Renin-Angiotensin System Inhibitors Might Help to Reduce the Development of Symptomatic Radiation Pneumonitis After Stereotactic Body Radiotherapy for Lung Cancer

Bracci, Stefano; Valeriani, Maurizio; Agolli, Linda; Sanctis, Vitaliana De; Enrici, Riccardo Maurizi; Osti, Mattia Falchetto

doi:10.1016/j.cllc.2015.08.007

Cited by 27 publications

(14 citation statements)

References 42 publications

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“…Findings in animal model systems promoted the study of ACE and ARBs for treatment of human fibrotic disease. Clinical trials have also demonstrated that ACE inhibitors reduce medical radiotherapy‐induced kidney and lung fibrosis . The mechanism(s) by which ACE inhibitors and Ang II receptor antagonists inhibit fibrotic remodelling are not completely understood.…”

Section: Discussionmentioning

confidence: 99%

Captopril mitigates splenomegaly and myelofibrosis in the Gata1^low murine model of myelofibrosis

Corey

Jha

McCart

et al. 2018

J Cellular Molecular Medi

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Allogeneic stem cell transplantation is currently the only curative therapy for primary myelofibrosis (MF), while the JAK2 inhibitor, ruxolitinib. Has been approved only for palliation. Other therapies are desperately needed to reverse life‐threatening MF. However, the cell(s) and cytokine(s) that promote MF remain unclear. Several reports have demonstrated that captopril, an inhibitor of angiotensin‐converting enzyme that blocks the production of angiotensin II (Ang II), mitigates fibrosis in heart, lung, skin and kidney. Here, we show that captopril can mitigate the development of MF in the Gata1 low mouse model of primary MF. Gata1 low mice were treated with 79 mg/kg/d captopril in the drinking water from 10 to 12 months of age. At 13 months of age, bone marrows were examined for fibrosis, megakaryocytosis and collagen expression; spleens were examined for megakaryocytosis, splenomegaly and collagen expression. Treatment of Gata1 low mice with captopril in the drinking water was associated with normalization of the bone marrow cellularity; reduced reticulin fibres, splenomegaly and megakaryocytosis; and decreased collagen expression. Our findings suggest that treating with the ACE inhibitors captopril has a significant benefit in overcoming pathological changes associated with MF.

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Section: Discussionmentioning

confidence: 99%

Captopril mitigates splenomegaly and myelofibrosis in the Gata1^low murine model of myelofibrosis

Corey

Jha

McCart

et al. 2018

J Cellular Molecular Medi

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“… 77 78 Second, inhibiting the Renin-Angiotensin system may reduce the development of symptomatic radiation pneumonitis. 79 80 However, evidence in defining this issue is largely lacking. Therefore, by combined severe pneumonopathy as a whole, our data confirmed CKD increased a small but substantial risk of hospitalised pneumonia/pneumonitis occurrence in post-operative irradiated lung cancer patients (adjusted HR, 1.41; 95% CI, 1.10–1.82; p=0.006; table 2 and figure 3D ), supporting a potential hazard effect of CKD in radiation-associated pneumonopathy.…”

Section: Discussionmentioning

confidence: 99%

Irradiation enhanced risks of hospitalised pneumonopathy in lung cancer patients: a population-based surgical cohort study

et al. 2017

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ObjectivePulmonary radiotherapy has been reported to increase a risk of pneumonopathy, including pneumonitis and secondary pneumonia, however evidence from population-based studies is lacking. The present study intended to explore whether postoperative irradiation increases occurrence of severe pneumonopathy in lung cancer patients.Design, setting and participantsThe nationwide population-based study analysed the Taiwan National Health Insurance Research Database (covered >99% of Taiwanese) in a real-world setting. From 2000 to 2010, 4335 newly diagnosed lung cancer patients were allocated into two groups: surgery-RT (n=867) and surgery-alone (n=3468). With a ratio of 1:4, propensity score was used to match 11 baseline factors to balance groups.Interventions/exposure(s)Irradiation was delivered to bronchial stump and mediastinum according to peer-audited guidelines.Outcome(s)/measure(s)Hospitalised pneumonia/pneumonitis-free survival was the primary end point. Risk factors and hazard effects were secondary measures.ResultsMultivariable analysis identified five independent risk factors for hospitalised pneumonopathy: elderly (>65 years), male, irradiation, chronic obstructive pulmonary disease (COPD) and chronic kidney disease (CKD). Compared with surgery-alone, a higher risk of hospitalised pneumonopathy was found in surgery-RT patients (HR, 2.20; 95% CI, 1.93–2.51; 2-year hospitalised pneumonia/pneumonitis-free survival, 85.2% vs 69.0%; both p<0.0001), especially in elderly males with COPD and CKD (HR, 13.74; 95% CI, 6.61–28.53; p<0.0001). Unexpectedly, we observed a higher risk of hospitalised pneumonopathy in younger irradiated-CKD patients (HR, 13.07; 95% CI, 5.71–29.94; p<0.0001) than that of elderly irradiated-CKD patients (HR, 4.82; 95% CI, 2.88–8.08; p<0.0001).ConclusionsA high risk of hospitalised pneumonopathy is observed in irradiated patients, especially in elderly males with COPD and CKD. For these patients, close clinical surveillance and aggressive pneumonia/pneumonitis prevention should be considered. Further investigations are required to define underlying biological mechanisms, especially for younger CKD patients.

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“…Subcutaneous Tumor-Bearing of Nude Mice BALB/cJGpt-Foxn1 nu /Gpt mice were subcutaneously injected with 1×10 6 of Rac1-NC/Rac1-SH LLC cells on the right hind leg. Tumor volume (mm 3 ) of each mouse was measured by a Vernier caliper on the 12 nd , 15 th , 18 th , 21 st and 24 th days after tumor-bearing, and was calculated as the longest diameter (mm)×the shortest diameter (mm )2 .…”

Section: Rili Mouse Modelmentioning

confidence: 99%

“…After cell counting, each mouse was injected with 2×10 6 corresponding cells (LLC) suspended in a 50ul mixture of 1:1 medium and matrigel, on the right lung through incision under the right axillary. On the designed week after tumor bearing, mice from each group were sacri ced by cervical dislocation and the tumor mass of each mouse was measured.…”

Section: Orthotopic Lung Tumor-bearing Mouse Modelmentioning

confidence: 99%

“…Therefore, seeking the molecular target that can mediate such a bidirectional effect has become the key to improving tumor radiotherapy. According to previous studies, being involved in oxidative stress [4][5][6] , DNA damage 7,8 and epithelial-mesenchymal transition (EMT) 9,10 , Rac1 may be an important molecule that mediates radiation damage. Besides, Rac1 is over-expressed or mutated in various tumors 11 .…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of Rac1 Attenuates Radiation-Induced Lung Injury while Sensitizes Lung Tumor to Radiotherapy

Yan

et al. 2020

Preprint

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Backgrounds: There is still little progress in the effective treatment of radiation-induced lung injury (RILI), a key dose-limiting factor for thoracic radiotherapy. Ras-related C3 botulinum toxin substrate1, Rac1, is a small guanosine triphosphatase involved in various mechanisms of radiation-induced damage and is over-expressed/mutated in various tumors. The gain-of-function mutation of Rac1 mediates tumor cells’ resistance to radiotherapy. Therefore, inhibiting Rac1 has the potential of protecting normal tissues from radiation-induced injury, and at the same time, sensitizing tumor to radiation therapy, which makes it a promising ideal target for radiation protection. To investigate the protective effects and mechanisms of Rac1 inhibition on RILI, and explore the possible mechanisms that mediate the differential effects of Rac1 inhibition on normal lung tissue and tumor cells.Methods: 60Co radioactive source was used for ionizing radiation (IR). RILI mouse model was constructed. Influence of Rac1 inhibition which was achieved by Rac1-specific inhibitor, NSC23766, on RILI were studied by H & E and Masson staining, and immunohistochemical staining of vimentin, TGF-βand γ-H2AX. Normal mouse lung epithelial cell line, MLE-12, and mouse lung cancer cell line, LLC, were used to study the effects of Rac1 inhibition on the cellular level. RNA-seq analysis was used for screening differential gene expression caused by Rac1 knockdown. The molecular mechanisms of Rac1 inhibition were studied at the cellular level. Subcutaneous tumor-bearing nude mouse model and orthotopic lung tumor-bearing mouse model were constructed to verify the bidirectional effects of Rac1 inhibition in vivo. Results: RILI of mouse was alleviated by intraperitoneal injection of NSC23766. Rac1 inhibition/knockdown reduced the radiation-induced damage of MLE-12 while aggravated that of LLC. Rac1 translocated from cytoplasm to nucleus after radiation. Tumor protein p53-inducible nuclear protein 1, Trp53inp1, was down-regulated by Rac1 knockdown. In vivo study further proved the differential effects of Rac1 inhibition. Rac1 was over-expressed and mutated in LLC cells, and the expression level of Trp53inp1 significantly lower, compared with that of MLE-12.Conclusion: Rac1 inhibition reduced the radiation-induced damage of normal lung epithelial cells, thereby alleviating RILI of mouse. These effects were partially mediated by down-regulating the expression of Trp53inp1. However, Rac1 inhibition significantly increased the sensitivity of LLC to radiation damage and inhibited its growth. The over-expression and mutation of Rac1, and the significant low expression of Trp53inp1 in LLC, may be the fundamental reasons mediating the differential effects of Rac1 inhibition.

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Renin-Angiotensin System Inhibitors Might Help to Reduce the Development of Symptomatic Radiation Pneumonitis After Stereotactic Body Radiotherapy for Lung Cancer

Cited by 27 publications

References 42 publications

Captopril mitigates splenomegaly and myelofibrosis in the Gata1^low murine model of myelofibrosis

Captopril mitigates splenomegaly and myelofibrosis in the Gata1^low murine model of myelofibrosis

Irradiation enhanced risks of hospitalised pneumonopathy in lung cancer patients: a population-based surgical cohort study

Inhibition of Rac1 Attenuates Radiation-Induced Lung Injury while Sensitizes Lung Tumor to Radiotherapy

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Renin-Angiotensin System Inhibitors Might Help to Reduce the Development of Symptomatic Radiation Pneumonitis After Stereotactic Body Radiotherapy for Lung Cancer

Cited by 27 publications

References 42 publications

Captopril mitigates splenomegaly and myelofibrosis in the Gata1low murine model of myelofibrosis

Captopril mitigates splenomegaly and myelofibrosis in the Gata1low murine model of myelofibrosis

Irradiation enhanced risks of hospitalised pneumonopathy in lung cancer patients: a population-based surgical cohort study

Inhibition of Rac1 Attenuates Radiation-Induced Lung Injury while Sensitizes Lung Tumor to Radiotherapy

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Captopril mitigates splenomegaly and myelofibrosis in the Gata1^low murine model of myelofibrosis

Captopril mitigates splenomegaly and myelofibrosis in the Gata1^low murine model of myelofibrosis