KR101458821B1 - Plasma biomarker composition for distinguishing aecopd from copd and the method of detecting the same - Google Patents

Abstract

The present invention relates to a plasma biomarker composition for distinguishing between acute exacerbation chronic obstructive pulmonary disease (AECOPD) and chronic obstructive pulmonary disease (COPD), and a method for detecting the same.
The present invention relates to a pharmaceutical composition comprising retinoic acid receptor alpha (RAR alpha), Ninein isoform CRA_a, a homologous protein that binds to the Ninein GSK3B interacting protein, alpha-1 antidripsin (Alpi), tyrosyl- (COAC), serpin peptidase inhibitor member (6), complement factor B (6), and T-cell receptor delta chain, human Igm RF * and Igg1 Fc, (WD repeat-containing protein 1 isoform 1, WD repetitive homologous protein 1), a complement factor B preproprotein, Chain B of Crig Bound To 3, and WDR1 The present invention provides a plasma biomarker composition for distinguishing between acute exacerbation chronic obstructive pulmonary disease (AECOPD) and chronic obstructive pulmonary disease (COPD).
According to the present invention, it is possible to predict the risk of developing AECOPD according to whether or not the degree of expression of specific protein isolated from plasma is increased or decreased. It is possible to distinguish between COPD patients and AECOPD patients, And can be usefully used in therapeutic fields.

Description

TECHNICAL FIELD [0001] The present invention relates to a plasma biomarker composition for distinguishing between acute exacerbation chronic obstructive pulmonary disease (AECOPD) and chronic obstructive pulmonary disease (COPD), and a method for detecting the plasma biomarker composition.

The present invention relates to a plasma biomarker composition for distinguishing between acute exacerbation chronic obstructive pulmonary disease (AECOPD) and chronic obstructive pulmonary disease (COPD), and a method for detecting the same.

Chronic obstructive pulmonary disease (COPD) is a chronic, progressive, infectious disease of the lung. According to WHO estimates in 2004, 64 million people currently suffer from COPD and 3 million people die from COPD, accounting for 5% of the world 's death rate for the year. COPD is now the leading cause of disease and is the third leading cause of death in the United States. The total COPD deaths will increase to more than 10 years later and will be the third leading cause of death worldwide by 2030, unless there are restrictions, such as the elimination of risk factors, such as exposure to tobacco smoke in particular.

The frequency of acute exacerbation, previous history, and ICU support have been considered important clinical manifestations related to death among COPD patients. Therefore, it is important to identify patients at risk of acute exacerbation and subsequent hospital admissions, and it is important to take steps to avoid such complications.

St. expiratory volume in 1 second effort (FEV ₁₎ shows that there is a connection with the bar, worsening the symptoms of the previous year and the incidence is increasing the risk of deterioration, increased length of hospital stay and mortality have been found in relation to the death of patients with COPD. The age, comorbidity, and severity of functional dyspnea and low body-mass index (BMI) are significantly associated with frequent deterioration and hospitalization risk. As a combination of these clinical parameters, the BODE index shows better than one parameter in predicting mortality risk in COPD patients. However, these clinical parameters are not sufficiently accurate predictions to be applied to each patient. Other indicators are needed to predict hospital admission and mortality of these COPDs.

In peripheral bloods, the dissolution profile of CRP, fibrinogen, alpha10-antitrypsin, eotaxin, IL-4, IL-8, MCP-I and VEGF and TNFRII and VCAM-1 is associated with a rapid aggravation of COPD And is associated with an increased risk of hospital admissions in the future. Although no single biomarker is widely accepted, these biomarkers are expected to be useful in the clinical prediction of COPD progression.

Therefore, investigation of other COPD-specific proteins is an important issue as such proteins will be helpful in the early diagnosis, prediction and treatment of disease. To understand the proteomic contribution of COPD, a large-scale, large-scale, full-proteomic study is required. In a recent study, the inventors developed a novel protein marker for predicting worsening hospital admission in COPD patients by comparing plasma protein expression from stable COPD patients and malignant COPD patients.

The present invention has been proposed in order to solve the above problems, and provides a plasma biomarker composition for distinguishing acute exacerbation chronic obstructive pulmonary disease (AECOPD) and chronic obstructive pulmonary disease (COPD), a detection kit, .

In order to achieve the above object, the present invention provides a pharmaceutical composition comprising retinoic acid receptor alpha (RAR alpha), Ninein isoform CRA_a, a homologous protein binding to Ninein GSK3B interacting protein, alpha-1 antidepressin A1ci), tyrosyl-DNA phosphodiesterase 2, the T cell receptor delta chain, the crystal structure of the autoimmune complex between human Igm RF * and Igg1 Fc (COAC), the serpin peptidase inhibitor 6 member 6), complement factor B preproprotein, chain B bound to C3c (Chain B, Crig Bound To C3c) and WDR1 (WD repeat-containing protein 1 isoform 1, WD repeat homologous protein 1 < / RTI > of the plasma biomarker composition for acute exacerbation chronic obstructive pulmonary disease (AECOPD) and chronic obstructive pulmonary disease (COPD).

The present invention also provides a plasma biomarker composition for distinguishing between acute exacerbation chronic obstructive pulmonary disease (AECOPD) and chronic obstructive pulmonary disease (COPD), characterized by comprising retinoic acid receptor alpha (RAR alpha).

The present invention also provides a kit for diagnosing acute exacerbation chronic obstructive pulmonary disease (AECOPD) and chronic obstructive pulmonary disease (COPD) by the plasma biomarker composition.

The present invention also relates to a method of treating a subject's plasma in plasma of a subject comprising administering to the subject plasma a therapeutically effective amount of at least one of RET alpha, (A1pi), tyrosyl-DNA phosphodiesterase 2 or T cell receptor delta chains, or the crystal structure (COAC) of the autoimmune complex between Human Igm RF * and Igg1 Fc, Serpin peptidase inhibitor member 6, complement factor B preproprotein, Chain B and Crig Bound To C3c bound to C3c, and WD repeat-containing protein 1 isoform 1, WD repetitive homoprotein 1) is reduced in order to detect progression of acute exacerbation chronic obstructive pulmonary disease (AECOPD) In order to use the lightning biomarkers providing acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and chronic obstructive pulmonary disease (COPD) information needed to differentiate, there is provided a method for detecting a plasma biomarker.

According to the present invention, it is possible to predict the risk of developing AECOPD according to whether or not the degree of expression of specific protein isolated from plasma is increased or decreased. It is possible to distinguish between COPD patients and AECOPD patients, And can be usefully used in therapeutic fields.

Figure 1 A shows the results of 2DE and MALDI-TOF / TOF in 17 patients with COPD ballast and worsening patients Plasma proteins were identified.
FIG. 1B shows the relative intensities of the proteins identified in FIG. 1A.
Figure 2 shows the results of measurement of the retinoic acid receptor alpha (RAR alpha) in plasma in the steady and worsened states of COPD patients.
Figure 3 is a graph comparing levels of retinoic acid receptor alpha (RAR alpha) in the control (n = 37) and COPD patients (n = 35).
Figure 4 is a receiver operating curve (ROC) analysis graph of the retinoic acid receptor alpha (RAR alpha) protein. ROCs were made at the level of the retinoic acid receptor alpha (RAR alpha) in the COPD subjects in the steady state.

TECHNICAL FIELD The present invention relates to a plasma biomarker composition through a change in the expression of proteins present in a plasma to distinguish between acute exacerbation chronic obstructive pulmonary disease (AECOPD) and chronic obstructive pulmonary disease (COPD), and a method for detecting the same.

Hereinafter, the present invention will be described in detail with reference to examples. It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the spirit or scope of the invention. The scope of the present invention is not limited by these variations and modifications.

[ Example  1: subject]

Table 1 summarizes the characteristics of COPD patients and controls. The control group ( n = 37) and COPD ( n = 35) were Korean, participants in the study received informed consent and the protocol was approved by the Ethics Committee (No. 2012-005).

All patients received physician diagnosis and treatment, and the Global Initiative approved the COPD (GOLD) guideline [14]. Briefly, the clinical diagnosis of COPD included smokers who complained of respiratory distress, chronic cough, or sputum, and older smokers (more than 10 packs a year). In the present invention, patients with COPD include those with an initial post-bronchodilator FEV1 / FVC of less than 0.70 and an FEV1% of less than 70%.

All subjects observed symptoms and pulmonary function for at least 3 years with a 2-month periodic cycle. A stable state of COPD is defined as a condition in which no further treatment for maintenance therapy is needed for 30 days without symptoms of chest infection.

Signs of hospitalization due to acute exacerbations include: Significant increase in the severity of dyspnea, signs of hypoxia, appearance of peripheral edema, and purulent sputum, fever, leukocytosis with increased ESR and CRP.

Records of causative agents causing aggravation were performed by culture of bacteria and respiratory virus PCR of sputum. Patients previously diagnosed with bronchial asthma or other pulmonary diseases such as bronchiectasis, tuberculosis and tumors or other immune system diseases were excluded prior to this study.

The control group was selected as those who responded negatively to the questionnaire on respiratory symptoms, with FEV1> 75% predicted, FEV1 / FVC> 70%, and normal chest radiograph.

Peripheral venous blood of the subjects was collected in a tube containing ethylenediamine tetraacetic acid (EDTA, 0.20 g / 10 mL per blood) and the plasma was centrifuged at 2000 rpm for 15 minutes Separated by separation, specimens were stored at -80 ° C. Acute exacerbation samples were also collected shortly after the diagnosis of deteriorating preclinical intervention.

[ Example  2 : plasma  Preparation and 2-D Gel-Electrophoresis (2 DE )]

A total of 24 plasma samples of 8 control and 8 COPD stable and deteriorated states were separated by 2DE. Each clinical feature is summarized in Table 1.

<Table 1> Clinical characteristics of subjects

Immobiline DryStrips (24 cm, pH 3-10, pH 3-7; Amersham Biosciences) was used for isoelectric focusing (IEF) in IPGphor system (Amersham Biosciences) using 1 mg protein as described above [15]. After IEF, the proteins were separated on a 5 - 18.5% SDS-polyacrylamide gel using the Ettan Dalt II system (AP Biotech). After each separation, the gel was stained with Coomassie brilliant blue G-250. The digitized image of the stained gel was analyzed using ImageMaster 2D (ver. 4.0, Amersham Pharmacia Biotech). Coomassie-stained spots were quantified based on the normalized volume, i.e., the volume of the spot divided by the sum of the total spot volumes.

[ Example  3: Intra - Gel decomposition and mass spectrometry analysis]

The differentially expressed protein spots were cleaved from the gel, cut into smaller pieces, digested with trypsin (Promega) and then subjected to MALDI-TOF [16]. For MALDI-TOF mass spectrometry (MS) analysis, trypsin peptides were concentrated on a POROS® R2 column (Applied Biosystems). After continuously washing the column with 40% methanol, 100% acetonitrile and 50 mM ammonium bicarbonate, the samples were applied to a column, diluted with 2 ml of cyano-4-hydroxycinnamic acid, loaded onto a Voyager DE PROMALDI- TOF spectrometer (Applied Biosystems) to obtain MALDI-TOF spectra. Monoisotopic peaks were used to perform protein database searches with the MSFit program (http://prospector.ucsf.edu/ucsfhtml3.4/msfit.htm). The first analysis proceeded with a mass error within 50 ppm; The system was re-measured continuously at 20 ppm using the protein list from the initial analysis. The spectrum was initially measured using trypsin autodisperse products. Peptide matching and protein searches for Swiss-Prot and NCBI databases were performed using Mascot (http://www.matrixscience.com/) and Pro Found (http://prowl.rockefeller.edu/) .

[ Example  4 : ELISA Using In the plasma RAR α measurement]

37 normal control and 35 COPD steady-state plasma samples were performed by ELISA (Uscn Life Science Inc.), and COPD 14 subjects were subjected to additional RARα measurements in the aggravated phase. The lower detection level is 0.063 ng / ml. Values below this threshold are assumed to be zero for statistical analysis purposes.

[ Example  5: Statistics]

Statistical analysis was performed using SPSS 13.0. The Mann-Whitney U test (two independent samples) and the Wilcoxon signed rank sum test (two related samples) were applied as FEV1 adjustments to the difference in density and RARalpha concentration at 2DE spots. Association analysis was performed using SPSS 13.0 between clinical parameters such as the number of acute exacerbations and the level of RARα protein. In order to determine how well the patients were admitted to the hospital for the previous three years, we used the area under the receiver operating char- acteristic curve (ROC). All data are expressed as means and SD, with significance defined as P <0.05.

[ Example  6: Results - Clinical characteristics of the study subjects]

Clinical features are summarized in Table 1. We chose COPD male patients and controls. All COPD subjects were smokers or former smokers (> 10 packs per year), whereas 10% of controls were non-smokers. All control subjects were post bronchodilator FEV1 / FVC> 0.7, while all COPD subjects had a value of <0.7.

BMI was slightly lower in the COPD group compared to the control group, but the difference was slight (P> 0.05). In COPD subjects (n = 8) with 2DE plasma, FEV1 was significantly reduced in malignant conditions compared to steady state (p <0.001). All 35 COPD subjects were stratified by hospital admission due to deterioration during the following period. 21 subjects were hospitalized and they had significantly lower FEV1, FVC, and FEV1 / FVC ratios compared to non-hospitalized COPD subjects (n = 14). Of the 21 individuals, 14 were irradiated with plasma samples on the day of hospital admission. The causes of acute exacerbation were bacterial infection (n = 1) and viral infection (n = 4). Causal factors (n = 7) were not documented.

[ Example  7: COPD  Stabilizer and deterioration In patients  2 DE  And MALDI - TOF / TOF On by Plasma However,

Median value 561 (range, 430-730) protein spot in the control, median 555 (range 452-653) in the ballistic subject with COPD after the coomassie blue staining and median value 566 , 477-696) was detected in 1 mg of plasma protein. 17 proteins showed a significant difference in the relative strength between the stabilizer and the aggravator of 8 subjects with COPD (Fig. 1a). The relative intensity (%) in the spot is shown in FIG. 1B, and the position of the identified protein spot appears in the master image. Of these, 7 spots increased significantly, while the other 10 spots were reduced in deteriorated state compared to ballast.

[ Example  8 : MALDI - TOF MS &Lt; / RTI &gt;

These spots were separated from the gel, cultured in an in-gel degradation state with trypsin, and then confirmed with MALDI-TOF / TOF. The results are summarized in Table 2. (RAR alpha, spot 13), Ninein (GSK3B interacting protein) isoform CRA_a (spot 5), alpha-1 antidripsin (A1pi, spot 8), fibrinogen gamma (spot 1) While the tyrosyl-DNA phosphodiesterase 2 (spot 14) and the T cell receptor delta chain (spot 15) increased in the plasma of COPD deterioration, fibrin beta (spots 2, 3 and 4), human Igm RF * and Igg1 Fc (COAC, spot 6), trans- ferrin (spot 7), serpin peptidase inhibitor member 6 (Serpin B6), spot 9), complement factor B prepro- (WD repeat-containing protein 1 isoform 1, WD repetitive homologous protein 1, spot 12), complementer B preproprotein (spot 10), chain B bound to C3c (Chain B and Crig Bound To C3c) Respectively.

Fibrinogen gamma and fibrin beta are coagulation proteins. Ninein, a GSK3B interacting protein, is a cytoskeleton. COAC and transperine are involved in the immune response protein. Serpin peptidase inhibitor member 6, Alpha-1 antidripsin (A1pi) and Serpin peptidase inhibitor member 6 (Chain B, Crig Bound To C3c) Are included in the infectious protein. WD repeat containing protein 1, retinoic acid receptor alpha (RAR alpha), tyrosyl-DNA phosphodiesterase 2, T cell receptor delta chain are signaling modifiers.

[ Example  9: COPD  Ballast and Worsening In the plasma Retinoic acid  Changes in receptor alpha]

To demonstrate a change in retinoic acid receptor alpha (RAR alpha) protein levels upon exacerbation from the ballast, the retinoic acid receptor alpha (RAR alpha) was measured in plasma in the steady state and aggravated state of COPD patients (n = 15, 2). Of these, 12 individuals show an increase in levels of retinoic acid receptor alpha (RAR alpha) in the exacerbations compared to the balloons. The mean concentration of retinoic acid receptor alpha (RAR alpha) was 2-fold higher in the exacerbated group compared to the ballast condition.

[ Example  10: At the ballast Retinoic acid  Relationship between Alpha Level of Receptor and Hospital Incidence Frequency]

In the control (n = 37) and COPD patients (n = 35), the retinoic acid receptor alpha (RAR alpha) protein level in the steady state correlated with the hospital admission frequency due to deterioration (RAR alpha) levels (Figure 3). Patients with COPD were stratified by the frequency of hospital worsening.

Patients in the COPD group (n = 14) who were not hospitalized were similar to the RAR alpha levels of the control group (p> 0.05). The COPD subjects (n = 21) who were admitted to the hospital were significantly higher than those who were not admitted to the hospital ( P = 0.0004). At least 0.4 inpatient COPD subjects per year (n = 10) had very high retinoic acid receptor alpha (RAR alpha) protein levels, and less than 0.4 inpatient COPD subjects per year (n = 11) were intermediate.

The receiver operating curve (ROC) analysis of the retinoic acid receptor alpha (RAR alpha) protein is a predictor of deterioration in COPD. ROCs were measured in the resting COPD subjects (n = 35, Figure 4) (RAR alpha) levels were measured at 95% confidence intervals using plasma level variance estimates. The ROC analysis of retinoic acid receptor alpha (RAR alpha) occupies the area below the 0.844 curve (Figure 2) The 0.154 ng / ml cutoff of retinoic acid receptor alpha (RAR alpha) predicts hospital admission with a sensitivity of 71.4% and a specificity of 92.8%.

[ Review ]

In the present invention, 17 protein spots were found to be differentially expressed in the plasma in the deteriorated state, as compared to the COPD subjects of the ballast. Of these, retinoic acid (RA), as a ligand for the retinoic acid receptor alpha (RAR alpha), has been demonstrated to be RAR-alpha because it is associated with lung development and recovery [17].

In the control and COPD validation trials, the concentration of retinoic acid receptor alpha (RAR alpha) increased more than two fold in the subjects who were exacerbated compared to the control subjects. Also, the level at the ballast was related to the frequency of hospital admission. This data suggests that the plasma concentration of retinoic acid receptor alpha (RAR alpha) may be a predictor of hospital admission for COPD. This is the first study of the relationship between hospital admission and RAR level due to the deterioration of COPD.

RA is a lifelong need to maintain alveoli. In experimental mice lacking retinol as food, the alveoli was lost and showed the characteristic of emphysema [18]. All transport retinol (ATRA), the transport form of vitamin A, is reversibly converted to retinyl esters, which act primarily as a storage form in the lungs as well as the liver [19].

In this experiment, ATRA is regulated so that MMP-9 is decreased and the phage is increased by TIMP-1-induced alveolar macrophage [20]. Moreover, administration of ATRA to model patients reduces plasma MMP-9 and MMP-9 enzyme activity [21]. Thus, ATRA can restore the protease-anti-protease imbalance of COPD. Significantly, smokers have a tendency to increase plasma levels of retinoic acid and retinol, all of which can supplement the retinoid levels of the lungs, whereas oxidative stress resulting from exposure to tobacco smoke reduces RAR expression [23 ]. In the present invention, since all COPD subjects are past or present smokers, 90% of the general control group were matched to smokers and past smokers.

Apoptosis of rescue cells in the lungs can be an important upstream activity in COPD outbreaks. In COPD lungs, apoptosis and endothelial cell apoptosis are increased [24]. Cellular suicide processes are not mutually balanced by the increase in the proliferation of these structural cells causing destruction of lung tissue and development of the model [25]. Cellular suicide in the lungs occurs outside the lungs, including skeletal muscle [26] and circulating T cells [27], so intracellular proteins such as RAR are not detected in peripheral blood. At this point, the cause of the greater increase in the rise and deterioration of the plasma RAR of the ballast COPD was not revealed.

However, an increase in RAR can be induced from apoptotic cells, which are stressed in COPD exacerbation, in consideration of the relationship between COPD with retinoic acid in lung development and the increase in apoptosis in lung tissue and lung tissue. As a marker for increased intercellular turnover, the systemic release of apoptotic-specific proteins is accompanied by COPD progression. The cytoskeletal content of cytoskeletal-18 and histone-associated-DNA-fragments increased in the peripheral blood of patients with COPD [28].

In the present invention, Ninein significantly increased at the time of exacerbation. Interestingly, the Ninein gene level was increased in the small airway epithelium of smoking COPD [29]. Ninein (Ninein) is one of the proteins important for the fixation of the microtubule and the pancreatic function in epithelial cells. The airway epithelium is the first line of defense against cigarette smoking and the airway epithelium of smokers demonstrates a significant change in gene expression compared to non-smokers [30,31]. Considering the onset of COPD exacerbation in airway epithelium and pulmonary fibrosis, molecules released from the epithelium may increase in the peripheral blood of subjects subject to COPD exacerbation. WD repeat-containing protein 1 is a cytoplasmic protein involved in actin filament degradation. The assembly and maintenance of microtubule-dependent ciliary and plagiar structures depends on intraflagellar transport (IFT). Anterograde IFT acts as a means of transporting proteins in the ciliary body and retrograde IFT is used to recycle IFT machinery back into the ciliary base [32].

Ciliary beatings decline in nasal cilia of subjects with COPD [33]. The molecular mechanism has not yet been elucidated, but a low level of WD repeat-containing protein 1 may be associated with decreased CODD through ciliary movement. Tyrosyl-DNA phosphoesterase 1 restores DNA damage induced by topoisomerases I and II [34]. This increase in protein can be induced from an increase in apoptosis in COPD.

In the present invention, the T cell receptor delta chain is increased in COPD and is further increased in the aggravated state. T-lymphocytes are the major infectious and regulatory cells involved in the inflammatory response of COPD. TCR-γδ lymphocytes correspond to only 5% of the total T-cell subpopulation. However, they play a major role in the recovery response to mucosal homeostasis and tissue damage [35]. Turnover and BAL γδ-lymphocytes are higher in smokers with normal lung function than non-smokers, and this response is slowed in COPD patients [36]. However, the T-cell receptor delta chain is increased in the peripheral blood of this study, which represents another aspect of the T-cell receptor delta chain in COPD.

In the present invention, A1p (alpha-1-antitrypsin, SERPINA1) was increased in the aggravated group compared to COPD of the ballast, while Serpin B6 was decreased. Serpins are a group of proteins that have structures similar to those found initially in a set of proteins that can inhibit proteases. Alpha-1 antidrypsin (A1pi) predominantly complexes with elastase as well as trypsin, chymotrypsin, thrombin and bacterial proteases [37].

In the absence of this, neutrophil elastase is degraded into elastin, causing the model. An increase in alpha-1 antidepressant synthase (A1pi) has also been reported to be present in stable COPD and, as demonstrated in the present invention, is exacerbated in COPD exacerbations.

Serpin B6 is a serine proteinase inhibitor present in cytoplasmic fragments of myelomonocytes, capillary endothelial cells, platelets and epithelial cells. Serpin B6 binds to endogenous membrane-associated serine proteases such as cathepsin G [38]. When the complete vacuole is destroyed during phagocytosis, Serpin B6 deactivates all of the proteases released into the cell rapidly. Intercellular cathepsin G regulation may be particularly important, as this activates caspase-7, a cell apoptotic protease [39]. Thus, in the present invention, low levels of Serpin B6 may result in increased apoptosis of lung or systemic tissues [40].

In the coagulation proteins, fibrinogen gamma was increased while fibrin beta was decreased upon aging. These are acute phase glycoproteins that are first synthesized in the liver and converted from thrombin to fibrin during the blood coagulation process. There is evidence that there is a strong relationship between fibrinogen levels and the presence and mortality of COPD [14]. Fibrinogen is a dimer of three polypeptide chains, alpha, beta and gamma [41]. All three chains are important for the normal function of fibrinogen, but due to the tangled tertiary structure, the gamma chain contains many sites that interact with clotting factors, growth factors and integrins [42].

In the present invention, spots 2, 3 and 4 were found to be fibrin beta. Since spots 3 and 4 have a pIs of 5.95, while spots 2 have pIs of 6.25, spots 3 and 4 appear to be modifications after transfer of spot 2. All spots were significantly reduced in the COPD exacerbator compared to the ballast COPD. Currently, the reason why the deterioration process is associated with a decrease in the amount of fibrinogen beta in this study is unknown.

Transferrin is an iron-ion-binding plasma plasma glycoprotein that regulates the level of free iron ion in physiological fluids. Transferrin is also associated with the innate immune system. Through the process of iron withholding, iron is combined with iron by inhibiting bacterial viability, creating an environment that lowers the free iron ion concentration, and is found in mucous membranes. Decreased transreneglene concentrations in the lower respiratory tract can reduce defense against oxidative injuries and bacterial infections in patients with respiratory defects due to COPD. In vivo protein storage is analyzed using blood parameters such as albumin, prealbumin or trans-perrine. Protein-caloric malnutrition can be seen in COPD patients and patients with acute respiratory disorders [43]. In this study, BMI is significantly lower in COPD, which is slowly reduced in COPD exacerbations, suggesting impaired nutritional status in COPD.

Infection is one of the key processes in the onset of COPD, characterized by increased inflammatory cells in COPD patients and over- or under-production of infection mediators in bronchoalveolar lavage fluid, germane, and lung tissue [44 ]. Systemic inflammatory hypo-reactions occur during acute exacerbations, whether it is due to acute exacerbations or not.

Plasma CRP levels, serum interleukin (IL) -6 and copeptin are useful in identifying COPD aggravation [45, 46, 47], although major changes in these mediators have not been observed in the present invention. This may be due to the use of other types of deterioration between the present invention and other studies.

The definition of aggravation in COPD is controversial [48]. If symptoms or pulmonary function are entirely dependent on the criteria, the criteria are highly subjective, depending on the patient or physician. In the present invention, the inventors designated COPD patients who were admitted to the hospital as subjects to be exacerbated. This indicates that the subjects of the present invention have more severe symptoms of COPD deterioration than other studies [16, 47].

In summary, the inventors have identified that 17 proteins are differentially expressed in plasma at the COPD ballast and aggravator using 2 DE and MALDI-TOF / TOF as new candidate plasma biomarkers for predicting COPD deterioration. Of these, quantitative determination of RAR alpha was performed in the plasma of the general control group and COPD subjects. In steady-state plasma, retinoic acid receptor alpha (RAR alpha) protein levels were associated with the presence and frequency of hospitalization due to COPD worsening. The cut-off of 0.154 ng / ml retinoic acid receptor alpha (RAR alpha) showed 71.4% sensitivity and 92.8% specificity for hospitalization due to exacerbations. These results can provide a new perspective of protein markers in deteriorating COPD.

Claims (4)

Retinoic acid receptor alpha (RAR alpha), Ninein isoform CRA_a, homologous protein binding to Ninein GSK3B interacting protein, alpha-1 antidrypsin (A1pi), tyrosyl-DNA phosphodiesterase 2 , The T cell receptor delta chain, the crystal structure of the autoimmune complex between human Igm RF * and Igg1 Fc (COAC), the serpin peptidase inhibitor member 6, the complement factor B preproprotein complement factor B preproprotein, Chain B, Crig Bound To C3c) and WDR1 (WD repeat-containing protein 1 isoform 1, WD repeat homoprotein 1) A plasma biomarker composition for distinguishing between obstructive pulmonary disease (AECOPD) and chronic obstructive pulmonary disease (COPD). A plasma biomarker composition for distinguishing between acute exacerbation chronic obstructive pulmonary disease (AECOPD) and chronic obstructive pulmonary disease (COPD), characterized by comprising retinoic acid receptor alpha (RAR alpha). A kit for the diagnosis of acute exacerbation chronic obstructive pulmonary disease (AECOPD) and chronic obstructive pulmonary disease (COPD) comprising the plasma biomarker composition according to claim 1 or 2. (RAR alpha), Ninein isoform CRA_a, a homologous protein that binds to the Ninein GSK3B interacting protein, alpha-1 antidrypsin (A1pi), tyrosyl-DNA One or more of the phosphodiesterase 2 or T cell receptor delta chains is increased,
The crystal structure (COAC) of the autoimmune complex between human Igm RF * and Igg1 Fc, the serpin peptidase inhibitor member 6, the complement factor B preproprotein, (Chain B, Crig Bound To C3c) and WDR1 (WD repeat-containing protein 1 isoform 1, WD repeat homoprotein 1) of the Bound Tryptic 3 seed
(AECOPD) and chronic obstructive pulmonary disease (COPD) using the plasma biomarker of claim 1 or 2 for the detection of progression of acute exacerbation chronic obstructive pulmonary disease (AECOPD) Wherein the plasma biomarker is a plasma biomarker.

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