CN111679071A - Use of heme oxygenase-1 for diagnosis and treatment of radiation-induced lung injury - Google Patents
Use of heme oxygenase-1 for diagnosis and treatment of radiation-induced lung injury Download PDFInfo
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Abstract
The invention belongs to the field of molecular biological diagnosis and treatment of radioactive lung injury, and particularly relates to application of heme oxygenase-1 in diagnosis and treatment of radioactive lung injury. The invention finds that insufficient HO-1 content can cause serious radioactive lung injury, so that the radioactive lung injury can occur if HO-1 in blood is reduced for a patient treated by high-dose X-ray radiation. Drugs that enhance the expression and function of HO-1, such as Hemin, can be used as new methods for the treatment of radiation-induced lung injury.
Description
Technical Field
The invention belongs to the field of molecular biological diagnosis and treatment of radioactive lung injury, and particularly relates to application of heme oxygenase-1 in diagnosis and treatment of radioactive lung injury.
Background
Radiation-induced lung injury (RILI) is a very common complication following radiation therapy of breast malignancies and is a fatal disease characterized primarily by interstitial pneumonia and pulmonary fibrosis. The clinical manifestations of RILI are cough, shortness of breath, fever, respiratory insufficiency and severe respiratory failure. At present, only hormone can be used for treatment by combining antibiotics, vitamins, antioxidants and other medicaments, and although certain curative effect can be achieved, the adverse reaction caused by the hormone is more (see the documents: Kalman NS, Zhao SS, Anscher MS, Urdaneta AI. Current Status of targeted radiotherapy and Radiation injection and treatment agents: A Critical Review of the liver, int J radial Oncolol Biophys 2017; 98: 662) is provided. At present, the occurrence mechanism of RILI is not clear, effective prediction indexes and treatment measures are lacked, the radiotherapy dosage of tumors is limited, the subsequent treatment and the life quality of patients are seriously influenced, the bottleneck for improving the radiotherapy curative effect of breast tumors is formed, and even the life safety of the patients is endangered. Because the RILI has high morbidity (15.5-36 percent) and a special treatment means is lacked, a heavy burden is brought to the society and families. Therefore, the molecular pathological mechanism of early RILI is explored, and effective drug targets are discovered and identified, so that the method has great significance for preventing and treating RILI.
The latest research finds that: excessive macrophage activation, production and release of large amounts of inflammatory factors to damage lung tissue are key mechanisms of RILI. Promotion of the conversion of macrophage M1 to M2 phenotype improved the development of RILI, while M1-type macrophages promoted the pathological progression of RILI (ref: Li Y, Lu H, Lv X, Tang Q, Li W, Zhu H, et al. Block of Aquaporin 4 inhibitors Irradation-Induced purification and modulation of pathological Polarization in Mice. Inflammation 2018; 41: 2196-20). Therefore, finding a way to inhibit macrophage hyperactivity upon high dose radiation is a novel approach to control RILI.
Heme oxygenase 1 (HO-1) is a rate-limiting enzyme for heme metabolism, and is mainly present in macrophages. As a stress protein, HO-1 has important functions of obvious anti-inflammation, anti-oxidative stress, anti-airway smooth muscle cell proliferation and the like, and HO-1 not only has anti-inflammation and anti-oxidation effects after high expression, but also has strong anti-inflammation and anti-oxidation effects of catalytic products of the HO-1, such as biliverdin, bilirubin, ferrous iron and carbon monoxide. HO-1 has been found to show protective effect on a plurality of lung diseases such as acute lung injury of sepsis, pulmonary fibrosis induced by bleomycin and chronic obstructive disease, but the effect and the mechanism of HO-1 in RILI induced by large-dose X-ray are not researched and reported at present.
Disclosure of Invention
In response to the current lack of an accurate predictive and effective method for treating RILI, the present invention provides for the use of heme oxygenase 1. The expression of various inflammatory factors of macrophage specificity HO-1 knockout mice RILI is obviously increased, and lung tissues are obviously aggravated.
In order to solve the above technical problems, the present invention provides a basis for the use of heme oxygenase-1 in the diagnosis and treatment of RILI drugs.
Use of heme oxygenase-1 in the manufacture of a kit for diagnosis of RILI.
Use of heme oxygenase-1 in the manufacture of a medicament for the treatment of RILI.
The role of HO-1 in the generation of RILI was first clarified. Establishing a RILI mouse model, extracting total protein in lung tissues of the RILI mouse, and detecting the expression level of HO-1 through immunoblotting, wherein experimental results show that X-ray can remarkably induce the expression of HO-1 in the lung tissues; in addition, by isolating RILI mouse lung macrophages and detecting their HO-1 expression, the results showed that X-ray can induce increased HO-1 expression in lung macrophages. These findings indicate that large doses of X-rays can promote large amounts of HO-1 expression in macrophages.
Mouse bone marrow-derived macrophage (BMDMs) cells are pretreated by using a HO-1 specific inhibitor ZnPP (10 mu M) for 30 minutes, then the cells are irradiated by X-ray, after 6 hours, the cells are lysed by Trizol, and the expression conditions of TNF-alpha, IL-1 beta and IL-6 are detected by fluorescent quantitative PCR (polymerase chain reaction), so that the mRNA levels of the TNF-alpha, the IL-1 beta and the IL-6 can be obviously increased by the ZnPP. It is suggested that inhibition of HO-1 function will cause macrophages to produce large amounts of pro-inflammatory factors, causing severe inflammatory reactions in lung tissue. The specific inhibitor ZnPP promotes macrophage activation induced by irradiation.
To accurately elucidate the role of heme oxygenase-1 in the diagnosis and treatment of RILI, the present invention further providesStep (a) establishes a specific HO-1 knockout (HO-1) of macrophageLyz2-KO) Mouse RILI model. The results show that: the number of inflammatory cells in the lung tissue of the macrophage-specific HO-1 gene knockout mouse is obviously increased, and the lung tissue is obviously damaged. At the same time, at the cellular level, we isolated HO-1Lyz2-WTAnd HO-1Lyz2-KOMouse BMDM is irradiated by X-rays, cells are lysed by Trizol after 6 hours, the expression conditions of TNF- α, IL-1 β and IL-6 are detected by fluorescence quantitative PCR, and the result shows that the mRNA level of proinflammatory factors such as TNF- α, IL-1 β, IL-6 and the like is remarkably increased after the macrophage with HO-1 deletion is irradiated, which indicates that the macrophage induced by the X-rays releases a large amount of inflammatory factors due to the HO-1 deletion, and the fact that the reduction of HO-1 content inevitably promotes the occurrence of RILI is confirmed by using the mouse and the BMDM subjected to macrophage specific HO-1 knockout.
Further illustrating the use of heme oxygenase-1 in the diagnosis and treatment of RILI, the present invention investigates the role of MK2 and FoxO3a, in which heme oxygenase-1 plays a key role in inflammatory factor production. The results show that: HO-1Lyz2-KOThe phosphorylation level of macrophage FoxO3a of the mouse is obviously increased; the HO-1 specific inhibitor ZnPP can also remarkably up-regulate the phosphorylation of MK2 in the macrophage derived from the bone marrow of an X-ray irradiated mouse; while the HO-1 inducer, Hemin, can inhibit X-ray induced phosphorylation of MK 2.
The invention has the beneficial effects that:
the present inventors have found that insufficient levels of HO-1 will result in severe RILI, so that treatment of patients with large doses of X-ray radiation will result in RILI if HO-1 in the blood is reduced, and thus the determination of HO-1 levels in peripheral blood can be used as a new biomarker for diagnosis of RILI. Meanwhile, since the reduction of HO-1 content or the functional limitation will cause serious radioactive lung tissue damage, drugs for enhancing the expression and function of HO-1, such as HO-1 inducer Hemin, can be used as a new method for RILI treatment.
Drawings
FIG. 1 is a graph of the establishment of the mouse RILI model.
FIG. 2 is a graph showing the expression of HO-1 in lung tissue and lung macrophages after chest irradiation with X-rays (13.5Gy) and 7 days later.
FIG. 3 is a graph showing the expression of HO-1 in BMDM after different times (0,1,3,6,12,24h) after X-ray (6Gy, dose rate of 600cGy/min) irradiation.
FIG. 4 is a schematic diagram of the construction and identification of macrophage-specific HO-1 knockout mice.
FIG. 5 RILI lung tissue pathology section of macrophage specific HO-1 knockout mice.
FIG. 6 is a graph of the change in inflammatory factor expression following 6Gy radiation for macrophage specific HO-1 knockout and undeleted BMDM.
FIG. 7A graph of the change in expression of the 10 μ M ZnPP pre-treatment on X-ray stimulated BMDM inflammatory factor for the HO-1 specific inhibitor.
FIG. 8X-ray stimulated HO-1Lyz2-WTAnd HO-1Lyz2Graph of activation level of BMDM FoxO3a in KO mice.
FIG. 9 is a graph of the effect of the HO-1 specific inhibitor ZnPP on MK2 phosphorylation in X-ray stimulated BMDM.
FIG. 10 is a graph of the effect of the HO-1 inducer, Hemin, on MK2 phosphorylation in X-ray stimulated BMDM.
Detailed Description
The following examples are given to enable a person skilled in the art to fully understand the invention, but do not limit it in any way.
Example 1: establishment of mouse RILI model
To match as closely as possible the secondary RILI induced by clinical thoracic tumor radiotherapy, we chose to locally irradiate the lungs of mice: after anesthetizing, the mice were fixed in an X-RAD SmART small animal radiotherapy simulated locator by using a biological adhesive tape, so that the mice were kept in a prone position, the two upper limbs are forward, the two lower limbs are backward, the four limbs are balanced and straightened, and the lung irradiation range is outlined under the guidance of CT positioning (figure 1A) to avoid the heart and the spine as much as possible (figure 1B). After the lung of the mouse is positioned, X-ray single irradiation is adopted for 13.5Gy, the dose rate is 3Gy/min, after irradiation is finished, the mouse is taken down and put back into a feeding cage for normal feeding, the material is taken after 7 days, and the lung injury condition of the mouse is analyzed.
The experimental results are as follows:
by H & E staining analysis of mouse lung tissue section pathology, we found that after X-ray irradiation, alveolar structure destruction, erythrocytosis and inflammatory cell infiltration increase in mouse lung tissue (FIG. 1C), indicating that the research successfully establishes a mouse RILI model.
Example 2: measurement of HO-1 expression in Lung tissue and Lung macrophages of RILI mice
To investigate whether HO-1 is involved in the regulation of RILI, total protein in lung tissue of RILI mice was extracted and the expression level of HO-1 was detected by immunoblotting.
The experimental results are as follows: x-ray can significantly induce the expression of HO-1 in lung tissue (FIGS. 2A and 2C), suggesting that HO-1 is involved in X-ray induced RILI. In addition, the results of this study, which isolated RILI mouse lung macrophages and tested for HO-1 expression, showed that X-ray induced increased HO-1 expression in lung macrophages (FIGS. 2B and 2D), suggesting that HO-1 may be involved in RILI by regulating macrophage function.
EXAMPLE 3 measurement of HO-1 expression at different times in Lung macrophages induced by high dose (6Gy, dose rate of 600cGy/min)
Mouse bone marrow-derived macrophages (BMDMs) were isolated and harvested after X-ray irradiation for various periods of time (0,1,3,6,12,24h) and the expression level of HO-1 was detected by immunoblotting.
The experimental results are as follows: the immunoblotting found that HO-1 was induced to be expressed in X-ray irradiated macrophages and reached a peak expression at 6 hours (FIG. 3)
Example 4 construction and identification of macrophage HO-1 specific knockout mice
Macrophage HO-1 specific knockout (HO-1)Lyz2-KO) The mice are hybridized by Cre-loxP technology, and after 2 weeks of birth, the mouse tails are cut off from the F1 mouse, and genomic DNA is extracted to detect the mouse genotype by PCR. Isolation and culture of Alveolar Macrophages (AMs): collecting 8-10 week old wild type (HO-1)Lyz2-WT) And macrophage specific HO-1 knockout (HO-1)Lyz2-KO) Injecting DPBS into a lung through a trachea to wash an alveolus, collecting alveolar lavage fluid, after red blood cells are cracked, incubating in an incubator for 2 hours, and then discarding a supernatant, wherein adherent cells are alveolar macrophages. The content of HO-1 in macrophages is detected by an immunoblotting method.
The experimental results are as follows:
the PCR identification result of the 1F 1 mouse is shown in FIG. 2A, the upper part is HO-1loxPIdentification of (2), PCR product size: the wild type is 254bp, and KI is 288 bp. Cre identification is carried out below, and the size of a PCR product is 272 bp. As can be seen from the results of the identification, 5 of the 10F 1-generation mice obtained were heterozygous mice (mice numbered 3,6, 7, 9, and 10 in FIG. 3A), among which
Breeding 11 mice of F2 generation after the mice of F1 generation are caged, and obtaining the target HO-1 by adopting the same identification method as the F1 generation after identification Lyz22 mice with-KO (mice numbered 3 and 8 in FIG. 3B).
The detection of the HO-1 expression of the knockout mouse by the immunoblotting method also proves that the HO-1 isLyz2-KOThe derived macrophages did not express HO-1 (FIG. 3D), while there was no significant change in HO-1 expression in lung tissue (FIG. 3E), suggesting that we succeeded in establishing macrophage-specific HO-1 knockout mice.
Example 5 Effect of HO-1 on mouse RILI
By HO-1Lyz2-WTMouse and HO-1Lyz2-KOMouse, RILI model, 7 days later, lung tissue section pathological H&E staining analysis of mouse lung injury.
The experimental results are as follows:
lung tissue section pathology H&E staining shows HO-1Lyz2-KOThe mice had significantly increased inflammatory cell infiltration and increased lung injury (FIG. 5), indicating that HO-1 mediates RILI by regulating macrophages.
Example 6 role of HO-1 in X-ray-induced secretion of proinflammatory cytokines from macrophages
Isolation of mouse Bone Marrow Differentiated Macrophages (BMDMs) and HO-1Lyz2-KOOn a wild bone marrow differentiation macrophage model, a HO-1 specific inhibitor Znpp (10 mu M) is selected to pre-treat BMDM cells for 30 minutes, then the BMDM cells are irradiated by 6GyX-ray, after 6 hours, the cells are lysed by Trizol, and the change conditions of the HO-1 specific inhibitor Znpp and the macrophage specific knockout HO-1 to TNF- α, IL-1 β and IL-6mRNA are detected by fluorescent quantitative PCR.
The experimental results are as follows:
fluorescent quantitative PCR found that the mRNA levels of TNF- α, IL-1 β and IL-6 were elevated in macrophages 6h after X-ray irradiation, indicating that irradiation was able to induce macrophage activation (FIG. 6)Lyz2-WTMouse macrophage, HO-1Lyz2-KOAfter mouse macrophages are irradiated by X rays, the expressions of TNF- α, IL-1 β and IL-6 are obviously increased (figure 7), which shows that the inhibition of HO-1 function or gene deletion can cause macrophage activation induced by irradiation and release of a large amount of inflammatory factors.
Example 7 HO-1 inhibits the level of macrophage FoxO3a activation
The release of macrophage inflammatory mediators is an important link for RILI generation, the generation of M1 cytokines such as TNF- α, IL-6 and the like induced by radiation is inhibited, early RILI can be relieved, FoxO3a is mainly expressed in myeloid cells such as macrophages and is mainly regulated and controlled after translation by phosphorylation, FoxO3a can be combined with NF-kappa B in cytoplasm, and the transport of NF-kappa B to nucleus is promoted after phosphorylation, so that the transcriptional activity of NF-kappa B is enhanced, and the expression of proinflammatory factors such as TNF- α, IL-6 and the like is increasedLyz2-WTAnd HO-1Lyz2-KOMouse BMDM and irradiated by X-ray (6Gy), after 6 hours the cells were lysed with RIPA lysate containing protease inhibitors, and the phosphorylation levels of FoxO3a and NF-. kappa.B were determined by immunoblotting.
The experimental results are as follows:
x-ray is capable of inducing FoxO3a phosphorylation, and HO-1Lyz2-KOThe phosphorylation level of mouse macrophage FoxO3a was significantly increased (fig. 8), which suggests that FoxO3a is involved in X-ray induced macrophage activation, and HO-1 is an important signaling molecule that regulates phosphorylation of FoxO3 a.
Example 8 HO-1 modulates levels of protein kinase 2(MK2) activation by macrophage MAPK activation
MK2 is capable of modulating the release of inflammatory mediators such as TNF-alpha and IL-6 from macrophages. Thus, the pathological process of MK2RILI plays an important role. BMDM cells are pretreated by using a HO-1 specific inhibitor Znpp (10 mu M) and a HO-1 inducer Heme (10 mu M) for 30 minutes respectively, then are irradiated by X-ray, and after 6 hours, the cells are cracked by RIPA lysate containing a protease inhibitor, and the phosphorylation level of an MK 2T 334 site is detected by immunoblotting.
The experimental results are as follows:
x-ray can induce MK2 phosphorylation, suggesting that MK2 is involved in X-ray-induced macrophage activation. Furthermore, we found that the HO-1 specific inhibitor ZnPP can significantly up-regulate the phosphorylation of MK2 (FIG. 9), while the HO-1 inducer Hemin can inhibit X-ray induced phosphorylation of MK2 (FIG. 10), which suggests that MK2 is involved in X-ray induced macrophage activation, and HO-1 is an important signal molecule for regulating MK2 phosphorylation.
The above experimental results fully demonstrate that inhibition of HO-1 function or underexpression will lead to severe RILI, so that RILI can be predicted by detecting the HO-1 content in blood for patients treated with large clinical doses of X-ray radiation. At the same time, the search for drugs that are effective in increasing the expression and function of HO-1 can be used for the treatment of RILI. Therefore, the HO-1 can be used as a new important target for clinically diagnosing and treating RILI, and has great clinical application value in the prevention and treatment of RILI.
The above examples are only for illustrating the technical idea and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the content of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
Claims (2)
1. Use of heme oxygenase-1 in the manufacture of a kit for the diagnosis of radiation-induced lung injury.
2. Use of heme oxygenase-1 in the manufacture of a medicament for the treatment of radiation-induced lung injury.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112618731A (en) * | 2020-12-16 | 2021-04-09 | 江南大学 | Application of HO-1 gene in preparation of drugs for treating drowning lung injury |
| WO2024090329A1 (en) * | 2022-10-24 | 2024-05-02 | 国立大学法人東北大学 | Composition for ameliorating inflammation associated with chronic hypoxia |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080159962A1 (en) * | 2005-05-19 | 2008-07-03 | Imba-Institute Fur Molekulare Biotechnologie Gmbh | Use of Inhibitors of the Renin-Angiotensin System for the Treatment of Lung Injuries |
| CN104107419A (en) * | 2014-05-29 | 2014-10-22 | 四川大学华西医院 | Application of ghrelin in prevention or/and treatment of radiation-induced lung injury |
| CN107823211A (en) * | 2017-11-22 | 2018-03-23 | 中国人民解放军第二军医大学 | Application of the gucosamine in preparing ionising radiation and causing induced lung injury protective agents |
-
2020
- 2020-06-17 CN CN202010554764.0A patent/CN111679071A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080159962A1 (en) * | 2005-05-19 | 2008-07-03 | Imba-Institute Fur Molekulare Biotechnologie Gmbh | Use of Inhibitors of the Renin-Angiotensin System for the Treatment of Lung Injuries |
| CN104107419A (en) * | 2014-05-29 | 2014-10-22 | 四川大学华西医院 | Application of ghrelin in prevention or/and treatment of radiation-induced lung injury |
| CN107823211A (en) * | 2017-11-22 | 2018-03-23 | 中国人民解放军第二军医大学 | Application of the gucosamine in preparing ionising radiation and causing induced lung injury protective agents |
Non-Patent Citations (3)
| Title |
|---|
| P.R.GRAVES等: "The Role of Nitric Oxide Synthase and Heme Oxygenase I in Radiation-induced Lung Injury", 《INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY*BIOLOGY*PHYSICS》 * |
| 俞静等: "HO-1激动剂Copp对放射所致内皮细胞凋亡的抑制作用", 《上海交通大学学报(医学版)》 * |
| 杨涪等: "表没食子儿茶素没食子酸酯作为Nrf2/ARE信号通路激活剂的研究进展", 《中国药理学与毒理学杂志》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112618731A (en) * | 2020-12-16 | 2021-04-09 | 江南大学 | Application of HO-1 gene in preparation of drugs for treating drowning lung injury |
| WO2024090329A1 (en) * | 2022-10-24 | 2024-05-02 | 国立大学法人東北大学 | Composition for ameliorating inflammation associated with chronic hypoxia |
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