C57Bl/6 mice were immobilized in a lead shield exposing only the thoracic cavity, and were irradiated with a single dose of 14 Gy. Animals were sacrificed and lungs collected at different time points (1, 4, 8, and 16 weeks) followin ...[more]

PMID: 25412238

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Project description:BackgroundDespite great advances in surgical techniques for rotator cuff tear (RCT) over the past decades, the postoperative failure rate of RCT is still high due to the poor healing competence of bone-tendon interface (BTI). The lymphatic vasculature plays a regulatory role in inflammatory disease and affects tissue healing. However, whether lymphangiogenesis and the role of lymphatic vasculature in the physiopathological process of rotator cuff （RC）injury remains unknown.MethodsIn this study, we constructed a mouse RC injury model and the BTI samples were collected for measurement. Firstly, immunofluorescence was used to investigate the temporal and spatial distribution of lymphangiogenesis in BTI area at different post-injury time points. Subsequently, the mice of experimental group were gavaged with the lymphatic inhibitors (SAR131675) on the first postoperative day to inhibit lymphangiogenesis, while the control group was treated with the vehicle. At postoperative week 2 and 4, the samples were collected for immunofluorescence staining to evaluate lymphatic angiogenesis inhibition. At postoperative week 4 and 8, The supraspinatus (SS) tendon-humeral complexes were collected for bone morphometric, histological and biomechanical tests to assess the healing outcome of the BTI.ResultsImmunofluorescence results showed that the lymphatic proliferation in the BTI injury area and increased in consistence with the healing time, and the lymphatic hyperplasia area significantly diminished at postoperative week 4. The lymphatic hyperplasia area in the SAR group was significantly lower than that in the control group both at 2 and 4 weeks postoperatively. Moreover, the administration of SAR131675 significantly impeded RC healing, as evidenced by lower histological scores, lower bone morphometric parameters, and worse biomechanical properties in comparison with that in control group at postoperative weeks 4 and 8.ConclusionLymphangiogenesis plays a positive role in RC healing, and targeting the lymphatic drainage at healing site may be a new therapeutic approach to promote RC injury repair.The translational potential of this articleThis is the first study to assess the specific role of lymphatic vessels in RC healing, and improving lymphatic drainage may be a potential new therapeutic approach to facilitate repair of BTI. Further, our study provides a reference for possible future treatment of BTI by intervening the lymphatic system.

Project description:Recent functional lung imaging studies have presented evidence of an "indirect effect" on perfusion damage, where regions that are unirradiated or lowly irradiated but that are supplied by highly irradiated regions observe perfusion damage post-radiation therapy (RT). The purpose of this work was to investigate this effect using a contrast-enhanced dynamic CT protocol to measure perfusion change in five novel swine subjects. A cohort of five Wisconsin Miniature Swine (WMS) were given a research course of 60 Gy in five fractions delivered locally to a vessel in the lung using an Accuray Radixact tomotherapy system with Synchrony motion tracking to increase delivery accuracy. Imaging was performed prior to delivering RT and 3 months post-RT to yield a 28-36 frame image series showing contrast flowing in and out of the vasculature. Using MIM software, contours were placed in six vessels on each animal to yield a contrast flow curve for each vessel. The contours were placed as follows: one at the point of max dose, one low-irradiated (5-20 Gy) branching from the max dose vessel, one low-irradiated (5-20 Gy) not branching from the max dose vessel, one unirradiated (<5 Gy) branching from the max dose vessel, one unirradiated (<5 Gy) not branching from the max dose vessel, and one in the contralateral lung. Seven measurements (baseline-to-baseline time and difference, slope up and down, max rise and value, and area under the curve) were acquired for each vessel's contrast flow curve in each subject. Paired Student t-tests showed statistically significant (p < 0.05) reductions in the area under the curve in the max dose, and both fed contours indicating an overall reduction in contrast in these regions. Additionally, there were statistically significant reductions observed when comparing pre- and post-RT in slope up and down in the max dose, low-dose fed, and no-dose fed contours but not the low-dose not-fed, no-dose not-fed, or contralateral contours. These findings suggest an indirect damage effect where irradiation of the vasculature causes a reduction in perfusion in irradiated regions as well as regions fed by the irradiated vasculature.

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Radiation-induced impairment in lung lymphatic vasculature.

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Radiation-induced impairment in lung lymphatic vasculature.

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