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Purpose: To assess whether BIO 300, a synthetic genistein nanosuspension, improves the therapeutic index in prostate cancer treatment by preventing radiation-induced erectile dysfunction (ED) without reducing tumor radiosensitivity., Methods and Materials: Male Sprague-Dawley rats were exposed to 25 Gy of 220-kV prostate-confined x-rays. Animals were randomized to receive sham radiation therapy (RT), RT alone, RT with daily BIO 300 at 2 experimental dosing regimens, or RT with daily genistein. Erectile response was evaluated over time. Penile shaft tissue was harvested for histologic analyses. Murine xenograft studies using prostate cancer cell lines determined the effects of BIO 300 dosing on RT efficacy., Results: Prostate-confined RT significantly decreased apomorphine-induced erectile response (P < .05 vs sham RT). Erection frequency in animals receiving prophylactic treatment with BIO 300 starting 3 days before RT was similar to sham controls after RT. Treatment with synthetic genistein did not mitigate loss in erectile frequency. At week 14, post-RT treatment with BIO 300 resulted in significantly higher quality of erectile function compared with both the RT arm and the RT arm receiving genistein starting 3 days before irradiation (P < .05). In hormone-sensitive and insensitive prostate tumor-bearing mice, BIO 300 administration did not negatively affect radiation-induced tumor growth delay., Conclusions: BIO 300 prevents radiation-induced ED, measured by erection frequency, erectile function, and erection quality, when administered 3 days before RT and continued daily for up to 14 weeks. Data also suggest that BIO 300 administered starting 2 hours after RT mitigates radiation-induced ED. Data provide strong nonclinical evidence to support clinical translation of BIO 300 for mitigation of ED while maintaining treatment response to RT., (Copyright © 2019. Published by Elsevier Inc.)

Purpose: Biomarkers serve a number of purposes during drug development including defining the natural history of injury/disease, serving as a secondary endpoint or trigger for intervention, and/or aiding in the selection of an effective dose in humans. BIO 300 is a patent-protected pharmaceutical formulation of nanoparticles of synthetic genistein being developed by Humanetics Corporation. The primary goal of this metabolomic discovery experiment was to identify biomarkers that correlate with radiation-induced lung injury and BIO 300 efficacy for mitigating tissue damage based upon the primary endpoint of survival., Methods: High-throughput targeted metabolomics of lung tissue from male C57L/J mice exposed to 12.5 Gy whole thorax lung irradiation, treated daily with 400 mg/kg BIO 300 for either 2 weeks or 6 weeks starting 24 h post radiation exposure, were assayed at 180 d post-radiation to identify potential biomarkers., Results: A panel of lung metabolites that are responsive to radiation and able to distinguish an efficacious treatment schedule of BIO 300 from a non-efficacious treatment schedule in terms of 180 d survival were identified., Conclusions: These metabolites represent potential biomarkers that could be further validated for use in drug development of BIO 300 and in the translation of dose from animal to human.

Background: The objective of the present study was to determine whether single administration of the antioxidant enzyme bovine superoxide dismutase (bSOD) after radiation therapy (RT) mitigates development of pulmonary toxicity in rats., Methods: Female F344 rats (n = 60) were divided among six experimental groups: (1) RT, single dose of 21 Gy to the right hemithorax; (2) RT + 5 mg/kg bSOD; (3) RT + 15 mg/kg bSOD; (4) No RT; (5) sham RT + 5 mg/kg bSOD; and (6) sham RT + 15 mg/kg bSOD. A single subcutaneous injection of bSOD (5 or 15 mg/kg) was administered 24 h post-radiation. The effects of bSOD on radiation-induced lung injury were assessed by measurement of body weight, breathing frequency, and histopathological changes. Immunohistochemistry was used to evaluate oxidative stress (8-OHdG(+), NOX4(+), nitrotyrosine(+), and 4HNE(+) cells), macrophage activation (ED1(+)), and expression of profibrotic transforming growth factor-β or TGF-β in irradiated tissue., Results: Radiation led to an increase in all the evaluated parameters. Treatment with 15 mg/kg bSOD significantly decreased levels of all the evaluated parameters including tissue damage and breathing frequency starting 6 weeks post-radiation. Animals treated with 5 mg/kg bSOD trended toward a suppression of radiation-induced lung damage but did not reach statistical significance., Conclusions: The single application of bSOD (15 mg/kg) ameliorates radiation-induced lung injury through suppression of reactive oxygen species/reactive nitrogen species or ROS/RNS-dependent tissue damage.

AEOL 10150 is a catalytic metalloporphyrin superoxide dismutase mimic being developed as a medical countermeasure for radiation-induced lung injury (RILI). The efficacy of AEOL 10150 against RILI through a reduction of oxidative stress, hypoxia and pro-apoptotic signals has been previously reported. The goal of this study was to determine the most effective dose of AEOL 10150 (daily subcutaneous injections, day 1-28) in improving 180-day survival in CBA/J mice after whole-thorax lung irradiation (WTLI) to a dose of 14.6 Gy. Functional and histopathological assessments were performed as secondary end points. Estimated 180-day survival improved from 10% in WTLI alone to 40% with WTLI-AEOL 10150 at 25 mg/kg (P = 0.065) and to 30% at 40 mg/kg (P = 0.023). No significant improvement was seen at doses of 5 and 10 mg/kg or at doses between 25 and 40 mg/kg. AEOL 10150 treatment at 25 mg/kg lowered the respiratory function parameter of enhanced pause (Penh) significantly, especially at week 16 and 18 (P = 0.044 and P = 0.025, respectively) compared to vehicle and other doses. Pulmonary edema/congestion were also significantly reduced at the time of necropsy among mice treated with 25 and 40 mg/kg AEOL 10150 compared to WTLI alone (P < 0.02). In conclusion, treatment with AEOL 10150 at a dose of 25 mg/kg/day for a total of 28 days starting 24 h after WTLI in CBA/J mice was found to be the optimal dose with improvement in survival and lung function. Future studies will be required to determine the optimal duration and therapeutic window for drug delivery at this dose.

With the goal to enhance the distribution of cationic Mn porphyrins within mitochondria, the lipophilic Mn(III)meso-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin, MnTnHex-2-PyP(5+) has been synthesized and tested in several different model of diseases, where it shows remarkable efficacy at as low as 50 µg/kg single or multiple doses. Yet, in a rat lung radioprotection study, at higher 0.6-1 mg/kg doses, due to its high accumulation and micellar character, it became toxic. To avoid the toxicity, herein the pulmonary radioprotection of MnTnHex-2-PyP(5+) was assessed at 50 µg/kg. Fischer rats were irradiated to their right hemithorax (28 Gy) and treated with 0.05 mg/kg/day of MnTnHex-2-PyP(5+) for 2 weeks by subcutaneously-implanted osmotic pumps, starting at 2 h post-radiation. The body weights and breathing frequencies were followed for 10 weeks post-radiation, when the histopathology and immunohistochemistry were assessed. Impact of MnTnHex-2-PyP(5+) on macrophage recruitment (ED-1), DNA oxidative damage (8-OHdG), TGF-β1, VEGF(A) and HIF-1α were measured. MnTnHex-2-PyP(5+) significantly decreased radiation-induced lung histopathological (H&E staining) and functional damage (breathing frequencies), suppressed oxidative stress directly (8-OHdG), or indirectly, affecting TGF-β1, VEGF (A) and HIF-1α pathways. The magnitude of the therapeutic effects is similar to the effects demonstrated under same experimental conditions with 120-fold higher dose of ~5000-fold less lipophilic Mn(III)meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin, MnTE-2-PyP(5+).

The development of normal lung tissue toxicity after radiation exposure results from multiple changes in cell signaling and communication initiated at the time of the ionizing event. The onset of gross pulmonary injury is preceded by tissue hypoxia and chronic oxidative stress. We have previously shown that development of debilitating lung injury can be mitigated or prevented by administration of AEOL10150, a potent catalytic antioxidant, 24h after radiation. This suggests that hypoxia-mediated signaling pathways may play a role in late radiation injury, but the exact mechanism remains unclear. The purpose of this study was to evaluate changes in the temporal expression of hypoxia-associated genes in irradiated mouse lung and determine whether AEOL10150 alters expression of these genes. A focused oligo array was used to establish a hypoxia-associated gene expression signature for lung tissue from sham-irradiated or irradiated mice treated with or without AEOL10150. Results were further verified by RT-PCR. Forty-four genes associated with metabolism, cell growth, apoptosis, inflammation, oxidative stress, and extracellular matrix synthesis were upregulated after radiation. Elevated expression of 31 of these genes was attenuated in animals treated with AEOL10150, suggesting that expression of a number of hypoxia-associated genes is regulated by early development of oxidative stress after radiation. Genes identified herein could provide insight into the role of hypoxic signaling in radiation lung injury, suggesting novel therapeutic targets, as well as clues to the mechanism by which AEOL10150 confers pulmonary radioprotection., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To identify temporal changes in protein expression in the irradiated rat lung and generate putative mechanisms underlying the radioprotective effect of the manganese superoxide dismutase mimetic MnTE-2-PyP(5+)., Methods and Materials: Female Fischer 344 rats were irradiated to the right hemithorax with a single dose of 28 Gy and killed from day 1 to 20 weeks after irradiation. Proteomic profiling was performed to identify proteins that underwent significant changes in abundance. Some irradiated rats were administered MnTE-2-PyP(5+) and changes in protein expression and phosphorylation determined at 6 weeks after irradiation., Results: Radiation induced a biphasic stress response in the lung, as shown by the induction of heme oxygenase 1 at 1-3 days and at 6-8 weeks after irradiation. At 6-8 weeks after irradiation, the down-regulation of proteins involved in cytoskeletal architecture (filamin A and talin), antioxidant defense (biliverdin reductase and peroxiredoxin II), and cell signaling (β-catenin, annexin II, and Rho-guanosine diphosphate dissociation inhibitor) was observed. Treatment with MnTE-2-PyP(5+) partially prevented the apparent degradation of filamin and talin, reduced the level of cleaved caspases 3 and 9, and promoted Akt phosphorylation as well as β-catenin expression., Conclusion: A significant down-regulation of proteins and an increase in protein markers of apoptosis were observed at the onset of lung injury in the irradiated rat lung. Treatment with MnTE-2-PyP(5+), which has been demonstrated to reduce lung injury from radiation, reduced apparent protein degradation and apoptosis indicators, suggesting that preservation of lung structural integrity and prevention of cell loss may underlie the radioprotective effect of this compound., (2010 Elsevier Inc. All rights reserved.)

Purpose: To determine whether an anti-transforming growth factor-beta (TGF-beta) type 1 receptor inhibitor (SM16) can prevent radiation-induced lung injury., Methods and Materials: One fraction of 28 Gy or sham radiotherapy (RT) was administered to the right hemithorax of Sprague-Dawley rats. SM16 was administered in the rat chow (0.07 g/kg or 0.15 g/kg) beginning 7 days before RT. The rats were divided into eight groups: group 1, control chow; group 2, SM16, 0.07 g/kg; group 3, SM16, 0.15 g/kg; group 4, RT plus control chow; group 5, RT plus SM16, 0.07 g/kg; group 6, RT plus SM16, 0.15 g/kg; group 7, RT plus 3 weeks of SM16 0.07 g/kg followed by control chow; and group 8, RT plus 3 weeks of SM16 0.15 g/kg followed by control chow. The breathing frequencies, presence of inflammation/fibrosis, activation of macrophages, and expression/activation of TGF-beta were assessed., Results: The breathing frequencies in the RT plus SM16 0.15 g/kg were significantly lower than the RT plus control chow from Weeks 10-22 (p <0.05). The breathing frequencies in the RT plus SM16 0.07 g/kg group were significantly lower only at Weeks 10, 14, and 20. At 26 weeks after RT, the RT plus SM16 0.15 g/kg group experienced a significant decrease in lung fibrosis (p = 0.016), inflammatory response (p = 0.006), and TGF-beta1 activity (p = 0.011). No significant reduction was found in these measures of lung injury in the group that received SM16 0.7 g/kg nor for the short-course (3 weeks) SM16 at either dose level., Conclusion: SM16 at a dose of 0.15 g/kg reduced functional lung damage, morphologic changes, inflammatory response, and activation of TGF-beta at 26 weeks after RT. The data suggest a dose response and also suggest the superiority of long-term vs. short-term dosing.

Development of radiation therapy (RT)-induced lung injury is associated with chronic production of reactive oxygen and nitrogen species (ROS/RNS). MnTE-2-PyP5+ is a catalytic Mn porphyrin mimic of SOD, already shown to protect lungs from RT-induced injury by scavenging ROS/RNS. The purpose of this study was to compare MnTE-2-PyP5+ with a newly introduced analogue MnTnHex-2-PyP5+, which is expected to be a more effective radioprotector due to its lipophilic properties. This study shows that Fischer rats which were irradiated to their right hemithorax (28 Gy) have less pulmonary injury as measured using breathing frequencies when treated with daily subcutaneous injections of MnTE-2-PyP5+ (3 and 6 mg/kg) or MnTnHex-2-PyP5+ (0.3, 0.6, or 1.0 mg/kg) for 2 weeks after RT. However, at 16 weeks post-RT, only MnTE-2-PyP5+ at a dose of 6 mg/kg is able to ameliorate oxidative damage, block activation of HIF-1alpha and TGF-beta, and impair upregulation of CA-IX and VEGF. MnTnHex-2-PyP5+ at a dose of 0.3 mg/kg is effective only in reducing RT-induced TGF-beta and CA-IX expression. Significant loss of body weight was observed in animals receiving MnTnHex-2-PyP5+ (0.3 and 0.6 mg/kg). MnTnHex-2-PyP5+ has the ability to dissolve lipid membranes, causing local irritation/necrosis at injection sites if given at doses of 1 mg/kg or higher. In conclusion, both compounds show an ability to ameliorate lung damage as measured using breathing frequencies and histopathologic evaluation. However, MnTE-2-PyP5+ at 6 mg/kg proved to be more effective in reducing expression of key molecular factors known to play an important role in radiation-induced lung injury.

Purpose: This study was performed to evaluate the protective benefit of amifostine against esophageal injury from fractionated radiation in a rodent model., Methods: Fractionated or sham esophageal irradiation was administered to Fisher-344 rats for 5 consecutive daily fractions of 9 Gy using 150 kV X-rays. Animals received an intraperitoneal injection of amifostine or placebo 30 min before each fraction. Histopathologic analyses for mucosal thickness, submucosal collagen deposition, activation of macrophages, oxidative stress and expression/activation of integrinalphavbeta6 and transforming growth factor (TGF)-beta were performed 5 days and 10 weeks after irradiation., Results: Pre-RT mean mucosal thickness was 35 microm in both the placebo and the amifostine groups. Five days post-RT, mean mucosal thicknesses were 30 microm in the placebo group versus 37 microm in the amifostine group (p = 0.024). At 10 weeks post-RT, the group receiving amifostine experienced a significant decrease in tunica muscularis damage (p = 0.002), submucosal collagen deposition (p = 0.027), and macrophage accumulation (p = 0.026) when compared with the placebo group. The levels of immunoreactivity for oxidative stress, TGF-beta, and integrinalphavbeta6 were significantly decreased 10 weeks post-RT in the group receiving amifostine treatment compared with placebo group., Conclusions: This study demonstrates that amifostine given before each radiation fraction protects against acute and chronic esophageal injury in a rodent model. Protection of the mucosal epithelium integrity by amifostine prevents integrinalphavbeta6 expression which reduces TGF-beta activation and subsequent development of chronic esophageal injury in this model. Further investigation is necessary to determine the clinical relevance of these findings.

Purpose: To determine whether administration of a catalytic antioxidant, Mn(III) tetrakis(N,N'-diethylimidazolium-2-yl) porphyrin, AEOL 10150, with superoxide dismutase (SOD) mimetic properties, reduces the severity of radiation-induced injury to the lung from single-dose irradiation (RT) of 28 Gy., Methods and Materials: Rats were randomly divided into four different dose groups (0, 1, 10, and 30 mg/kg/day of AEOL 10150), receiving either short-term (1 week) or long-term (10 weeks) drug administration via osmotic pumps. Rats received single-dose irradiation (RT) of 28 Gy to the right hemithorax. Breathing rates, body weights, blood samples, histopathology, and immunohistochemistry were used to assess lung damage., Results: There was no significant difference in any of the study endpoints between the irradiated controls and the three groups receiving RT and short-term administration of AEOL 10150. For the long-term administration, functional determinants of lung damage 20 weeks postradiation were significantly worse for RT + phosphate-buffered saline (PBS) and RT + 1 mg/kg/day of AEOL 10150 as compared with the irradiated groups treated with higher doses of AEOL 10150 (10 or 30 mg/kg/day). Lung histology at 20 weeks revealed a significant decrease in structural damage and collagen deposition in rats receiving 10 or 30 mg/kg/day after radiation in comparison to the RT + PBS and 1 mg/kg/day groups. Immunohistochemistry demonstrated a significant reduction in macrophage accumulation, oxidative stress, and hypoxia in rats receiving AEOL 10150 (10 or 30 mg/kg/day) after lung irradiation compared with the RT + PBS and 1 mg/kg/day groups., Conclusions: The chronic administration of a novel catalytic antioxidant, AEOL 10150, demonstrates a significant protective effect from radiation-induced lung injury. AEOL 10150 has its primary impact on the cascade of events after irradiation, and adding the drug before irradiation and its short-term administration have no significant additional benefits.

Purpose: The aim of this study was to determine whether a neutralizing transforming growth factor-beta (TGFbeta) antibody can prevent radiation (RT) induced lung injury., Methods and Materials: Fractionated and sham right lung irradiation in Fischer 344 rats was delivered to assess the radioprotective effect of the antibodies. Animals were divided into the following groups: (1) control (sham RT, control antibody 13C4); (2) RT (800cGy x 5)+13C4); (3) RT + 0.1 mg/kg 1D11 anti-TGFbeta antibody; and (4) RT + 1 mg/kg 1D11 antibody. Antibodies were intraperitoneally administered immediately after the last fraction of RT. Animals were sacrificed at 6 and 26 weeks after irradiation. Lungs were assessed for histologic changes, activation of macrophages, expression/activation of TGFbeta and its signal transduction pathway., Results: At 6 weeks post-RT, there was a significant reduction in macrophage accumulation (p = 0.041), alveolar wall thickness (p = 0.0003), and TGF-beta activation (p = 0.032) in animals receiving 1.0 mg/kg 1D11 vs. in the control group. However, at 6 weeks, the low dose of 1D11 antibody (0.1 mg/kg) failed to produce any significant changes. At 6 months post-RT, radioprotection is apparent for the group receiving 1.0 mg/kg 1D11, with activated macrophages (p = 0.037), alveolar wall thickness (p = 0.0002), TGFbeta activation (p = 0.002) and its signal transduction proteins (p < 0.05) compared with the control group., Conclusions: Administration of a single dose of 1.0 mg/kg of the anti-TGFbeta antibody 1D11 resulted in decreased morphologic changes, inflammatory response, and reduced expression and activation of TGFbeta 6 weeks and 6 months after 40 Gy to the right hemithorax. Targeting the TGFbeta pathway may be a useful strategy to prevent radiation-induced lung injury.

Purpose: Radiation-induced lung toxicity is a significant dose-limiting side effect of radiotherapy for thoracic tumors. Recombinant human keratinocyte growth factor (rHuKGF) has been shown to be a mitogen for type II pneumocytes. The purpose of this study was to determine whether rHuKGF prevents or ameliorates the severity of late lung damage from fractionated irradiation in a rat model., Methods and Materials: Female Fisher 344 rats were irradiated to the right hemithorax with a dose of 40 Gy/5 fractions/5 days. rHuKGF at dose of 5 mg/kg or 15 mg/kg was given via a single intravenous injection 10 min after the last fraction of irradiation. Animals were followed for 6 months after irradiation., Results: The breathing rate increased beginning at 6 weeks and reached a peak at 14 weeks after irradiation. The average breathing frequencies in the irradiated groups with rHuKGF (5 mg/kg and 15 mg/kg) treatment were significantly lower than that in the group receiving radiation without rHuKGF (116.5 +/- 1.0 and 115.2 +/- 0.8 vs 123.5 +/- 1.2 breaths/min, p < 0.01). The severity of lung fibrosis and the level of immunoreactivity of integrin alphavbeta6, TGFbeta1, type II TGFbeta receptor, Smad3, and phosphorylated Smad2/3 were significantly decreased only in the group receiving irradiation plus high-dose rHuKGF treatment compared with irradiation plus vehicle group, suggesting a dose response for the effect of rHuKGF., Conclusions: This study is the first to demonstrate that rHuKGF treatment immediately after irradiation protects against late radiation-induced pulmonary toxicity. These results suggest that restoration of the integrity of the pulmonary epithelium via rHuKGF stimulation may downregulate the TGF-beta-mediated fibrosis pathway. These data also support the use of rHuKGF in a clinical trial designed to prevent radiation-induced lung injury.

The objective of this study was to assess the radioprotective effects of amifostine in the rat model of radiation-induced lung injury using fractionated doses of radiation, to determine whether amifostine given before irradiation protects tumor from radiation cytotoxicity, and to determine whether changes in plasma levels of transforming growth factor (TGF)-beta correlate with radioprotective effect of amifostine. R3230 AC mammary adenocarcinoma was transplanted on the right posterior chest wall of female Fisher-344 rats. Both tumor-bearing and non-tumor-bearing animals were irradiated to the tumor or right lung using 4 MV photons and fractionated dose of 35 Gy/5 fractions/5 days. Animals with tumors and those without were randomized into 4 groups, respectively (8 to 10 rats per group), to receive (1) radiation alone; (2) radiation + amifostine; (3) amifostine alone; (4) sham radiation. Amifostine (150 mg/kg) was given intraperitoneally 30 minutes before each fraction of irradiation. The tumor size was measured twice a week. Breathing rate was assessed every 2 weeks. TGF-beta levels in plasma were assessed monthly after treatment. Six months after irradiation, animals were euthanized and lung tissue was processed for hydroxyproline content analysis. A significant increase in breathing frequency started 9 weeks after irradiation in animals that received radiation only. In the radiation + amifostine group, there was both a delay and a significantly lower peak in breathing frequency (P < .001). Hydroxyproline content was higher in the radiation-alone group than in rats given amifostine prior to radiation (P < .05). The TGF-beta levels in plasma showed an increase from 1 to 3 months after radiation, peaking at 2 months in the rats with (2.80 +/- 0.23) or without (5.32 +/- 1.21) amifostine compared to sham irradiation. TGF-beta levels were significantly lower at 1 to 3 months in rats receiving amifostine plus radiation versus those receiving radiation alone. Tumor growth delay and regrowth rate after radiation were not different between radiation-alone and radiation + amifostine groups. This study confirms the protective effect of amifostine in reducing radiation-induced pulmonary toxicity. No tumor protection was demonstrated after fractionated radiotherapy. The reduction in pulmonary injury with amifostine in paralleling lower plasma levels of TGF-beta, suggesting that monitoring plasma levels of this cytokine may reflect the efficacy of an intervention aimed at preventing radiation-induced lung injury.

Radiation-induced pulmonary toxicity causes significant morbidity and mortality in patients irradiated for lung cancer, breast cancer, lymphoma or thymoma. Amifostine is an important drug in the emerging field of cytoprotection. Recent advances in our understanding of the mechanism of radiation-induced injury at the molecular and cellular levels have stimulated interest in the development of effective radioprotective strategies. Accumulation of macrophages with associated production of reactive oxygen species (ROS) and production and activation of cytokines is a key process involved in the pathophysiology of radiation injury in the lung. The purpose of this study was to determine whether the mechanism of radioprotection by amifostine includes reduction in both macrophage activity and the expression and activation of profibrogenic cytokines. Our results demonstrated a reduction in both functional and histological radiation-induced lung injury by amifostine. In addition, this study is the first to demonstrate that amifostine given prior to irradiation reduced both the accumulation of macrophages and the expression/activation of lung tissue Tgfb1 which was followed by the reduction of plasma Tgfb1 levels during the development of radiation-induced lung injury. Future studies are needed to determine whether administration of amifostine both during and after radiotherapy may further increase its radioprotective effect.

Cerium oxide nanoparticles (CNPs) have a unique surface regenerative property and can efficiently control reactive oxygen/nitrogen species. To determine whether treatment with CNPs can mitigate the delayed effects of lung injury after acute radiation exposure, CBA/J mice were exposed to 15 Gy whole-thorax radiation. The animals were either treated with nanoparticles, CNP-18 and CNP-ME, delivered by intraperitoneal injection twice weekly for 4 weeks starting 2 h postirradiation or received radiation treatment alone. At the study's end point of 160 days, 90% of the irradiated mice treated with high-dose (10 μ M) CNP-18 survived, compared to 10% of mice in the radiation-alone ( P < 0.0001) and 30% in the low-dose (100 n M) CNP-18. Both low- and high-dose CNP-ME-treated irradiated mice showed increased survival rates of 40% compared to 10% in the radiation-alone group. Multiple lung functional parameters recorded by flow-ventilated whole-body plethysmography demonstrated that high-dose CNP-18 treatment had a significant radioprotective effect on lethal dose radiation-induced lung injury. Lung histology revealed a significant decrease ( P < 0.0001) in structural damage and collagen deposition in mice treated with high-dose CNP-18 compared to the irradiated-alone mice. In addition, significant reductions in inflammatory response ( P < 0.01) and vascular damage ( P < 0.01) were observed in the high-dose CNP-18-treated group compared to irradiated-alone mice. Together, the findings from this preclinical efficacy study clearly demonstrate that CNPs have both clinically and histologically significant mitigating and protective effects on lethal dose radiation-induced lung injury. [ABSTRACT FROM AUTHOR]