Radiation-induced lung injury

About: Radiation-induced lung injury is a research topic. Over the lifetime, 258 publications have been published within this topic receiving 6877 citations. The topic is also known as: Radiation Pneumonitis.

A Comparative Dose-response Relationship Between Sexes for Mortality and Morbidity of Radiation-induced Lung Injury in the Rhesus Macaque.

Abstract: Radiation-induced lung injury is a characteristic, dose- and time-dependent sequela of potentially lethal, delayed effects of acute radiation exposure. Understanding of these delayed effects to include development of medical countermeasures requires well-characterized and validated animal models that mimic the human response to acute radiation and adhere to the criteria of the US Food and Drug Administration Animal Rule. The objective herein was to establish a nonhuman primate model of whole-thorax lung irradiation in female rhesus macaques. Definition of the dose-response relationship to include key signs of morbidity and mortality in the female macaque served to independently validate the recent model performed with male macaques and importantly, to establish the lack of sex and institutional bias across the dose-response relationship for radiation-induced lung injury. The study design was similar to that described previously, with the exception that female rhesus macaques were utilized. In brief, a computed tomography scan was conducted prior to irradiation and used for treatment planning. Animals in 5 cohorts (n = 8 per cohort) were exposed to a single 6-MV photon exposure focused on the lung as determined by the computed tomography scan and treatment planning at a dose of 9.5, 10, 10.5, 11, or 11.5 Gy. Subject-based supportive care, including administration of dexamethasone, was based on trigger-to-treat criteria. Clearly defined euthanasia criteria were used to determine a moribund condition over the 180-day study duration post-whole-thorax lung irradiation. Percent mortality per radiation dose was 12.5% at 9.5 Gy, 25% at 10 Gy, 62.5% at 10.5 Gy, 87.5% at 11 Gy, and 100% at 11.5 Gy. The resulting probit plot for the whole-thorax lung irradiation model estimated an LD50/180 of 10.28 Gy, which was not significantly different from the published estimate of 10.27 Gy for the male rhesus. The key parameters of morbidity and mortality support the conclusion that there is an absence of a sex influence on the radiation dose-response relationship for whole-thorax lung irradiation in the rhesus macaque. This work also provides a significant interlaboratory validation of the previously published model.

Acute Radiation-induced Lung Injury in the Non-human Primate: A Review and Comparison of Mortality and Co-morbidities Using Models of Partial-body Irradiation with Marginal Bone Marrow Sparing and Whole Thorax Lung Irradiation.

Abstract: The nonhuman primate, rhesus macaque, is a relevant animal model that has been used to determine the efficacy of medical countermeasures to mitigate major signs of morbidity and mortality of radiation-induced lung injury. Herein, a literature review of published studies showing the evolution of lethal lung injury characteristic of the delayed effects of acute radiation exposure between the two significantly different exposure protocols, whole thorax lung irradiation and partial-body irradiation with bone marrow sparing in the nonhuman primate, is provided. The selection of published data was made from the open literature. The primary studies conducted at two research sites benefitted from the similarity of major variables; namely, both sites used rhesus macaques of approximate age and body weight and radiation exposure by LINAC-derived 6 MV photons at dose rates of 0.80 Gy min and 1.00 Gy min delivered to the midline tissue via bilateral, anterior/posterior, posterior/anterior geometry. An advantage relative to sex difference resulted from the use of male and female macaques by the Maryland and the Washington sites, respectively. Subject-based medical management was used for all macaques. The primary studies (6) provided adequate data to establish dose response relationships within 180 d for the radiation-induced lung injury consequent to whole thorax lung irradiation (male vs. female) and partial-body irradiation with bone marrow sparing exposure protocols (male). The dose response relationships established by probit analyses vs. linear dose relationships were characterized by two main parameters or dependent variables, a slope and LD50/180. Respective LD50/180 values for the primary studies that used whole thorax lung irradiation for respective male and female nonhuman primates were 10.24 Gy [9.87, 10.52] (n = 76, male) and 10.28 Gy [9.68, 10.92] (n = 40, female) at two different research sites. The respective slopes were steep at 1.73 [0.841, 2.604] and 1.15 [0.65, 1.65] probits per linear dose. The LD50/180 value and slope derived from the dose response relationships for the partial-body irradiation with bone marrow sparing exposure was 9.94 Gy [9.35, 10.29] (n = 87) and 1.21 [0.70, 1.73] probits per linear dose. A secondary study (1) provided data on limited control cohort of nonhuman primates exposed to whole thorax lung irradiation. The data supported the incidence of clinical, radiographic, and histological indices of the dose-dependent lung injury in the nonhuman primates. Tertiary studies (6) provided data derived from collaboration with the noted primary and secondary studies on control cohorts of nonhuman primates exposed to whole thorax lung irradiation and partial-body irradiation with bone marrow sparing exposure. These studies provided a summary of histological evidence of fibrosis, inflammation and reactive/proliferative changes in pneumonocytes characteristic of lung injury and data on biomarkers for radiation-induced lung injury based on matrix-assisted laser desorption ionization-mass spectrometry imaging and gene expression approaches. The available database in young rhesus macaques exposed to whole thorax lung irradiation or partial-body irradiation with bone marrow sparing using 6 MV LINAC-derived radiation with medical management showed that the dose response relationships were equivalent relative to the primary endpoint all-cause mortality. Additionally, the latency, incidence, severity, and progression of the clinical, radiographic, and histological indices of lung injury were comparable. However, the differences between the exposure protocols are remarkable relative to the demonstrated time course between the multiple organ injury of the acute radiation syndrome and that of the delayed effects of acute radiation exposure, respectively.

Impaired permeability in radiation-induced lung injury detected by technetium-99m-DTPA lung clearance.

Abstract: UNLABELLED This study evaluates the use of the 99mTc-DTPA aerosol lung clearance method to investigate radiation-induced lung changes in eight patients undergoing radiotherapy for lung or breast carcinoma. The sensitivity of the method was compared with chest radiography for detecting radiation-induced changes in the lung, regional alterations within (irradiated region) and outside (shielded region) the treatment ports, effect of irradiated lung volume, and dependence on time after radiotherapy. METHODS Serial DTPA lung clearance studies were performed before the first radiation treatment (baseline), then weekly during a 5- to 7-wk course, and up to 12 times post-therapy over periods of 56-574 days. The total activity deposited in the lungs for each study was approximately 150 microCi (approximately 5.6 MBq). DTPA clearance, expressed in terms of the biological half-time, t 1/2, was computed from the slopes of the least-squares fit regression lines of the time-activity curves for the first 10 min for irradiated and shielded lung regions. RESULTS Major findings include: (a) significant and early DTPA t 1/2 changes were observed in all patients during and after radiotherapy; (b) changes in DTPA t 1/2 values were observed in both irradiated and shielded lung regions in all patients suggesting a radiation-induced systemic reaction; (c) changes in DTPA t 1/2 values were correlated (p < 0.05) with the irradiated lung volumes; (d) significantly reduced DTPA t 1/2 values were observed in three patients who subsequently presented with clinical symptoms and/or radiographic changes consistent with radiation pneumonitis (t1/2 felt to 19% +/- 6% of baseline values, compared with 64% +/- 17% in the remaining patients [p < 0.01]); (e) the onset of decreased DTPA t 1/2 values in these three patients occurred 35-84 days before clinical symptoms and/or radiographic changes; and (f) DTPA t 1/2 tended to approach baseline values with time after radiotherapy, suggesting a long-term recovery in lung injury. CONCLUSION These observations show significant and early alterations in DTPA lung clearance during and after radiotherapy that may provide a sensitive assay to monitor changes in radiation-induced lung injury and may facilitate early therapeutic intervention.

Lung tissue extracellular matrix-derived hydrogels protect against radiation-induced lung injury by suppressing epithelial-mesenchymal transition.

Abstract: This study aimed to examine whether lung tissue extracellular matrix (ECM) hydrogels have protective effects on radiation-induced lung injury (RILI). The cytocompatibility and histocompatibility were tested for the obtained ECM-derived hydrogel. Sprague-Dawley rats were randomly divided into three groups (n = 18): control group (control); rats receiving irradiation and intratracheal injection of normal saline (IR + NS); and rats receiving irradiation and intratracheal injection of lung ECM-derived hydrogel (IR + ECM). The wet/dry weight ratio was used to evaluate the congestion and edema of the lungs. Histopathological analysis of lung tissues was performed using hemotoxylin and eosin staining and Masson's trichrome staining. Immunohistochemical staining and western blot analyses were carried out to determine the expression of epithelial-mesenchymal transition (EMT)-related proteins in lung tissues (E-cadherin, α-smooth muscle actin [α-SMA], and vimentin). In addition, tumor necrosis factor-α (TNF-α), transforming growth factor-β1 (TGF-β1) and interleukin-6 (IL-6), hydroxyproline, malondialdehyde (MDA), and superoxide dismutase (SOD) levels were also evaluated. The ECM-derived hydrogels had good cytocompatibility and histocompatibility. ECM-derived hydrogel treatment improved lung histopathology injury and pulmonary edema. Higher expression of E-cadherin and lower expression of vimentin and α-SMA were found in the IR + ECM group compared with those in the IR + NS group. Hydroxyproline levels were reduced by ECM-derived hydrogel treatment compared with those in the IR + NS group. Obvious increases of TNF-α, IL-6, and TGF-β1 were identified following irradiation. Marked reductions in MDA content and increases in SOD were induced by ECM-derived hydrogel treatment in rats after radiation. ECM-derived hydrogels were shown to protect against RILI, potentially by reducing EMT, inflammation, and oxidative damage.

Protection against acute radiation-induced lung injury: A novel role for the anti-angiogenic agent Endostar

Abstract: Radiotherapy is commonly used to treat thoracic malignancies, but often causes severe lung injury. Currently there are no effective protective strategies against radiation-induced lung injury (RILI). This study aimed to evaluate the ability of an angiogenesis antagonist, Endostar, against RILI, and the underlying mechanism in a mouse model. A total of 108 C57BL/6 female mice were randomized into 4 groups (n=27): i) control group; ii) Endostar group, animals were administered 7.75 ml/kg Endostar through intraperitoneal injection; iii) irradiation group, RILI was induced by exposing the animals to a single external irradiation on the thoraces (6 MV X-ray, 12 Gy); and iv) irradiation plus Endostar group, animals were subjected to Endostar treatment and irradiation as in groups 2 and 3. A total of 3 animals from each of the 4 groups were sacrificed at 1, 6, 12, 24 and 72 h and at 2, 4, 8 and 24 weeks following treatment. Clinical signs and pathology of RILI were examined. The expression of transforming growth factor-β 1 (TGF-β1) in lungs was analyzed by real-time quantitative polymerase chain reaction (RT-QPCR) and immunohistochemistry. Compared with the control group, irradiation induced evident interstitial edema and a significant increase in inflammatory cells in the lungs (P<0.05). Correlated with these changes, a notable increase in TGF-β1 mRNA level and a robust increase in TGF-β1 immunoreactivity were observed in lung tissues in a time-dependent manner following irradiation (P<0.05). Endostar administration effectively attenuated the magnitude of the increase in inflammatory cells as well as the elevation of TGF-β1 expression in lung tissues after RILI (P<0.05). In conclusion, radiation induced an increased expression of the inflammatory mediator TGF-β1 and the associated pathogenesis in the lung, while Endostar was able to at least partially attenuate RILI through downregulating the expression of TGF-β1 in mice. Our findings suggest that Endostar may be a novel protective agent against RILI.