CN115282151A - Application of lamitiniron - Google Patents
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- CN115282151A CN115282151A CN202211017164.6A CN202211017164A CN115282151A CN 115282151 A CN115282151 A CN 115282151A CN 202211017164 A CN202211017164 A CN 202211017164A CN 115282151 A CN115282151 A CN 115282151A
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- pulmonary fibrosis
- lamitriptonide
- lamivudine
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- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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Abstract
The invention discloses an application of lamivudine in preventing and treating pulmonary fibrosis diseases. The invention determines the regulating effect and the acting potential mechanism of lamitriptonide on lung tissue lesion, uses the lamitriptonide as a novel drug action target spot, is applied to preventing and treating pulmonary fibrosis diseases, and finds that the application of lamitriptonide can inhibit the pathological change of lung in the pulmonary fibrosis process. The lamitriptonide is found to inhibit the activation of fibroblasts and improve the deposition of extracellular matrix, and the lamitriptonide is found to have the effects of preventing and treating the progressive pulmonary fibrosis of mice, and can be used as a medicament for preventing and treating the pulmonary fibrosis.
Description
Technical Field
The invention relates to the technical field of lamianten, in particular to application of lamianten.
Background
Idiopathic Pulmonary Fibrosis (IPF) is a chronic progressive interstitial lung disease, the etiology and pathogenesis of which are not clear. Lesions are mainly localized to the lungs, well-established in middle-aged and elderly men, whose lung histopathology and/or high-resolution CT (HRCT) of the chest characteristically manifest as interstitial pneumonia of the usual type. Clinical features are progressive scarring or fibrosis localized to the interstitial spaces of the lungs, leading to loss of lung function, with symptoms including dry cough, exertional dyspnea, and fatigue. In the advanced stages of the disease, the skin may appear blue stained (cyanosis) and the tips of the fingers may thicken or rod-like as the blood oxygen level decreases. As the condition progresses, signs of pulmonary hypertension and right heart failure are also observed, eventually leading to death, with median survival of only 3-5 years after patient diagnosis. Prednisone, azathioprine and N-acetylcysteine (NAC) have begun to be used to treat the symptoms associated with IPF, but do not significantly increase life expectancy. Lung transplantation is the choice of a subset of patients and can improve quality of life and life expectancy.
Melatonin belongs to indole heterocyclic compounds, and is mainly used for improving sleep quality and participating in synchronization of circadian rhythms. In addition, research shows that the medicine has an anti-fibrosis effect in organs such as heart, liver, lung, kidney and the like. In earlier studies, we found that melatonin was able to exert anti-pulmonary fibrosis effects via its receptors MT1/MT 2. Lamisterone is approved as a selective melatonin receptor agonist in the U.S. and japan for the treatment of insomnia characterized by difficulty in sleep onset, while lamisterone also has anti-inflammatory, antioxidant, etc. effects. Therefore, the invention proves the function of lamivudine in pulmonary fibrosis, explores the therapeutic effect of lamivudine on pulmonary fibrosis, and brings hope for clinical pulmonary fibrosis patients.
Based on the method, the invention provides an application of lamitiniron.
Disclosure of Invention
In view of the drawbacks of the prior art, the present invention is directed to providing an application of lamisterone to solve the problems mentioned in the background above.
The technical scheme adopted by the invention for solving the technical problem is as follows:
the invention provides an application of lamivudine in preventing and treating pulmonary fibrosis diseases.
Preferably, the lamivudine inhibits pathological changes in the lung during the course of pulmonary fibrosis.
Preferably, the lamivudine inhibits fibroblast activation and improves extracellular matrix deposition
Preferably, the lamivudine has a prevention and treatment effect on the progressive pulmonary fibrosis of mice, and the lamivudine is a drug for preventing and treating the pulmonary fibrosis.
The invention discloses application of lamivudine in preventing and treating pulmonary fibrosis diseases. The inventor proves the improvement effect of lamivudine on the pulmonary fibrosis process and the prevention and treatment effect of lamivudine on pulmonary tissue diseases through experiments, finds that the new drug indications of the marketed drugs can be used for preventing and treating human pulmonary fibrosis diseases.
Compared with the prior art, the invention has the following beneficial effects:
the invention determines the regulating effect and the acting potential mechanism of lamilteon on lung tissue lesion, and uses the lamilteon as a novel drug action target spot to be applied to preventing and treating pulmonary fibrosis diseases. The use of lamitriptonide was found to inhibit pathological changes in the lung during the course of pulmonary fibrosis. Lamisterone was found to inhibit fibroblast activation and improve extracellular matrix deposition. The lamivudine is found to have the effects of preventing and treating the progressive pulmonary fibrosis of mice, and the lamivudine can be used as a medicament for preventing and treating the pulmonary fibrosis.
Drawings
FIG. 1 is a lung collagen production map of a mouse with inhibition of fibrosis by lamibactam according to the present invention;
FIG. 2 is a graph showing that lamisterone affects the expression of extracellular matrix proteins;
fig. 3 is a graph of inhibition of BLM-induced increase in pulmonary fibrosis area by lamibactam.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The application of lamivudine in preventing and treating pulmonary fibrosis diseases is provided by the embodiment.
Lamivudine of this example inhibits pathological changes in the lungs during the course of pulmonary fibrosis.
The lamitriptonide of the present example inhibits fibroblast activation and improves extracellular matrix deposition
The lamivudine in the embodiment has a preventive and therapeutic effect on the progressive pulmonary fibrosis of mice, and the lamivudine is a drug for preventing and treating the pulmonary fibrosis.
The specific operation method of inhibiting collagen deposition in mouse lung by lamibactron in this example is as follows:
establishing a C57BL/6 mouse pulmonary fibrosis model by adopting disposable intratracheal injection of bleomycin, selecting a healthy male C57BL/6 mouse of 6-8 weeks old, exposing the trachea after anesthesia by 1% pentobarbital sodium, and performing intratracheal injection of Bleomycin (BLM) or normal Saline (Saline) for 5mg/kg to form the pulmonary fibrosis model after 21 days;
then, the lung tissues of the mice of all components are taken, RNA and protein of the lung tissues of the mice are extracted, and the fact that the lung collagen deposition and extracellular matrix protein expression of the mice of the BLM group are obviously higher than those of the Saline group is found, and meanwhile, the differentiation of lung fibroblasts to myofibroblasts is increased;
the mouse lung tissue RNA is extracted conventionally, real-time PCR shows that after BLM injection, the contents of Collagen I and Collagen III in the mouse lung tissue are obviously increased, meanwhile, the single intratracheal instillation of lamiantel has no obvious influence on the mouse lung, but the lamiantel instillation of lamiantel obviously inhibits the generation of Collagen in pathological states.
The operation method of lamivudine for inhibiting fibroblast to secrete extracellular matrix protein comprises the following steps:
A. through Western blot detection, lamivudine inhibits protein expression of FN1 and LC3 in mouse lung tissues induced by BLM; n =5; * P is less than 0.05vs control group;
B. separating and culturing primary lung fibroblasts, and improving the Fn1 up-regulation caused by TGF-beta 1 by lamivudine.
Lamitriptolide of this example prophylactically treated mice for progressive pulmonary fibrosis;
A. a mouse profile of preventive and therapeutic dosing of lamivudine;
B. the lamitriptonide has a preventive effect on the progressive pulmonary fibrosis induced by BLM;
C. intraperitoneal injection of lamivudine inhibits the increase of fibrotic area after pulmonary fibrosis is formed.
In the prophylactic and therapeutic mice of the present example, the mice were subjected to intraperitoneal injection of lamivudine every other day 3 days after intratracheal instillation of BLM until the material was taken 21 days after BLM induction;
and the mice in the treatment group form an idiopathic pulmonary fibrosis model after 3 weeks of BLM induction, and then are subjected to intraperitoneal injection of lamivudine every other day until 6 weeks, and the mice are sacrificed and taken;
lung tissue was collected and immediately frozen in liquid nitrogen or fixed in 4% paraformaldehyde for further study. Staining by Masson;
after 3 weeks of intratracheal instillation of BLM, the mice were administered with lamivudine intraperitoneal injection every other day, which effectively reduced the fibrotic area, indicating that lamivudine can inhibit the morphological changes of lung tissue and increase of fibrotic area caused by BLM.
Example 1:
lamitentalong inhibits collagen deposition in mouse lung
In the experiment, a C57BL/6 mouse pulmonary fibrosis model is established by adopting disposable intratracheal injection of bleomycin. Selecting 6-8 week-old healthy male C57BL/6 mice, anesthetizing with 1% sodium pentobarbital, exposing trachea, injecting Bleomycin (BLM) or normal Saline (Saline) 5mg/kg into trachea, and forming a pulmonary fibrosis model after 21 days.
Subsequently, the lung tissues of the mice of all components are taken, RNA and protein of the lung tissues of the mice are extracted, and the fact that the lung collagen deposition and extracellular matrix protein expression of the mice of the BLM group are obviously higher than those of the Saline group is found, and meanwhile, the differentiation of lung fibroblasts to myofibroblasts is increased (fig. 1A-D).
Since massive secretion of collagen by myofibroblasts is one of the characteristics of pulmonary fibrosis, we examined the regulation of collagen production by lamitinine. RNA of a mouse lung tissue is extracted conventionally, and the content of Collagen I and Collagen III in the mouse lung tissue is obviously increased after the BLM is injected by real-time PCR. Meanwhile, the mere intratracheal instillation of lamivudine did not have a significant effect on the mouse lung, but the instillation of lamivudine significantly inhibited collagen production in pathological states (fig. 1E);
pcr results showed increased mRNA levels of fibrotic mouse lung collagen (Col 1), fibronectin (Fn 1), myofibroblast marker (ACTA 2), n =5; western Blot detection shows that the content of Fn1 of the mouse with pulmonary fibrosis is obviously up-regulated, and n =3; E. intraperitoneal injection of lamitriptonide can prevent bleomycin-induced collagen deposition, n =4.* P < 0.05vs control group,. P < 0.01vs control group;
example 2: lamiterone inhibits fibroblast cells from secreting extracellular matrix proteins
Fn1 is an extracellular matrix protein and is important in various processes such as cell adhesion, proliferation, differentiation, etc. Western blots results showed that ramitinin can reverse BLM-induced increases in Fn1 protein levels (fig. 2A). Studies have shown that LC3 expression is increased in lung tissue of IPF patients, while melatonin receptor agonists are believed to have antioxidant effects, participating in the regulation of mitochondrial function. Based on the protein results, we found that lamilteon also has an inhibitory effect on the autophagy marker LC 3. (FIG. 2A)
Meanwhile, lung fibroblasts are the main effector of pulmonary fibrosis, and the excessive activation of the fibroblasts promotes the occurrence and development of fibrotic diseases. We isolated lung fibroblasts from 1-3 day old mice, and Fn1 expression was up-regulated after TGF- β 1 induction, while lamitiniron decreased the protein level of Fn1 (fig. 2B). These data indicate that lamisterone can exert a protective effect in pulmonary fibrosis by acting on lung fibroblasts, inhibiting their secretion of fibronectin.
A. Lamiterone inhibited FN1 and LC3 protein expression in BLM-induced mouse lung tissue by Western blot assay. n =5; * P < 0.05vs control group. B. Separating and culturing primary lung fibroblasts, and improving the Fn1 up-regulation caused by TGF-beta 1 by lamivudine.
Example 3: lamitentalong for preventing/treating progressive pulmonary fibrosis of mice
Since melatonin is widely believed to exert biological activity in combination with its receptor MT1/MT2, we explored whether lamisterone, as a melatonin receptor agonist, is also involved in the development of pulmonary fibrosis. We discuss the prophylactic and therapeutic effects of lamisterone, respectively (fig. 3A). For the mice in the prevention group, injecting LAIMITALON into the abdominal cavity every other day 3 days after intratracheal instillation of BLM until the materials are obtained 21 days after BLM induction; and the mice in the treatment group form an idiopathic pulmonary fibrosis model after 3 weeks of BLM induction, and then are subjected to intraperitoneal injection of lamivudine every other day until 6 weeks, and the mice are sacrificed and the materials are obtained. Lung tissue was collected and immediately frozen in liquid nitrogen or fixed in 4% paraformaldehyde for further study. By Masson staining, we found that lamivudine itself had no effect on lung tissue morphology, but pre-intraperitoneal administration of lamivudine reversed BLM-induced lung fibrosis in mice (fig. 3B). Also, administration of lamivudine to mice intraperitoneally every other day after 3 weeks of intratracheal instillation of BLM effectively reduced the area of fibrosis (fig. 3C), indicating that lamivudine was able to inhibit the morphological changes of lung tissue and increase of the area of fibrosis caused by BLM.
A. Mouse model plots for the prophylactic and therapeutic dosing of lamibactron. B. Lamizalone has a preventive effect on BLM-induced progressive pulmonary fibrosis. C. Intraperitoneal injection of lamivudine inhibits the increase of fibrotic area after pulmonary fibrosis is formed.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
Furthermore, it should be understood that although the present description refers to embodiments, not every embodiment may contain only a single embodiment, and such description is for clarity only, and those skilled in the art should integrate the description, and the embodiments may be combined as appropriate to form other embodiments understood by those skilled in the art.
Claims (4)
1. Application of lamitriptonide in preventing and treating pulmonary fibrosis diseases is provided.
2. The use of lamibactam for the prevention and treatment of pulmonary fibrotic diseases according to claim 1, wherein the lamibactam inhibits pathological changes in the lung during the course of pulmonary fibrosis.
3. The use of lamisterone for the prevention and treatment of pulmonary fibrosis as claimed in claim 1, wherein said lamisterone inhibits fibroblast activation and improves extracellular matrix deposition.
4. The use of lamitriptonide as claimed in claim 1, wherein the lamitriptonide is effective in preventing and treating pulmonary fibrosis in mice, and the lamitriptonide is a drug for preventing and treating pulmonary fibrosis.
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