CN108434439A - The medical usage of calprotectin - Google Patents
The medical usage of calprotectin Download PDFInfo
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- A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
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Abstract
The present invention relates to biomedicine fields, in particular to the medical usage of calprotectin.More particularly it relates to purposes of the calprotectin in preventing and/or treating acute high altitude sickness.
Description
Technical field
The present invention relates to biomedicine fields, in particular to the medical usage of calprotectin.More specifically, this hair
The bright purposes for being related to calprotectin in preventing and/or treating acute high altitude sickness.
Background of invention
It is anti-that acute high altitude sickness (acute mountain sickness, AMS) enters the acute anoxia occurred when plateau at the beginning of referring to people
It answers or disease, is divided into light-duty and heavy AMS according to its severity.Light-duty AMS refers to acute high altitude reaction；Heavy AMS is divided into
For：Plateau brain edema, plateau pneumochysis and mixed type (comprehensive plateau brain edema and plateau pneumochysis).
It is mostly at present ladder acclimatization during plateau enters about the control measure of acute high altitude sickness, and anxious for patient
The symptomatic treatment of the acute anoxias symptoms such as property pulmonary edema, brain edema.There is interim of high cost, conventional therapy and implement in such means
Time lag, the problems such as of affecting the treatment.Therefore, there is an urgent need in the art to easy, the effective medicines of new prevention acute high altitude sickness
Object.
Summary of the invention
In a first aspect, the present invention provides calprotectin purposes in medicine preparation, the drug for preventing and/or
Treat acute high altitude sickness.In some embodiments, the calprotectin is people's calprotectin, preferably Human Recombinant Calreticulin.
In some embodiments, the calprotectin includes to be selected from SEQ ID NO:The amino acid sequence of 1-5.In some embodiment party
In case, the acute high altitude sickness is selected from acute high altitude reaction, plateau pneumochysis, plateau brain edema or combinations thereof.
In second aspect, the present invention provides a kind of pharmaceutical composition for preventing and/or treating acute high altitude sickness, packet
Calprotectin containing therapeutically effective amount and pharmaceutically acceptable carrier.In some embodiments, the calprotectin is people
Calprotectin, preferably Human Recombinant Calreticulin.In some embodiments, the calprotectin includes to be selected from SEQ ID NO:1-
5 amino acid sequence.In some embodiments, the acute high altitude sickness is selected from acute high altitude reaction, plateau pneumochysis, plateau
Brain edema or combinations thereof.
In the third aspect, the present invention provides a kind of method for preventing and/or treating acute high altitude sickness, including having given need to
The object wanted applies the calprotectin of therapeutically effective amount.In some embodiments, the calprotectin is people's calprotectin, excellent
Select Human Recombinant Calreticulin.In some embodiments, the calprotectin includes to be selected from SEQ ID NO:The amino acid sequence of 1-5
Row.In some embodiments, the acute high altitude sickness be selected from acute high altitude reaction, plateau pneumochysis, plateau brain edema or its
Combination.
Description of the drawings
Fig. 1 each group lung tissue of rats weight in wet bases and dry weight.
The wet dry weight ratio of Fig. 2 each group induced lungs.
Fig. 3 each groups rat cerebral tissue's weight in wet base and dry weight.The * P compared with Normal group<0.05, compared with model group, #P<
0.05。
The wet dry weight ratio of Fig. 4 each groups rat cerebral tissue.*P<0.05, compared with Normal group, #P<0.05, with model group
Compare.
Fig. 5 each group rat artery blood pH value.
Fig. 6 each group rat artery blood PCO2.
Fig. 7 each group rat artery blood PO2.
Fig. 8 each group rat artery blood Beecf.
Fig. 9 each group rat artery blood HCO3.
Figure 10 each group rat artery blood TCO2.
Figure 11 each group rat artery blood sO2%.
Figure 12 each group rat artery blood Na is horizontal.
Figure 13 each group rat artery serum potassiums.
Figure 14 each group rat artery blood iCa is horizontal.
Figure 15 each group rat artery blood glucose levels.
Figure 16 each group rat artery erythrocyte hematocrits.
Figure 17 each group rat artery blood hemoglobin levels.
Figure 18 lung tissue of rats HE colored graphs (100 ×).
Figure 19 calprotectin Strategies For The Clonings.
Specific implementation mode
In a first aspect, purposes the present invention provides calprotectin in medicine preparation, the drug for prevent and/
Or treatment acute high altitude sickness.
Acute high altitude sickness (acute mountain sickness, AMS) refers to people and rapidly enters plateau (such as 3000 meters of height above sea level
More than) when occur acute anoxia reaction or disease, be divided into light-duty and heavy AMS according to its severity.Light-duty AMS is referred to
Acute high altitude reaction；Heavy AMS be divided into for：Plateau brain edema, plateau pneumochysis and mixed type (comprehensive plateau brain edema and plateau
Pulmonary edema).
For the patient of acute high altitude reaction when entering plateau, symptom is most apparent within 1-2 days, rear gradually to mitigate, 6-7 days most
It is basic to disappear, a small number of sustainable presence.It is mainly shown as headache, memory and thinking ability decline, insomnia, dreaminess, respiratory intensity
With frequency increase, tachycardia etc..Some patientss have the symptoms such as cyanosis, blood pressure raising.Acute high altitude reaction should be in diagnosis
Viral disease such as influenza etc. mutually differentiates.
Plateau pneumochysis is generally Plain or the relatively low regional crowd of height above sea level quickly enters morbidity in 1-3 days behind plateau, also has late
Patient was sent out in 7-14 days, performance is identical as general pulmonary edema.Plateau pneumochysis diagnosis on should with pneumonia, pulmonary embolism, pneumothorax,
The discriminatings such as cardiac pulmonary edema or neurogenic pulmonary edema.
Plateau brain edema patient first has the symptom of acute high altitude reaction mostly, apparent Spirit nerve symptoms of disease then occurs such as
Severe headache, insanity, wandering, obstinate Nausea and vomiting, severe one stupor.Examination of cerebrospinal fluid has pressure to increase.High protocerebrum archicerebrum
Oedema should mutually differentiate in diagnosis be metabolized or be poisoned encephalopathy, cerebrovascular accident and craniocerebral trauma.
In some embodiments of the present invention, the acute high altitude sickness be selected from acute high altitude reaction, plateau pneumochysis or
Any one or more in plateau brain edema.
Calprotectin (calreticulin, CRT) is initially as calbindin in endocytoplasmic reticulum and chaperone quilt
It was found that having the effects that the folding of regulatory protein matter, calcium homeostasis and Apoptosis.The present inventor is it has surprisingly been found that calcium net egg
Plateau low pressure, anoxic related symptoms can effectively be mitigated in vain, especially alleviate plateau pneumochysis and plateau brain edema, so as to
For preventing and/or treating acute high altitude sickness.In some embodiments of the invention, the calprotectin is people's calprotectin.
Calprotectin described herein is also contemplated by the functional variant thereof of calprotectin other than wild type calprotectin.
In some embodiments, the functional variant thereof of calprotectin include have at least 80% with wild type calprotectin, at least 85%,
The amino acid sequence of at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% sequence identity,
And the biological activity with wild type calprotectin.In some embodiments, the functional variant thereof of calprotectin is opposite
There is the amino acid sequence that one or more amino acid residues replace, miss or add in wild type calprotectin, and with open country
The biological activity of raw type calprotectin.For example, the functional variant thereof of calprotectin includes to have relative to wild type calprotectin
There is 1,2,3,4,5,6,7,8,9 or amino acid that 10 amino acid residues replace, miss or add
Sequence.In some embodiments, the amino acid substitution is conservative substitution.In some embodiments, the wild type
Calprotectin includes SEQ ID NO:Amino acid sequence shown in 1 or 2.
" polypeptide ", " peptide " and " protein " is used interchangeably in the present invention, refers to the polymer of amino acid residue.The art
Language is suitable for the ammonia that wherein one or more amino acid residues are the artificial chemical analogues of corresponding naturally occurring amino acid
Base acid polymer, and it is suitable for naturally occurring amino acid polymer.Term " polypeptide ", " peptide ", " amino acid sequence " and " egg
White matter " may also include modified forms, including but not limited to the γ carboxylics of glycosylation, lipid connection, sulfation, glutaminic acid residue
Change, hydroxylation and ADP- ribosylation.
Sequence " the phase same sex " have art-recognized meaning, and can utilize disclosed technology calculate two nucleic acid or
The percentage of sequence identity between peptide molecule or region.It can be along the overall length of polynucleotides or polypeptide or along this point
The region of son measures sequence identity.(see, e.g.： Computational Molecular Biology,Lesk,A.M.,
ed.,Oxford University Press, New York,1988；Biocomputing:Informatics and
Genome Projects,Smith,D.W., ed.,Academic Press,New York,1993；Computer
Analysis of Sequence Data, Part I,Griffin,A.M.,and Griffin,H.G.,eds.,Humana
Press,New Jersey,1994； Sequence Analysis in Molecular Biology,von Heinje,G.,
Academic Press,1987； and Sequence Analysis Primer,Gribskov,M.and Devereux,J.,
eds.,M Stockton Press,New York,1991).Although measuring two between polynucleotides or polypeptide there are many
The method of the phase same sex, but term " the phase same sex " is (Carrillo, H.＆Lipman, D., SIAM J well known to technical staff
Applied Math 48:1073(1988))。
In peptide or protein, suitable Conservative amino acid substitution is known to the skilled in the art, and generally may be used
To carry out the bioactivity without changing gained molecule.In general, those skilled in the art recognize in the nonessential region of polypeptide
Single amino acids substitution not substantially changes bioactivity (see, e.g., Watson et al., Molecular Biology
of the Gene,4th Edition,1987,The Benjamin/Cummings Pub.co.,p.224)。
Herein, the functional variant thereof of calprotectin also includes the natural signals peptide of removal wild type calprotectin, removal
Endoplasmic reticulum is resident sequence, addition purification tag (such as His labels), addition increase protein expression or the letter for changing protein expression mode
The variant of number peptide (such as secreting signal peptide) acquisition.Such variant does not change the biological activity of calprotectin.At some
In embodiment, the functional variant thereof of the calprotectin includes SEQ ID NO:Amino acid sequence shown in one of 3-5.
In some embodiments, the calprotectin can be isolated from its natural origin.In some embodiments, institute
Stating calprotectin can be chemical synthesis.In some preferred embodiments, the calprotectin is that recombinant expression generates.
In some preferred embodiments, the calprotectin is Human Recombinant Calreticulin.
It is known in the art that recombinant expression, which produces protedogenous method,.For example, can be by the code nucleic acid of calprotectin
It is cloned into suitable expression vector, the expression vector is then imported into suitable host cell, by being trained in suitable condition
The host cell is supported to generate the calprotectin of recombinant expression.
Suitable expression vector includes the adenovirus etc. of plasmid vector, yeast shuttle vector, baculoviral, replication defective.
The expression vector of a large amount of obtainable calprotectins for being suitable for expressing the present invention as is generally known in the art.
The host cell of calprotectin suitable for expressing the present invention includes prokaryotes, yeast and higher eucaryotic cells.Show
The prokaryotic host cell of example property includes Bacillus coli cells, B. subtilis cell etc..Illustrative yeast host cell example
Such as saccharomyces cerevisiae, Pichia pastoris, Hansenula yeast cell.Illustrative higher eucaryotic cells include HEK293 cells, Chinese hamster ovary celI
(such as CHO3E7) etc..In a preferred embodiment, calprotectin of the invention passes through ExpiCHO-STMCell is expressed.
In second aspect, the present invention provides a kind of pharmaceutical composition for preventing and/or treating acute high altitude sickness, packet
Containing a effective amount of calprotectin and pharmaceutically acceptable carrier.The calprotectin and the acute high altitude sickness distinguish institute as above
Definition.
In the third aspect, the present invention provides a kind of method for preventing and/or treating acute high altitude sickness, including having given need to
The object wanted applies the calprotectin of therapeutically effective amount.The calprotectin and acute high altitude sickness difference are as defined above.
Preferably, the object is mammal, such as people.
As used herein, the individual of " treatment " with disease or disease condition indicates that the symptom of the individual is part or all of
Alleviate, or remains unchanged after the treatment." prevention ", which refers to, to be prevented potential disease and/or prevents symptom deterioration or disease from developing.
As used herein, " effective quantity " includes " therapeutically effective amount " or " prevention effective dose "." therapeutically effective amount " refers to application
At least it is enough to generate the compound (such as calprotectin of the present invention) of curative effect or comprising compound (such as calcium net of the present invention after object
Albumen) composition amount.Therefore, it is to prevent, cure, improving, blocking or the symptom of partial block disease or illness must
The amount needed.As used herein, " prevention effective dose " refers to can have the compound of expected preventive effect (such as when being applied to object
Calprotectin of the present invention) or composition comprising compound (as calprotectin of the present invention) amount, for example, preventing or postponing disease
Or the generation or recurrence of symptom, it reduces disease or symptom occurs or the possibility of recurrence.Complete prevention effective dose without going through
Occur using a dosage, and can only occur after a series of dosage of application.Therefore, prevention effective dose can be primary
Or it is applied in multiple applications.
The effective quantity of calprotectin to be administered depends on therapeutic purpose, administration method and the disease condition of patient.This
Outside, attending physician considers the known pharmaceutically-active various factors of change, including the severity of disease and type, and patient's is strong
Health, weight, gender, diet, administration time and approach, other drugs and other correlated clinical factors.Therefore, Therapist
The dosage of the calprotectin must be titrated as required and changes administration method to obtain optimum curative effect.In general, clinician
The calprotectin can be applied, until reaching the dosage for realizing desired effects.The progress of this treatment is held very much by conventional determining
Easily monitoring.
In general, being sufficiently large (such as anxious to generate desired effect using the dosage range of calprotectin provided in this article
Property altitude sickness symptom improve) dosage range.Dosage is not so big, will not cause harmful side effect, dosage can with the age,
Disease degree variation in disease condition, gender and patient, and can be determined by those skilled in the art.It is any in appearance
In the case of harmful side effect, solo practitioner can adjust dosage.Exemplary dose for preventing or treating acute high altitude sickness
Including but not limited to about 0.01mg/kg to about 300mg/kg, for example, about 0.01mg/kg, about 0.1mg/kg, about 0.5mg/kg,
About 1mg/kg, about 5mg/kg, about 10mg/kg, about 15mg/kg, about 20mg/kg, about 25mg/kg, about 30mg/kg, about 35mg/
Kg, about 40mg/kg, about 45mg/kg, about 50 mg/kg, about 100mg/kg, about 150mg/kg, about 200mg/kg, about 250mg/kg
Or about 300mg/kg.In some preferred embodiments, the administration dosage of calprotectin of the present invention is at least 5 mg/kg bodies
Weight.
In order to treat acute high altitude sickness, the dosage of the calprotectin can become according to the type and severity of disease
Change.Can with single dose, repeatedly be administered alone or by continuous transfusion apply the calprotectin.For according to disease condition several
Repetitive administration in it or longer time, can be with repetitive treatment until desired disease symptoms inhibit to occur or realize desired
The improvement of patient disease situation.Repetitive administration may include the calprotectin increased or decreased according to the progress for the treatment of
Amount.Also consider other dosages.
Calprotectin as described herein can be applied to object by any method known in the art using polypeptide,
Including for example applied systemically or topically.It can be by such as parenteral (for example, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous
Or intracavitary), body surface, Epidural cavity or mucous membrane (such as intranasal or oral) approach apply the calprotectin.It can be by any
Convenient approach applies the composition containing calprotectin, such as is penetrated by infusion or bolus, is viscous by epithelial or skin
Film (for example, oral mucosa, rectum and intestinal mucosa) absorbs.
Pharmaceutical composition provided herein can be various forms, for example, solid, semisolid, liquid, powder, aqueous solution
Or freeze-dried.The example of suitable pharmaceutically acceptable carrier known in the art, and including but not limited to water, buffering
Agent, saline solution, phosphate buffered saline solution, various types of wetting agents, sterile solution, alcohol, gum arabic, vegetable oil, benzyl
Alcohol, gelatin, glycerine, carbohydrate (such as lactose, sucrose, amylose or starch), magnesium stearate, talcum, silicic acid, sticky stone
Wax, aromatic oil, glycerine monofatty ester and two glyceride, pentaerythritol fatty ester, hydroxymethyl cellulose, powder etc..Herein
The pharmaceutical composition of offer can include other additives, including for example antioxidant, preservative, antimicrobial, analgestic,
Adhesive, disintegrant, colorant, diluent, excipient, incremental agent, glidant, solubilizer, stabilizer, tonicity agents, medium,
Thickener, flavoring agent, emulsion (such as oil/water emulsion), emulsification and suspending agent (such as Arabic gum, agar, alginic acid, mosanom, swelling
Soil, carbomer, carragheen, carboxymethyl cellulose, cellulose, cholesterol, gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyl
Propyl methocel, methylcellulose, octyl phenol polyethers -9, oleyl alcohol, polyvinylpyrrolidone, propylene glycol monostearate,
Lauryl sodium sulfate, sorbitan ester, stearyl alcohol, bassora gum, xanthans and its derivative), solvent and various composition, example
Such as crystal fibre element, microcrystalline cellulose, citric acid, dextrin, glucose, liquid glucose, lactic acid, lactose, magnesium chloride, metaphosphoric acid
Potassium, starch etc..Such carrier and/or additive can be prepared by conventional method, and can with suitable dosage to pair
As application.Stabilizer such as lipid, nucleic acid inhibitor, polymer and chelating agent can prevent composition degradation in vivo.
In the purposes, pharmaceutical composition and method of the present invention, the calprotectin can also be with other acute height for the treatment of
The Drug combination of former disease.For example, described pharmaceutical composition can also include the drug of other treatment acute high altitude sickness.Or
Person, the calprotectin can be administered simultaneously with the drug for the other treatment acute high altitude sickness individually prepared.Alternatively, the calcium net
Albumen such as can sequentially be applied with the drug separate administration of other treatment acute high altitude sickness.
In the present invention, unless otherwise stated, Science and Technology noun used herein has art technology
The normally understood meaning of personnel institute.Also, protein used herein and nucleic acid chemistry, molecular biology, cell and tissue
Culture, microbiology, immunology relational language and laboratory operation step be in corresponding field widely used term and often
Advise step.
Following embodiment has no intention to limit the scope of the invention in any way for illustrating the present invention.
Embodiment
Embodiment 1 recombinates calprotectin and prepares
The present invention uses Chinese hamster ovary (CHO) cell expression system expression recombination calprotectin.
1.1 gene cloning
417 amino acid (Genbank accession numbers of people CRT full length proteins：NM_004343).Inventor is by people's CRT PROTEIN Cs
The endoplasmic reticulum retention signal of 4, end amino acid (KDEL) is deleted so that recombinant C RT albumen is mainly expressed in cytoplasm.So
Afterwards, the original signal peptide of 17 amino acid of N-terminal is replaced with to the manual signal peptide for increasing expression
(MGWSCIILFLVATATGVHS).For the ease of purifying, increase by the purification tag of 6 × His in C-terminal.
According to the recombinant protein sequence of above-mentioned design, the codon optimization of nucleic acid sequence encoding is carried out for Chinese hamster ovary celI,
5 ' end addition Kozak sequences, in the both ends sites addition HindIII and EcoRI.The artificial synthesized coding nucleic acid segment, is cloned into
PUC57 carrier for expression of eukaryon.Strategies For The Cloning is shown in Figure 19.
1.2 cell culture and transient transfection
Make CHO-3E7 cells in serum-free FreeStyleTMCHO expresses culture medium (Life Technologies).It will be thin
Born of the same parents are maintained in the conical flask on orbital shaker, 37 DEG C, 5%CO2.The day before transfection, cell are inoculated in density appropriate
Conical flask.The transfection same day, DNA and transfection reagent are mixed with optimal proportion, are then added in the cell for preparing transfection.By coded Ca
The recombinant plasmid of plectin is transiently transfected into 100ml suspension CHO-3E7 cell cultures.Collect cells and supernatant within 6th day
Liquid is for purifying.
1.3 protein purifications and analysis
Cell culture medium is centrifuged and was loaded to 5ml HisTrap with 1.0ml/ minutesTM FF Crude(GE,
Cat.No.17-5286-01).After being washed and eluted with suitable buffer solution, the fraction of elution is merged and by buffer-exchanged
For the PBS of pH7.2.The protein purified by SEC-HPLC, SDS-PAGE and Western blot analysis using standard scheme into
Row molecular weight, yield and purity determination.It is carried out using the anti-his mAb (GenScript, Cat.No.A00186) of mouse
Western blot.
Embodiment 2 recombinates the pharmacodynamic study that calprotectin mitigates high altitude anoxia reaction
(1) experimental animal：Male SPF grades of SD rat (60, weight 200-220g) is purchased from Beijing China Fukang biotechnology
Limited liability company, experimental animal production licence number are SCXK (capital) 2016-0002.Quarantine observation 3 days.During this period, it sees
The indexs such as appearance sign, behavioral activity, fecal character, weight and the diet of animal are examined, ill animal is rejected.Animal house environment item
Part controls 18 DEG C~26 DEG C of room temperature；Relative humidity 40%~70%；12 hours light and shade alternatings of illumination.Cage tool, hamper, drinking bottle are every
It is rinsed once, and animal house ground and metope sterilize weekly once, is wiped with 84 thimerosals of 0.1% bromogeramine or 0.5%
Disinfection, two kinds of thimerosal cross-references.Normal diet is that mouse maintains material, is purchased from the limited public affairs of Beijing China Fukang biotechnology share
Department.Bedding and padding：Sterilize particle bedding and padding, is purchased from Beijing HFK Bio-Technology Co., Ltd..Drinking-water：Purified water is drunk, through acid
It is freely drunk after change.
(2) key instrument：Experimental animal low-voltage simulation storehouse (HCP-III Series), Abbotti-start blood gas analysis
Instrument, Powerlab physiographs, pressure sensor.
(3) main agents and its preparation：Recombination calprotectin is prepared, is purified as described in Example 1, and physiological saline is purchased from north
Hundred Ao Sentai Bioisystech Co., Ltd of capital, dexamethasone sodium phosphate injection are purchased from Sinopharm Group Rongsheng Pharmaceutical Co., Ltd..
(4) experiment packet：
1. normal oxygen control group：0.5ml physiological saline is injected intraperitoneally
2. hypoxia model group：0.5ml physiological saline is injected intraperitoneally
3. hypoxemia+dexamethasone 5mg/kg groups：Dexamethasone 5mg/kg is injected intraperitoneally
4. hypoxemia+CRT 5mg/kg groups：CRT 5mg/kg are injected intraperitoneally
5. hypoxemia+CRT 1mg/kg groups：CRT 1mg/kg are injected intraperitoneally
6. hypoxemia+CRT 0.2mg/kg groups：CRT 0.2mg/kg are injected intraperitoneally
(5) hypobaric hypoxia model copy：
Intraperitoneal injection 1 hour after, 2. -6. group rat be placed in simulated high altitude environment low-pressure oxygen cabin, with 10 ms-1Speed
Degree at the uniform velocity rises to altitude simulating 6500m levels, and temperature setting is daytime (8:00~18:00) 0 DEG C, night (18:00~08:
00) -4 DEG C, continuous 72h.After, make in cabin air pressure steady recovery to normal pressure, export in 45 minutes.Replace food within every 24 hours
Water is primary.
When terminating experiment, after the intraperitoneal injection 0.5ml/kg anesthesia of 2% yellow Jackets, artery is quickly taken through left neck artery
2 milliliters of blood, sealing are placed in curling stone, and vim and vigour are surveyed with Abbotti-start blood gas analyzers；And animal is quickly put to death, take the right side
Lung tissue and right brain hemisphere are used for the wet dry weight ratio of tissue, take inferior lobe in right lung, carry out lungs gross examination of skeletal muscle, take about 100mg lung groups
It knits and is immediately placed on room temperature fixation at least 48 hours in 10 times of 4% paraformaldehydes of volume, be ready for use on light microscopy specimen and make and observe.Separately
Take about 1 mm3Size lung 2-3 blocks are immediately placed in 3% glutaraldehyde of Fresh 4 DEG C of fixations at least 48 hours, are ready for use on
Radio mirror preparation of specimen and observation.By it is remaining tissue be divided into 3,4 parts be immediately placed in liquid nitrogen freeze it is spare.
(6) the wet dry weight ratio of lung (brain) tissue：Right lung tissue blots blood stains with filter paper, weighs rapidly, is placed in constant temperature roaster 80
After DEG C baking 48h to weight constant weight, then weigh dry weight, calculate right lung it is wet/dry weight ratio (W/D):Lung wet-dry ratio value=lung is wet
Weight/lung dry weight.Ibid calculate brain tissue weight in wet base/lung dry weight.
(7) lung tissue is observed：Above-mentioned lung tissue is fixed with 4% neutral formalin, paraffin embedding, slice, row HE dyeing, often
Rat selects 3 lung tissue sections, every slice to randomly select three visuals field at random, and light is under the microscope.
As a result：
(1) the wet dry weight ratio of lung tissue
The wet dry weight of lung tissue than the results are shown in Table 1 and Fig. 1, shown in 2.Lung weight in wet base the results show that with Normal group ratio
Compared with the model group lung tissue weight in wet base of simulated high altitude anoxic obviously increases (P<0.05)；Compared with model group, Dexamethasone group and
The basic, normal, high dosage each groups of CRT have reduction trend, but no significant difference (P>0.05)；And with positive drug fill in rice
Loose group is compared, CRT each group lung weight in wet base no significant differences (P>0.05).
Lung is wet/dry weight than analysis result show, compared with Normal group, the model group lung tissue of simulated high altitude anoxic
Wet/dry weight obviously increases (P<0.05)；Compared with model group, Dexamethasone group and the basic, normal, high dosage each group lung tissues of CRT
Wet/dry weight is substantially reduced (P<0.05)；And compared with positive drug Dexamethasone group, CRT 1ng groups significantly reduce (P<
, but CRT 0.2ng groups and CRT 5ng group no significant differences (P 0.05)>0.05).
The wet dry weight ratio of 1 each group lung tissue of rats of table
| Group | n | Lung weight in wet base (g) | Lung dry weight (g) | The wet dry weight ratio of lung |
| Control group | 20 | 0.47±0.04 | 0.12±0.02 | 4.12±0.57 |
| Model group | 16 | 0.64±0.06* | 0.10±0.01 | 6.43±0.86* |
| Dexamethasone group | 16 | 0.60±0.07* | 0.13±0.01 | 4.73±0.20*# |
| CRT 0.2ng groups | 13 | 0.60±0.04* | 0.12±0.01 | 4.98±0.16*# |
| CRT 1ng groups | 13 | 0.61±0.06* | 0.12±0.01 | 4.87±0.10*#△ |
| CRT 5ng groups | 17 | 0.62±0.06* | 0.13±0.01 | 4.93±0.22*# |
Note：*P<0.05, compared with Normal group；#P<0.05, compared with model group；△P<0.05 with Dexamethasone group ratio
Compared with.Compared with Normal group*P<0.05, compared with model group,#P<0.05。
(2) brain tissue it is wet/dry weight ratio
The wet dry weight of brain tissue than the results are shown in Table 2 and Fig. 3, shown in 4.Brain tissue weight in wet base the results show that and normal control
Group compares, and the model group lung tissue weight in wet base of simulated high altitude anoxic obviously increases (P<0.05)；Compared with model group, Dexamethasone group
And the basic, normal, high dosage each groups of CRT are substantially reduced (P<0.05)；Compared with positive drug Dexamethasone group, CRT each group lungs
Weight in wet base no significant difference (P>0.05).Brain stem weight：No difference of science of statistics between each group.
Brain is wet/dry weight than analysis result show, compared with Normal group, the model group lung tissue of simulated high altitude anoxic
Wet/dry weight obviously increases (P<0.05)；Compared with model group, Dexamethasone group and the basic, normal, high dosage each group brain tissues of CRT
Wet/dry weight is substantially reduced (P<0.05)；Compared with positive drug Dexamethasone group, CRT each group no difference of science of statistics (P<
0.05)。
The wet dry weight ratio of 2 each group rat cerebral tissue of table
| Group | n | Brain wet weight (g) | Brain stem weight (g) | The wet dry weight ratio of brain |
| Control group | 20 | 1.70±0.12 | 0.39±0.02 | 4.30±0.28 |
| Model group | 16 | 1.89±0.05* | 0.37±0.02 | 5.06±0.31* |
| Dexamethasone group | 16 | 1.71±0.12*# | 0.37±0.04 | 4.69±0.20*# |
| CRT 0.2ng groups | 13 | 1.71±0.08*# | 0.36±0.03 | 4.74±0.33*# |
| CRT 1ng groups | 13 | 1.79±0.06*# | 0.36±0.03 | 4.55±0.22*# |
| CRT 5ng groups | 17 | 1.67±0.11*# | 0.37±0.03 | 4.59±0.22*# |
Note：*P<0.05, compared with Normal group；#P<0.05, compared with model group.
(3) Results of Blood-gas (table 3)
As shown in figure 5, pH's the results show that compared with Normal group, the model group pH of simulated high altitude anoxic is without apparent
Change (P>0.05)；But it is respectively compared with model group and positive drug Dexamethasone group, CRT high dose group apparent increases (P<
0.05)。
As shown in fig. 6, PCO2's the results show that compared with Normal group, the model group PCO2 of simulated high altitude anoxic is bright
It is aobvious to reduce (P<0.05)；Compared with model group, CRT is basic, normal, high, and dosage each group is increased significantly (P<0.05)；With positive drug
Object Dexamethasone group compares, and CRT is low, high dose group is increased significantly (P<0.05).
As shown in fig. 7, PO2's the results show that compared with Normal group, the model group PO2 of simulated high altitude anoxic is apparent
Reduce (P<0.05)；Compared with model group, CRT high doses are increased significantly (P<0.05).
As shown in figure 8, Beecf's the results show that compared with Normal group, the model group Beecf of simulated high altitude anoxic
Obviously increase (P<0.05)；It is respectively compared with model group and positive drug Dexamethasone group, CRT is basic, normal, high, and dosage each group is equal
It is substantially reduced (P<0.05).
As shown in figure 9, HCO3's the results show that compared with Normal group, the model group HCO3 of simulated high altitude anoxic is bright
It is aobvious to reduce (P<0.05)；Compared with model group, positive drug Dexamethasone group, CRT are basic, normal, high, and dosage each group is increased significantly
(P<0.05)；Compared with positive drug Dexamethasone group, CRT is basic, normal, high, and dosage each group is increased significantly (P<0.05)
As shown in Figure 10, TO2's, the results show that compared with Normal group, the model group TO2 of simulated high altitude anoxic is apparent
Increase (P<0.05)；Compared with model group, positive drug Dexamethasone group, CRT are basic, normal, high, and dosage each group is substantially reduced (P
<0.05)；Compared with positive drug Dexamethasone group, CRT is basic, normal, high, and dosage each group is substantially reduced (P<0.05).
As shown in figure 11, SO2%'s the results show that compared with Normal group, the model group SO2% of simulated high altitude anoxic
No significant difference (P>0.05)；Compared with model group, the basic, normal, high dosage each group difference of positive drug Dexamethasone group, CRT
There are no significant (P>0.05).
As shown in figure 12, Na's the results show that compared with Normal group, the model group Na differences of simulated high altitude anoxic without
Conspicuousness (P>0.05)；Compared with model group, CRT is basic, normal, high, and dosage each group reduces (P<0.05)；With positive drug fill in
The loose group of rice compares, and CRT high dose groups reduce (P<0.05).
As shown in figure 13, K's the results show that compared with Normal group, and the model group K differences of simulated high altitude anoxic are without aobvious
Work property (P>0.05)；Compared with model group, the basic, normal, high dosage each group difference of positive drug Dexamethasone group, CRT is without significantly
Property (P>0.05)；Compared with positive drug Dexamethasone group, CRT high dose groups increase (P<0.05).
As shown in figs. 14-15, iCa and Glu's the results show that compared with Normal group, the model of simulated high altitude anoxic
Group iCa and Glu no significant differences (P>0.05)；Compared with model group, basic, normal, high dose of positive drug Dexamethasone group, CRT
Measure each group difference there are no significant (P>0.05).
As shown in figs. 16-17, Hct and Hb's the results show that compared with Normal group, the model group of simulated high altitude anoxic
Hct and Hb no significant differences (P>0.05)；It is respectively compared with model group and positive drug Dexamethasone group, CRT high doses have
It is substantially reduced (P<0.05).
Table 3 tests each group vim and vigour testing result
(4) pathologic result
Lung tissue of rats pathological observation representativeness picture is as shown in Figure 18.Visible bronchus is viscous under normal rat lung tissue mirror
Film liner simple ciliated columnar epithe lium cell, mucilage cell, along with the small artery and vein of lung；Most of alveolar is evenly distributed, alveolar
Wall has no and obviously thickens, the visible a small amount of neutrophil infiltration of interstitial.
The expansion of bronchus height is in cryptomere under hypoxemia processing group lung tissue of rats mirror, except liner simple ciliated columnar epithe lium is thin
Outside born of the same parents, mucilage cell, see also papillary hyperplasia region has no that apparent fiber axle center, nucleus slightly increase, and dyeing is deep, dyeing
Matter is uneven；It is expanded along with lung artery and vein, intravenously there is more red blood cell individually；About 1/2 alveolar wall slightly thickens, and interstitial can
See stove shape lymphocyte aggregation, more neutrophil infiltration and inflammatory granulation tissue are formed, and see that pulmonary cyst is formed.
Compared with hypoxemia processing group, hypoxemia+dexamethasone 5mg/kg group lung tissue of rats bronchiectasis mitigates, most of
The still visible thin papillary hyperplasia of lining cell *, the expansion of lung artery and vein mitigate；About 1/3 alveolar wall slightly thickens, and interstitial is in more
Property granulocyte infiltration, inflammatory granulation tissue area reduce.
Compared with hypoxemia processing group, hypoxemia+CRT 5mg/kg group lung tissue of rats bronchiectasis mitigate, lining cell * without
Papillary hyperplasia, lung artery and vein is without expansion；About 1/5 alveolar wall slightly thickens, and interstitial is with moderate neutrophil infiltration, inflammatory
It reduces granulation tissue area.
Hypoxemia+CRT 1mg/kg groups lung tissue of rats mitigates compared with hypoxemia processing group bronchiectasis, most of lining cell *
Still visible high papillary hyperplasia, along with lung artery and vein wall thickening, pulmonary vein expansion；Alveolar wall thickening merge, interstitial still see compared with
More neutrophil infiltrations and inflammatory granulation tissue are formed, individual intra-alveolar edemas.
Hypoxemia+CRT 0.2mg/kg groups lung tissue of rats mitigates compared with hypoxemia processing group bronchiectasis, lining cell * agalasisa
Papillary hyperplasia；It is thickened along with pulmonary arterial wall, lung artery and vein is without expansion；About 1/4 alveolar wall, which is shown slightly, to be thickened, and interstitial is visible focal
Thin vessels hyperplasia, expansion, extravasated blood, with more neutrophil infiltration, remaining alveolar has obviously restored normal.
Compared with hypoxemia+dexamethasone 5mg/kg groups, although 1mg/kg CRT handle the protection to hypoxia rats lung tissue
No significant difference is acted on, but 0.2mg/kg and 5mg/kg CRT processing is compared with dexamethasone to hypoxia rats lung tissue protective effect
Obviously, show as mitigating the change of bronchus lining cell * papillary hyperplasia, lung phlebarteriectasia and alveolar wall thickening.5mg/kg
CRT is substantially better than 5mg/kg Dexamethasone groups.
Conclusion：
The pulmonary edema and brain edema of the substantially reduced simulated high altitude hypoxia rat model of the people source basic, normal, high dosage of recombinant C RT,
It is similar with dexamethasone to improve disturbance of acid-base balance, therapeutic effect caused by histanoxia and anoxic；Prompt CRT can be controlled effectively
Treat acute high altitude sickness.
Sequence table：
SEQ ID NO:1 people's Calreticulin precursor
MLLSVPLLLGLLGLAVAEPAVYFKEQFLDGDGWTSRWIESKHKSDFGKFVLSSGKFY
GDEEKDKGLQTSQDARFYALSASFEPFSNKGQTLVVQFTVKHEQNIDCGGGYVKLFP
NSLDQTDMHGDSEYNIMFGPDICGPGTKKVHVIFNYKGKNVLINKDIRCKDDEFTHL
YTLIVRPDNTYEVKIDNSQVESGSLEDDWDFLPPKKIKDPDASKPEDWDERAKIDDPT
DSKPEDWDKPEHIPDPDAKKPEDWDEEMDGEWEPPVIQNPEYKGEWKPRQIDNPDY
KGTWIHPEIDNPEYSPDPSIYAYDNFGVLGLDLWQVKSGTIFDNFLITNDEAYAEEFGN
ETWGVTKAAEKQMKDKQDEEQRLKEEEEDKKRKEEEEAEDKEDDEDKDEDEEDEE DKEEDEEEDVPGQAKDEL
SEQ ID NO:2 no signal peptides at acquaintance's calprotectin
EPAVYFKEQFLDGDGWTSRWIESKHKSDFGKFVLSSGKFYGDEEKDKGLQTSQDARF
YALSASFEPFSNKGQTLVVQFTVKHEQNIDCGGGYVKLFPNSLDQTDMHGDSEYNIM
FGPDICGPGTKKVHVIFNYKGKNVLINKDIRCKDDEFTHLYTLIVRPDNTYEVKIDNSQ
VESGSLEDDWDFLPPKKIKDPDASKPEDWDERAKIDDPTDSKPEDWDKPEHIPDPDA
KKPEDWDEEMDGEWEPPVIQNPEYKGEWKPRQIDNPDYKGTWIHPEIDNPEYSPDPS
IYAYDNFGVLGLDLWQVKSGTIFDNFLITNDEAYAEEFGNETWGVTKAAEKQMKDK
QDEEQRLKEEEEDKKRKEEEEAEDKEDDEDKDEDEEDEEDKEEDEEEDVPGQAKDE L
SEQ ID NO:3 are resident the Human Recombinant Calreticulin of sequence without endoplasmic reticulum
EPAVYFKEQFLDGDGWTSRWIESKHKSDFGKFVLSSGKFYGDEEKDKGLQTSQDARF
YALSASFEPFSNKGQTLVVQFTVKHEQNIDCGGGYVKLFPNSLDQTDMHGDSEYNIM
FGPDICGPGTKKVHVIFNYKGKNVLINKDIRCKDDEFTHLYTLIVRPDNTYEVKIDNSQ
VESGSLEDDWDFLPPKKIKDPDASKPEDWDERAKIDDPTDSKPEDWDKPEHIPDPDA
KKPEDWDEEMDGEWEPPVIQNPEYKGEWKPRQIDNPDYKGTWIHPEIDNPEYSPDPS
IYAYDNFGVLGLDLWQVKSGTIFDNFLITNDEAYAEEFGNETWGVTKAAEKQMKDK
QDEEQRLKEEEEDKKRKEEEEAEDKEDDEDKDEDEEDEEDKEEDEEEDVPGQA
SEQ ID NO:4 no signal peptides are resident sequence, the Human Recombinant Calreticulin sequence with His labels without endoplasmic reticulum
EPAVYFKEQFLDGDGWTSRWIESKHKSDFGKFVLSSGKFYGDEEKDKGLQTSQDARF
YALSASFEPFSNKGQTLVVQFTVKHEQNIDCGGGYVKLFPNSLDQTDMHGDSEYNIM
FGPDICGPGTKKVHVIFNYKGKNVLINKDIRCKDDEFTHLYTLIVRPDNTYEVKIDNSQ
VESGSLEDDWDFLPPKKIKDPDASKPEDWDERAKIDDPTDSKPEDWDKPEHIPDPDA
KKPEDWDEEMDGEWEPPVIQNPEYKGEWKPRQIDNPDYKGTWIHPEIDNPEYSPDPS
IYAYDNFGVLGLDLWQVKSGTIFDNFLITNDEAYAEEFGNETWGVTKAAEKQMKDK
QDEEQRLKEEEEDKKRKEEEEAEDKEDDEDKDEDEEDEEDKEEDEEEDVPGQAHHH HHH
SEQ ID NO:5 are resident sequence, the Human Recombinant Calreticulin sequence with manual signal peptide and His labels without endoplasmic reticulum
MGWSCIILFLVATATGVHSEPAVYFKEQFLDGDGWTSRWIESKHKSDFGKFVLSSGKF
YGDEEKDKGLQTSQDARFYALSASFEPFSNKGQTLVVQFTVKHEQNIDCGGGYVKLF
PNSLDQTDMHGDSEYNIMFGPDICGPGTKKVHVIFNYKGKNVLINKDIRCKDDEFTHL
YTLIVRPDNTYEVKIDNSQVESGSLEDDWDFLPPKKIKDPDASKPEDWDERAKIDDPT
DSKPEDWDKPEHIPDPDAKKPEDWDEEMDGEWEPPVIQNPEYKGEWKPRQIDNPDY
KGTWIHPEIDNPEYSPDPSIYAYDNFGVLGLDLWQVKSGTIFDNFLITNDEAYAEEFGN
ETWGVTKAAEKQMKDKQDEEQRLKEEEEDKKRKEEEEAEDKEDDEDKDEDEEDEE DKEEDEEEDVPGQAHHHHHH
SEQ ID NO:6 manual signal peptides
MGWSCIILFLVATATGVHS。
Claims (12)
1. the purposes of calprotectin in medicine preparation, the drug is for preventing and/or treating acute high altitude sickness.
2. the purposes of claim 1, wherein the calprotectin is people's calprotectin, preferably Human Recombinant Calreticulin.
3. the purposes of claim 1, wherein the calprotectin includes to be selected from SEQ ID NO:The amino acid sequence of 1-5.
4. the purposes of any one of claim 1-3, wherein the acute high altitude sickness be selected from acute high altitude reaction, plateau pneumochysis,
Plateau brain edema or combinations thereof.
5. a kind of for preventing and/or treating the pharmaceutical composition of acute high altitude sickness, it includes the calprotectin of therapeutically effective amount,
And pharmaceutically acceptable carrier.
6. the pharmaceutical composition of claim 5, wherein the calprotectin is people's calprotectin, preferably Human Recombinant Calreticulin.
7. the pharmaceutical composition of claim 5, wherein the calprotectin includes to be selected from SEQ ID NO:The amino acid sequence of 1-5
Row.
8. the pharmaceutical composition of any one of claim 5-7, wherein the acute high altitude sickness is selected from acute high altitude reaction, plateau lung
Oedema, plateau brain edema or combinations thereof.
9. a kind of method for preventing and/or treating acute high altitude sickness, including object in need is given to apply therapeutically effective amount
Calprotectin.
10. the method for claim 9, wherein the calprotectin is people's calprotectin, preferably Human Recombinant Calreticulin.
11. the method for claim 9, wherein the calprotectin includes to be selected from SEQ ID NO:The amino acid sequence of 1-5.
12. the method for any one of claim 9-11, wherein the acute high altitude sickness is selected from acute high altitude reaction, plateau edema with the lung involved
Swollen, plateau brain edema or combinations thereof.
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| WO2023125600A1 (en) * | 2021-12-30 | 2023-07-06 | 北京医图百汇生物科技有限公司 | Use of recombinant calreticulin in hair growth, hair breeding, hair protection or anti-hair loss and related product |
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| WO2023125600A1 (en) * | 2021-12-30 | 2023-07-06 | 北京医图百汇生物科技有限公司 | Use of recombinant calreticulin in hair growth, hair breeding, hair protection or anti-hair loss and related product |
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