Serum metabolomics of chronic obstructive pulmonary disease with lung-Qi deficiency syndrome / 中国中药杂志

The present study analyzed the potential biomarkers of chronic obstructive pulmonary disease(COPD) with lung-Qi deficiency syndrome by non-targeted metabolomics and explored the biological basis of this syndrome. Blood samples of 96 COPD patients with lung-Qi deficiency syndrome(COPD with lung-Qi deficiency syndrome group) and 106 healthy people(healthy control group) were collected, and the metabolic profiles of both groups were analyzed by ultra-high performance liquid chromatography-quadrupole-time-of-flight mass spectrometry(UPLC-Q-TOF-MS). Multivariate statistical analysis and differential metabolite screening were carried out by using Progenesis QI and Simca-P. Metabolic pathways were constructed through the MetaboAnalyst. Seven potential biomarkers, such as L-cystathionine, protoporphyrinogen Ⅸ, and citalopram aldehyde, were identified. Compared with the results in the healthy control group, the content of citalopram aldehyde, N1-methyl-2-pyridone-5-carboxamide, and 11β,17β-dihydroxy-4-androsten-3-one was significantly up-regulated, while that of the other four compounds such as L-cystathionine, dihydrotestosterone, protoporphyrinogen Ⅸ, and D-urobilinogen was down-regulated. These potential biomarkers involved six metabolic pathways, including cysteine and methionine metabolism, porphyrin and chlorophyll metabolism, drug metabolism of cytochrome P450, steroid hormone biosynthesis, glycine, serine, and threonine metabolism, and nicotinate and nicotinamide meta-bolism. This study is expected to provide a certain scientific basis for the research on traditional Chinese medicine syndrome of COPD with lung-Qi deficiency syndrome from the molecular biology level.

Effect of Modified Yangxintang on Chronic Pulmonary Heart Disease with Syndrome of Deficiency of Heart and Lung Qi / 中国实验方剂学杂志

Objective:To discuss the effect of modified Yangxintang on chronic pulmonary heart disease (CPHD) with syndrome of deficiency of heart and lung Qi and progress of disease. Method:One hundred and twenty-eight patients were randomly divided into control group 64 cases and observation group 64 cases by random number table. Patients in control group got comprehensive rehabilitation measures of western medicine. Those who had respiratory distress got Salmeterol ticasone powder inhaler, 1-2 times/day, 1 inhale/time.And those who had cough and phlegm got Ambroxol hydrochloride tablets for 1-2 week, 1-2 tablet/time, 3 times/day. In addition to the therapy of control group, patients in observation group was also added with modified Yangxintang, 1 dose/day, 5 days/week. Record the and times of acute aggravate and cold, pulmonary artery systolic pressure (PASP), mean pulmonary artery pressure (MPAP), left ventricular ejection fraction (LVEF), stroke volume (SV) and cardiac output (CO) were recorded during 48 weeks. Before and after treatment, scores of modified British medical research council respiratory questionnaire (mMRC questionnaire), Minnesota Heart Failure Quality of life scale (MLHFQ), syndrome of deficiency of heart and lung Qi and 6-minute walking test (6 MWT) were scored. And levels of N-terminal B-type natriuretic peptide (NT-proBNP), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), nitric oxide (NO), endothelin (ET-1), CD3+, CD4+, CD8+ and CD4+/CD8+ were detected. Result:The clinical efficacy in observation group was better than that in control group (Z=2.108, P<0.05). During 48 weeks of observation period, times of acute aggravate and cold in observation group were less than those in control group (P<0.01). Levels of PASP, MPAP and NT-proBNP were lower than those in control group (P<0.01). And levels of LVEF, SV, CO, 6 MWT and NO were higher than those in control group (P<0.01), levels of CD3+, CD4+ and CD4+/CD8+ were higher than those in control group (P<0.05). And levels of mMRC, MLHFQ, score of syndrome of deficiency of heart and lung Qi, TNF-α , IL-6, ET-1, CD8+ and were all lower than those in control group (P<0.01, P<0.05). Conclusion:In addition to anti-inflammatory, anti-asthmatic and anti-tussive therapies, modified Yangxintang can improve the immune function, relieve the symptoms of heart and lung, improve the function of heart and lung and the quality of life, inhibit the inflammatory reaction, improve the function of vascular endothelium, reduce the pulmonary hypertension, control the progress of disease.

Effect of Addition and Subtraction Adjuvant Therapy of Bufeitang on Immune Inflammation After Tracheotomy in Stroke Patients with Syndrome of Deficiency of Spleen and Lung Qi / 中国实验方剂学杂志

Objective:To discuss the efficacy of addition and subtraction adjuvant therapy of Bufei decoction for pulmonary infection after tracheotomy in stroke patients (syndrome of deficiency of spleen and lung Qi) and investigate its effect on immune inflammation. Method:One hundred patients were randomly divided into control group (50 cases) and observation group (50 cases) by random number table. The patients in both groups got cefepime hydrochloride for injection, once every 12 hours, 2 g/time， at the same time, symptomatic and supportive comprehensive treatment was given. Patients in control group additionally got compound glycyrrhiza oral solution via gastric tube, 10 mL/time, 3 times/day. Patients in observation group got addition and subtraction adjuvant therapy of Bufeitang every morning and night via gastric tube, 1 dose/day. The treatment course was 14 days in both groups. At the 1st, 7th and 14th day after treatment, scores of clinical pulmonary infection scale (CPIS) and Acute Physiology and Chronic Health Evaluation Ⅱ (APACHE Ⅱ) were graded. The time to control pulmonary infection and the antibiotics use time were recorded. Before and after treatment, levels of T lymphocyte subsets (CD3+, CD4+，CD8+ and CD4+/CD8+), regulatory T cells of (Treg cells), immunoglobulin A (IgA), immunoglobulin G (IgG), immunoglobulin M(IgM), procalcitonin (PCT), tumor necrosis factor-α (TNF-α), interleukin-1β, IL-6 and IL-10 were detected, and safety was evaluated. Result:At the 7th and 14th day after treatment, scores of CPIS and APACHE Ⅱ in observation group were lower than those in control group (P<0.01). The time to control pulmonary infection and antibiotics use time were shorter than those in control group (P<0.01). Levels of Treg cells, CD4+ and CD4+/CD8+ were higher than those in control group (P<0.05). Levels of CD8+, PCT, TNF-α, IL-1β, IL-6 and IL-10 were lower than that in control group (P<0.01), while levels of IgA and IgM were higher than those in control group (P<0.01). There was no adverse reaction related to Bufeitang. Conclusion:Based on comprehensive treatment of western medicine for anti-infection and symptomatic support, addition and subtraction adjuvant therapy of Bufeitang can effectively control the severity of pulmonary infection caused by tracheotomy in stroke, reduce coughing and expectoration, shorten the course of pulmonary infection and the use time of antibiotics, regulate immune function and inhibit inflammatory reaction.

Clinical Efficacy of Wenfei Jianpi Decoction on Moderate to Severe Persistent Allergic Rhinitis with Lung Qi Deficiency and Cold Syndrome / 中国实验方剂学杂志

Objective::To observe the efficacy of Wenfei Jianpi decoction on moderate to severe persistent allergic rhinitis (AR) with Lung Qi deficiency and cold syndrome and its effect on substance P (SP) in nasal secretions and peripheral blood proinflammatory factors. Method::One hundred and sixty-six patients were randomly divided into control group and observation group by random number table. Patients in control group got budesonide nasal spray, 2 times/days, and cetirizine hydrochloride tablets, 10 mg/days. And patients in observation group got Wenfei Jianpi decoction for oral, 1 dose/day. A course of treatment was 8 weeks. Before and after treatment, nasal obstruction, itching, sneezing, runny nose, itchy eyes, tears and nasal sign were scored, nasal airway resistance was detected, and rhinoconjunctivits quality of life questionnaire (RQLQ) were scored. Before and after treatment, levels of SP immunoglobulin E (IgE) in peripheral blood, interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were detected, and eosinophil (EOS) were calculated. Result::By rank sum test, the clinical efficacy in observation group was better than that in control group (Z=2.073, P<0.05). Before and after treatment, scores of total score of nasal symptoms, ocular symptoms and subjective symptoms and nasal sign score were all lower than those in control group (P<0.05). Except sleep and emotion, scores of other dimensions and the total scores of RQLQ were all lower than those in control group (P<0.05). EOS in observation group was less than that in control group (P<0.05). And nasal resistance declined in observation group (P<0.05), and levels of IgE, SP, IL-4, IL-5, IL-6, TNF-α and nasal resistance were lower than those in control group (P<0.05, P<0.01). Conclusion::Wenfei Jianpi decoction can be used to treat moderate to severe persistent allergic rhinitis by relieving subjective symptoms and signs, improving quality of life, inhibiting inflammatory factors and reducing allergic reaction.

Therapeutic effect on chronic obstructive pulmonary disease of lung deficiency at the stable stage treated with ginger-separated moxibustion and Chinese herbal medicine atomization / 中国针灸

OBJECTIVE@#To compare the clinical effect on chronic obstructive pulmonary disease (COPD) of lung deficiency at the stable stage treated with ginger-separated moxibustion and Chinese herbal medicine atomizaiton.@*METHODS@#A total of 90 patients with COPD of lung deficiency at the stable stage were randomized into an observation group (45 cases, 1 case dropped off) and a control group (45 cases, 2 cases dropped off). In the observation group, the ginger-separated moxibustion was applied to Dazhui (GV 14), Feishu (BL 13) and Gaohuangshu (BL 43), 2 moxa cones at each acupoint in each treatment. Additionally, the atomized inhalation with decoction and decoction was combined for 20 min, once every two days. The treatment for 10 times was taken as one course and 2 courses of treatment were required for 20 min. In the control group, ambroxol hydrochloride oral solution (10 mL) and compound methoxynamine capsules (2 capsules), were taken orally. Additionally, salbutamol aerosol was combined, 1 spray each time, three times a day, consecutively for 40 days. Before treatment and in 1-year followup after treatment, percentage of the forced expiratory volume in the first second predicated value (FEV1%) and its ratio to the forced vital capacity (FVC) (FEV1/FVC%) were determined in patients of the two groups. Before and after treatment, and in 3 months, 6 months and 1 year of followup after treatment, the score of COPD assessment test (CAT) and the score of traditional Chinese medicine (TCM) symptom were observed in the two groups separately. The clinical effect was assessed in 3-month followup after treatment and the frequency of the acute attack of COPD was followed up in 1 year after treatment in patients of the two groups.@*RESULTS@#In 1-year followup, FEV1% and FEV1/FVC% were increased in patients of the two groups (0.05). In 1-year followup, the acute recurrence rate of COPD was 20.5% (9/44) in the observation group, lower than 32.6% (14/43) in the control group (<0.05).@*CONCLUSION@#As compared with western medication, the combination of ginger-separated moxibustion and Chinese herbal medicine atomizaiton achieves the superior effects of improving the lung functions, reducing the clinical symptoms and decreasing the frequency of acute attack in patients with COPD of lung deficiency at the stable stage.

Effect of Wenfei Zhiliudan in Treating Lung Qi Deficiency Cold Type Allergic Rhinitis and Its Mechanism / 中国实验方剂学杂志

Objective: To observe the efficacy and safety of Wenfei Zhiliudan in treatment of lung Qi deficiency cold type allergic rhinitis. Method: A total of 120 cases were randomly divided into control group and observation group, with 60 cases in each group. The control group was given desloratadine + momethasone furoate, while observation group was given Wenfei Zhiliudan. A course of treatment was 2 weeks. The rhino conjunctivitis quality of life questionnaire (RQLQ), total nasal symptom score (TNSS) and traditional Chinese medicine (TCM) syndrome differentiation scale for lung Qi deficiency cold (TCM scale) in two groups before and after treatment were observed. The serum inflammatory factor[tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-33 (IL-33)]and immune indexes[immunoglobulin E (IgE), eosinophils (EOS), eotaxin (EOT)]were determined. The total effective rate and the incidence of adverse reactions were compared between two groups. Result: Five cases felt off during the study period. The total effective rate in observation group was 91.5%(54/59), which was higher than 82.5%(47/57) in control group (PPα, IFN-γ, IL-33) in observation group were significantly lower than those in control group (PPPPConclusion: Wenfei Zhiliudan can significantly alleviate the clinical symptoms, serum inflammatory factors and immune indicators of lung Qi deficiency cold type allergic rhinitis, with a lower incidence of adverse reactions.

Normal and lung qi deficiency rats proteomics of lung tissue variance analysis / 中国免疫学杂志

Objective:Normal and lung qi deficiency rats of proteomics of lung tissue of rats differentially expressed and mass spectrometry.Methods:A total of 20 SD rats were randomly divided into control group,lung qi deficiency group,with 10 rats in each roup.Lung qi deficiency group model replication using composite method by intratracheal injection of lipopolysaccaride and smoked.All rats in each group before anesthesia 12 hours of fasting,water deprivation,weight after 28 days modeling,Thoracotomy to remove left lung tissue after anesthesia was 10 mg from each rat, 3 rats from each group, using two-dimensional electrophorsis analysis, two-dimensional gel electrophoresis image, peptide mass fingerprinting and electrospray tandem by mass spectrometry to protein identification.Results:2 differntial protin profiles for proteomics analysis,identified 14 protein in rat lung tissue,protein 5 expression, regulation 9 expression.Conclusion:By proteomic analysis,identify the protein have correlation with lung deficiency syndrome.

Effects of Yupingfeng Powder on Immune Function of Rats with Lung-qi Deficiency Syndrome / 中国药房

OBJECTIVE:To study the effects of Yupingfeng powder on immune function of rats with lung-qi deficiency syn-drome. METHODS:60 SD rats were randomly divided into normal group,model group,positive group [Renshen beiqi tablet 0.6 g (crude drug)/kg] and Yupingfeng powder high-dose,medium-dose and low-dose groups [24,12,6 g (crude drug)/kg],with 10 rats in each group. Except for normal group,those groups were given SO2+comprehensive cold stimulation to induce lung-qi defi-ciency syndrome model. After modeling,treatment groups were given relevant drug solutions intragastrically,and normal group and model group were given constant volume of normal saline intragastrically,once a day,for consecutive 13 d. After administra-tion,serum levels of IL-3 and IL-6,the proportion of CD3+,CD4+,CD8+in T lymphocyte were determined,and pathological chang-es of lung and bronchus were observed. RESULTS:Compared with normal group,serum levels of IL-3 and IL-6 and the propor-tion of CD8+ in T lymphocyte increased significantly in model group,while the proportions of CD3+ and CD4+ in T lymphocyte and the ratio of CD4+/CD8+ decreased(P<0.01);obvious lung and bronchus injury and inflammatory reaction were observed. Compared with model group,serum level of IL-3 decreased significantly in positive group and Yupingfeng powder high-dose group;serum level of IL-6 and the proportion of CD8 + in T lymphocyte decreased significantly in positive group and Yupingfeng powder high-dose and medium-dose groups,while the proportion of CD3+ in T lymphocyte increased significantly;the proportion of CD4+and the ratio of CD4+/CD8+increased significantly in treatment groups(P<0.05 or P<0.01);lung and bronchial injury,and inflam-mation reaction were relieved. CONCLUSIONS:Yupingfeng powder can enhance immune function of rats with lung-qi deficiency syndrome.

Research on Urine Metabolomics of HIV/AIDS Patients with Spleen-lung Qi-deifciency Based on H-NMR Technique / 世界科学技术-中医药现代化

This study was aimed to explore the characteristics of urine metabolomics among HIV/AIDS patients with spleen-lung qi-deficiency. H-NMR technique was combined with principal component analysis and cluster analysis in the comparison of urine metabolic products among 24 HIV/AIDS cases with spleen-lung qi-deficiency and 20 healthy control cases. The results showed that urine metabolic products of HIV/AIDS patients with spleen-lung qi-deficiency and healthy people by H-NMR technique detection and PLS-DA analysis can classify the outline of urine metabolites. There were about 20 variables in the difference between two groups. The speculated substances contained glycyl-L-leucine, L-valine, α-aminobutyric acid, methyl succinic acid, glycine propionyl, and etc. It was concluded that H-NMR technique was able to classify the outline of urine metabolites between HIV/AIDS cases with spleen-lung qi-deficiency and healthy people. Part of the potential existed characteristic markers contributed to the clinical diagnosis of traditional Chinese medicine (TCM) syndrome differentiation of AIDS. It had certain effect in its quantitative analysis.

Study on Expression of ENaC and rBSCl of Kidney Tissue in Lung-Qi Deficiency Model Rats / 中国中医药信息杂志

Objective To study the relationship of lung and kidney in TCM by detecting the protein expression related to Na+ transportation in the kidney tissue of Lung-Qi deficiency model rats.Methods Lung-Qi deficiency model of rats were copied.Immunohistochemistry was applied to measure the expressions of ENaC and rBSCl in renal tubular epithelium.RIA was used to detect ALD and ANP levels in plasma and lung tissue.Results Compared with the control group,expressions of ENaC and rBSCl of renal tubule were upregulated markedly,ALD level increased and ANP level decreased obviously in the model group.Conclusion Lung can regulate the expressions of ENaC and rBSCl in the renal tubule by secreting ALD and ANP,which can regulate Na+ and water reabsorption in the renal tubule and then influence the water metabolism of the body.

Study on Changes of Cytokine in COPD Patients with Lung Qi Deficiency Syndrome and Lung Yin Deficiency Syndrome / 中国中医药信息杂志

Objective To study the level and difference of cytokine in COPD patients with lung qi deficiency syndrome and lung yin deficiency syndrome. Methods The level of IL-8, IL-1? and TNF-? in COPD patients were detected respectively. There were 30 cases with lung qi deficiency syndrome and 30 cases with lung yin deficiency syndrome, meanwhile, thirty healthy people were selected as the control group. Results The cytokine level of lung qi deficiency syndrome and lung yin deficiency syndrome was significant higher than that of the health people (P

Experimental Study of Kidney Aquaporin-2 Expression in Lung-Qi Deficiency Model Rats / 中国中医药信息杂志

Objective To observe the effects of kidney aquaporin-2 (AQP2) expression in Lung-Qi deficiency model rats and provide experimental evidence for the traditional Chinese medical theory that the kidney is related with the lung in charge of regulating the water passage. Method Twenty healthy rats were divided into the model group and the control group. The method of immunohistochemistry and Western blot was used to determine the expression of AQP2 in kidney. RT-PCR was applied to analyze the expression of AQP2 mRNA in lung and kidney tissues. Result The expression of AQP2 and AQP2 mRNA in kidney in model group was higher than in the control group. Conclusion The expression of AQP2 in kidney was higher in Lung-Qi deficiency model rats. One of the substance basis of "lung in charge of regulating the water passage" may be related to the change of AQP2 expression in the kidney tissues.

Effects of Shenqi Bufeitang on Expessions of MMP-9 and TIMP-1 in Airway Remodeling of COPD Rat Model with Lung-Qi Deficiency Syndrome / 中国中医药信息杂志

Objective To observe the effects of Shenqi Bufeitang on expessions of metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in the airway remodeling of COPD rat model with lung-Qi deficiency syndrome. Methods Quantitative stimulation with tobacco,SO2 and papin was made to establish COPD rat model with lung-Qi deficiency syndrome. Sixty male rats were randomly divided into normal group (N),model group (M),low dose treatment group (LT),medium dose treatment group (MT),high dose treatment group (HT) and glucocorticoid treatment group (GCT). The thicknesses of the airway wall and smooth muscle layer of the small airway were measured by means of image analyzer. The protein expressions of MMP-9 and TIMP-1 were examined by immunohistochemical analysis. Results The protein expressions of MMP-9 and TIMP-1 in brouch us and lung and the thinknesses of the airway wall and smooth muscle layer in M group were significanthly higher than those in N group (P

Experimental Study of Lung and Kidney Aquaporin-1 Expression and Level of plasma ET in Lung-Qi Deficiency Model Rats / 中国中医药信息杂志

Objective To observe the changes of lung and kidney aquaporin-1 expression in Lung-Qi deficiency model rats and to investigate and compare the effects of endothlin(ET)on the expression of lung and kidney aquaporin-1.It provide expremental basis to the theory of mutual relationship of lung and kidney.Method Twenty healthy rats were divided into the model group and the control group.Sample blood was taken and ET was measured by radioimmunoassay.The method of Western blot was used to observe the expression of aquaporin-1 in lung and kidney.Result The expression of aquaporin-1 in kidney was higher in model group than in the control group,while the expression of aquaporin-1 in lung was on the contrary.Compared with the control group,ET in the plasma was higher in the model group(P

Acoustics Analysis to Phonation of Patients of Lung Qi Deficiency / 中华中医药杂志

Objective:To observe vox acoustics features of patients of lung Qi deficiency,understand the influence of different extents of lung Qi deficiency on phonation,and expound the relationship between lung Qi state and phonation. Methods:Apply computer vox analysis system to test the vox sustainable vowel signal(i) of 65 cases of lung Qi deficiency and 20 cases of healthy persons respectively,observe and analyse their acoustics parameters(basic frequency,micro bother of frequency,slight bother of swing and standard yawp energy) of natural sound lowest bourdon and comfort sound and natural sound most alt. Results:For lung Qi deficiency patients,the basic frequency of 3 different phonations is lower than healthy persons,whose lowering trend increases with degrees of lung Qi deficiency,among which,under lowest bourdon of natural sound,there's marked difference of basic frequency between middle and severe lung Qi deficiency and healthy adults(P

Effects of Shenqi Bufei Decoction on Air Passage and Lung Function of COPD Model Rats with Lung-qi Deficiency / 中国药房

OBJECTIVE: To observe the effects of Shenqi bufei decoction on air passage and lung function of COPD model rats with lung-qi deficiency.METHODS: Quantitative stimulation with tobacco and SO2 and papain aerosol inhalation were used to establish model COPD rats with lung-qI deficiency.Sixty male rats were randomly divided into: normal group (N),model group(M),low dose treatment group(LT),medium dose treatment group (MT),high dose treatment group (HT),and glucocorticoid treatment group (GCT).Pathomorphological change of lung tissue in rats was observed with light microscope.The thickness of airway wall and smooth muscle layer of the small airway and lung function were measured by means of semi-quantitative image analysis system with lung function detection and analysis system respectively.RESULTS: As compared to N group,in M group the thicknesses of the small airway wall and smooth muscle layer were significantly increased(P

Difference of Respiratory Function Between Spleen-qi Deficiency Pattern and Lung-qi Deficiency Pattern in Chronic Obstructive Pulmonary Disease / 广州中医药大学学报

To explore the difference of respiratory muscle strength and respiratory drive between lung qi deficiency pattern and spleen qi deficiency pattern in chronic obstructive pulmonary disease (COPD).Forty two cases of COPD were differentiated as lung qi deficiency pattern (n=23, Group A) and spleen qi deficiency pattern(n=19, Group B) and twenty healthy volunteers served as control (Group C). Pulmonary ventilatory function such as forced vital capacity(FVC), forced expiratory volume in one second (FEV 1), FVC/ FEV 1 and maximum voluntary ventilation (MVV) were examined; and the maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP) and oral blocking pressure were also detected.As compared with Group C, pulmonary ventilation was decreased in both Group A and Group B and more obviously in Group B (P0 05); MIP and MEP in Group B differed from those in Group C (P

Investigation on the Grading Method of Pulmonary Function of Lung Qi Deficiency Syndrome / 中医杂志

0.05).Conclusion The result of pulmonary function grading and symptom grading of Lung Qi Deficiency Syndrome was uniform,indicating that pulmonary fucntion grading may be as reference index for diagnosis of Lung Qi Deficiency Syndrome.

Analysis on Expression of NK Cells in Peripheral Blood in the Patients of Lung-Qi Deficiency and Lung-Yin Deficiency / 中医杂志

Objective:To observe expression of NK cells in peripheral blood in the patients of lung-Qi deficiency and lung-Yin deficiency. Methods:CD_(16)/CD_(56) were determined by flow cytometry in 58 cases of lung-Qi deficiency,12 cases of lung-Yin deficiency and 20 cases of healthy persons.Results:Activities of NK cells in both the patient of lung-Qi deficiency and the patient of lung-Yin deficiency decreased;There were significant differences in activities of NK cells among the various groups of lung-Qi deficiency syndrome.Conclusion:The immunological function in the patient of lung-Qi deficiency syndrome developed gradually to immunodepression of different degrees from active state at early stage,and then developed to lung-Yin deficiency syndrome,and finally leading to maladjustment of hemeostasis of immunological system.