1.Effects of hydrocortisone on oxygen free radicals released by polymorphonuclear neutrophils in lipopolysaccharide-induced acute lung injury in mice.
Li ZHANG ; Kun-ling SHEN ; Tao ZHOU ; Yue-qiang XUE ; Peng YANG
Chinese Journal of Pediatrics 2004;42(9):659-662
BACKGROUNDCorticosteroid treatment of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) has been one of the most controversial clinical issues in critical care. Although the administration of high-dose corticosteroids does not benefit patients with early septic shock and ARDS, recent clinical trials have indicated that treatment with relatively low-dose corticosteroids (2 to 3 mg/kg/day of methylprednisolone or equivalent) may improve outcome when used for late ARDS or persistent septic shock. The underlying mechanism was not fully clarified. Whether the administration of corticosteroids can arrest neutrophil-driven organ injury once started remains to be elucidated.
OBJECTIVETo observe the effects of hydrocortisone (HC, 6 mg/kg) on oxygen free radicals (OFR) released by PMN and pulmonary pathological changes in rat ALI model induced by lipopolysaccharide (LPS), to investigate the possible mechanism through which corticosteroids exert protective effect on ALI.
METHODSA rat model of ALI was induced by peritoneal injection of 2 x 10(12) Escherichia coli/kg. Fifty-six rats were randomly divided into three groups: normal control group, LPS group and HC group (6 mg/kg). Samples were collected 2 h, 4 h and 6 h after giving LPS to LPS and HC group (6 h after giving normal saline in normal control group) to measure the level of OFR released by PMN using chemiluminescence method based on lumino, and to compae of pulmonary pathological changes among the three groups.
RESULTSPathological examination with light microscope in LPS group showed thickened pulmonary interstitia, inflammatory cell infiltration, edema and hemorrhage, which were in accordance with the features of ALI. There were significant differences in the release of OFR by PMN among the three groups (P < 0.01). The level of OFR released by PMN in LPS group was significantly higher than that of the control group, and continued to increase during the observation period (2 - 6 h after LPS). The release of OFR by PMN in HC group was significantly suppressed as compared with LPS group, which was peaked at 4 h after LPS injection (to 98.2%); there were also significant differences in the grades of ALI pathologic changes among the three groups (P < 0.01). The grades of ALI pathologic changes in LPS group were significantly increased when compared with the normal control group (P < 0.05) while significantly decreased in HC group as compared with LPS group (P < 0.05).
CONCLUSIONIt was demonstrated in the LPS induced ALI model that OFR might play an important role in onset of ALI. Intervening with HC (6 mg/kg) treatment could ameliorate the lung injury and exert significant and sustained suppression on the release of OFR by PMN, showing that HC has a protective effect on LPS induced ALI and its theraputic effect occurs possibly through suppression on the release of OFR by PMN.
Acute Lung Injury ; etiology ; immunology ; Animals ; Disease Models, Animal ; Free Radicals ; metabolism ; Glucocorticoids ; pharmacology ; Hydrocortisone ; pharmacology ; Lipopolysaccharides ; adverse effects ; Lung ; immunology ; pathology ; Mice ; Neutrophils ; drug effects ; metabolism
2.Effect of montelukast sodium intervention on airway remodeling and percentage of Th17 cells/CD4+CD25+ regulatory T cells in asthmatic mice.
Li LI ; Chun-Yan LOU ; Min LI ; Jian-Bo ZHANG ; Jie CHEN
Chinese Journal of Contemporary Pediatrics 2016;18(11):1174-1180
OBJECTIVETo study the dynamic changes in the percentage of Th17 cells/CD4CD25regulatory T cells after intervention with montelukast sodium, a leukotriene receptor antagonist, in asthmatic mice and the association between them.
METHODSBalb/c mice were randomly divided into blank group, asthma group, and montelukast sodium group. The asthmatic mouse model of airway remodeling was established by sensitization with intraperitoneal injection of chicken ovalbumin (OVA) and aluminum hydroxide suspension and aerosol inhalation of OVA. The mice in the blank group were given normal saline, and those in the montelukast sodium group were given montelukast sodium by gavage before aerosol inhalation. Eight mice were randomly sacrificed within 24 hours after 2, 4, and 8 weeks of aerosol inhalation. The pathological sections of lung tissue were used to observe the degree of airway remodeling. Flow cytometry was used to measure the percentages of Th17 cells and CD4CD25regulatory T cells in CD4T cells.
RESULTSThe asthma group and the montelukast sodium group had significantly higher bronchial wall thickness and smooth muscle thickness at all time points compared with the blank group (P<0.05). At 8 weeks of intervention, the montelukast sodium group had significantly greater improvements in the above changes compared with the asthma group (P<0.05). Compared with the blank group, the asthma group and the montelukast sodium group had significant increases in Th17 cells (positively correlated with airway remodeling) and significant reductions in CD4CD25regulatory T cells (negatively correlated to airway remodeling) at all time points (P<0.05). At 8 weeks of intervention, the montelukast sodium group had a significant reduction in the number of Th17 cells and a significant increase in the number of CD4CD25regulatory T cells compared with the asthma group (P<0.05).
CONCLUSIONSMontelukast sodium intervention can alleviate airway remodeling and achieve better improvements over the time of intervention. The possible mechanism may be related to the improvement of immunologic derangement of CD4CD25regulatory T cells and inhibition of airway inflammation.
Acetates ; pharmacology ; Airway Remodeling ; drug effects ; Animals ; Asthma ; drug therapy ; immunology ; Female ; Lung ; pathology ; Mice ; Mice, Inbred BALB C ; Quinolines ; pharmacology ; T-Lymphocytes, Regulatory ; immunology ; Th17 Cells ; immunology
3.The effect of Qi'ao Decoction on ovalbumin induced and lipopolysaccharide enhanced severe asthma mice and its mechanism.
Chen-Xue JIANG ; Xin-Sheng FAN ; Peng-Cheng GU ; Hui-Qin XU
Chinese Journal of Natural Medicines (English Ed.) 2013;11(6):638-644
AIM:
To evaluate the effect of Qi'ao Deocoction (QAD) on the inflammation and hyperresponsiveness of asthma mice.
METHODS:
120 Balb/C mice were randomly divided into six groups: normal group, model group, dexamethasone group, high dose QAD group, medium dose QAD group and low dose QAD group. The asthma model was reproduced in Balb/C mice sensitized by ovalbumin, challenged by OVA and LPS. The mice of the normal group were sensitized, challenged and intranasally instilled by PBS. On day 28-34, 6.7, 13.4 and 26.8 g · kg(-1) Qi'ao Decoction were administrated; 0.002 4 g · kg(-1) dexamethasone solution was given to the dexamethasone group; normal and model groups were given the same amount of normal saline. Bronchoalveolar lavage fluid, airway hyperresponsiveness, lung histopathology and cytokines were then collected and analyzed.
RESULTS:
Compared with normal group, total cellular score, the number of macrophages, lymphocytes, eosinophils and neutrophils of model group significantly increased (P < 0.01). Compared with model group, the administration of dexamethasone induced a significant decrease in eosinophils and neutrophils (P < 0.05, P < 0.01). The number of eosinophils, which plays an important role in airway inflammatory reaction of asthma, of the three QAD groups all decreased (P < 0.01). RL before and after Ach (5 mg · mL(-1)) stimulation in the model group both overtook that in the normal group (P < 0.01). Compared with model group, dexamethasone group, high dose QAD group, medium dose QAD group and low dose QAD group groups all had significantly lower RL before and after Ach stimulation (P < 0.01). Normal pulmonary histopathology was found in the normal group. In the model group, mice exhibited marked increases in inflammatory cell infiltration, mostly including neutrophils and macrophages, perivascular inflammation and thickened alveolus wall (P < 0.01). Dexamethasone application mitigated inflammation around the bronchi (P < 0.05). These histopathological changes were ameliorated in the three decoction groups (P < 0.01, P < 0.05). In addition, alveolus and airway wall lesions of medium dose QAD group and high dose QAD group were reduced, the number of inflammatory cells infiltrated around the walls decreased, no clear degeneration of bronchial epithelial cells was found, and exudates in bronchi declined in different degrees. Compared with normal group, IFN-γ and IL-12 of model group significantly decreased, while IL-4 increased, showing statistic difference (P < 0.05). Compared with model group, IFN-γ and IL-12 level of dexamethasone group went up too, but IL-4 declined (P < 0.05). The level of IFN-γ of medium dose QAD group and high dose QAD group both increased; IL-4 and IL-12 of medium dose group were found significant differences (P < 0.05); but none of the cytokines of low dose QAD group showed statistical significance (P > 0.05).
CONCLUSION
QAD can significantly inhibit airway inflammation and airway hyperresponsiveness of mice with severe asthma induced by ovalumin and lipopolysaccharide, adjust the balance of cytokines, and improve lung histopathological condition. So, it exhibits great effect on severe asthma.
Animals
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Asthma
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chemically induced
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drug therapy
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immunology
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pathology
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Drugs, Chinese Herbal
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administration & dosage
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Female
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Humans
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Interleukin-12
;
immunology
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Interleukin-4
;
immunology
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Lipopolysaccharides
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adverse effects
;
immunology
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Lung
;
immunology
;
pathology
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Mice
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Mice, Inbred BALB C
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Ovalbumin
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adverse effects
;
immunology
4.Synthesis and evaluation of 2-cyano-3, 12-dioxooleana-1, 9(11)-en-28-oate-13β, 28-olide as a potent anti-inflammatory agent for intervention of LPS-induced acute lung injury.
Yi MOU ; Yan-Lin JIAN ; Tong CHEN ; Zhang-Jian HUANG ; Yi-Xue QIAO ; Si-Xun PENG ; Da-Yong ZHANG ; Hui JI ; Yi-Hua ZHANG
Chinese Journal of Natural Medicines (English Ed.) 2017;15(5):347-354
The present study was designed to synthesize 2-Cyano-3, 12-dioxooleana-1, 9(11)-en-28-oate-13β, 28-olide (1), a lactone derivative of oleanolic acid (OA) and evaluate its anti-inflammatory activity. Compound 1 significantly diminished nitric oxide (NO) production and down-regulated the mRNA expression of iNOS, COX-2, IL-6, IL-1β, and TNF-α in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Further in vivo studies in murine model of LPS-induced acute lung injury (ALI) showed that 1 possessed more potent protective effects than the well-known anti-inflammatory drug dexamethasone by inhibiting myeloperoxidase (MPO) activity, reducing total cells and neutrophils, and suppressing inflammatory cytokines expression, and thus ameliorating the histopathological conditions of the injured lung tissue. In conclusion, compound 1 could be developed as a promising anti-inflammatory agent for intervention of LPS-induced ALI.
Acute Lung Injury
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drug therapy
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genetics
;
immunology
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Animals
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Anti-Inflammatory Agents
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administration & dosage
;
chemical synthesis
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Bronchoalveolar Lavage Fluid
;
immunology
;
Cyclooxygenase 2
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genetics
;
immunology
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Female
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Humans
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Interleukin-1beta
;
genetics
;
immunology
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Interleukin-6
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genetics
;
immunology
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Lipopolysaccharides
;
adverse effects
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Lung
;
drug effects
;
immunology
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Macrophages
;
drug effects
;
immunology
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Male
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Mice
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Mice, Inbred BALB C
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Neutrophils
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drug effects
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immunology
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Oleanolic Acid
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administration & dosage
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analogs & derivatives
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chemical synthesis
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Peroxidase
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genetics
;
immunology
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RAW 264.7 Cells
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Tumor Necrosis Factor-alpha
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genetics
;
immunology
5.Effects of budesonide on chronic airway inflammation in guinea pigs sensitized with repeated exposure to allergen.
Li XIANG ; De-yu GUO ; Zai-fang JIANG ; Shi-ying LIU ; Zhen-yi XIONG
Chinese Journal of Pediatrics 2005;43(6):414-417
OBJECTIVEInhaled glucocorticosteroids (ICS) remains the first line controller medication for chronic airway inflammation in asthma till now. If the impact of allergen could not be eliminated, how would the improvement of airway inflammation be achieved with inhaled glucocorticosteroids therapy? What was its effect on airway remodeling? In this study, an animal model of asthma was established and the effects of budesonide on airway allergic inflammation and extracellular matrix (ECM) deposition in sensitized guinea pigs with repeated exposure to allergen were investigated.
METHODSThirty-two male Hartley guinea pigs were randomly divided into four groups with 8 in each group: (A) Group of repeated exposure to ovalbumin (OVA), (B) Group of repeated exposure to OVA plus budesonide (BUD) intervention, (C) Group of stopping repeated exposure to OVA plus stopping BUD intervention, (D) Control group. At 24 h after the last OVA challenge (8 weeks after the first OVA challenge), bronchoalveolar lavage fluid (BALF) was collected from each animal. Total and differential leukocyte counts in BALF was performed on cell suspension smear stained with May-Grünwald-Giemsa (MGG) method. The upper lobe of right lung was removed and regularly fixed, then paraffin embedded lung tissues sections were prepared. The count of eosinophils infiltrated in the airway wall was performed on H&E stained lung tissue sections with LEICA Q500IW computerized image analysis system. Fibronectin and collagen type III (Col-III) deposited in the airway wall were detected by immunohistochemical staining on the paraffin embedded lung tissues sections. The intensity of positive reaction of fibronectin or Col-III deposited in the airway wall was analyzed with LEICA Q500IW computerized image analysis system.
RESULTSThe count of eosinophils in BALF (x 10(5)/ml) of group A and B were higher than that of group C and D (35.70 +/- 25.22, 11.49 +/- 5.51 vs. 1.00 +/- 0.90, 1.02 +/- 0.78, P < 0.01), the difference between group A and B, group B and C was significant. The count of eosinophils infiltrated at each level of airway wall in group A and B were higher than that of group C and D (large airway: 6.95 +/- 2.28, 1.54 +/- 1.09 vs. 0.76 +/- 0.45, 0.88 +/- 0.25; medial airway: 9.22 +/- 3.89, 3.99 +/- 2.3 vs. 1.25 +/- 1.20, 0.64 +/- 0.36; small airway: 11.56 +/- 4.02, 2.67 +/- 1.15 vs. 1.32 +/- 0.83, 0.43 +/- 0.24, P < 0.01), the difference between group A and B, group B and C was significant. The gray values of fibronectin deposited in medial and small airway of group A and B were lower than those of group C and D (medial airway 122 +/- 22, 174 +/- 23 vs. 219 +/- 34, 229 +/- 20; small airway 135 +/- 29, 165 +/- 41 vs. 236 +/- 20, 220 +/- 16, P < 0.05), the difference between group A and B, group B and C was significant. The gray values of Col-III deposited in medial and small airway of group A and B were lower than those of group C and D (medial airway 153 +/- 21, 174 +/- 22 vs. 189 +/- 14, 200 +/- 18; small airway 133 +/- 23, 176 +/- 20 vs. 191 +/- 14, 198 +/- 20, P < 0.05), the difference between group A and B was significant.
CONCLUSIONInhaled budesonide could partially inhibit allergic inflammation and ECM deposition in airway wall in guinea pig chronic asthma model with repeated exposure to allergen. Early inhaled budesonide combined with avoidance of OVA exposure could completely inhibit allergic inflammation and ECM deposition. These results suggest that the inhibitory effect on airway allergic inflammation and airway remodeling of inhaled glucocorticosteroids would be limited when the allergen factor could not be avoided.
Administration, Inhalation ; Airway Remodeling ; drug effects ; immunology ; Allergens ; administration & dosage ; immunology ; Animals ; Asthma ; chemically induced ; drug therapy ; immunology ; Bronchitis, Chronic ; chemically induced ; drug therapy ; immunology ; Bronchoalveolar Lavage Fluid ; immunology ; Budesonide ; administration & dosage ; pharmacology ; Collagen Type III ; metabolism ; Disease Models, Animal ; Eosinophils ; immunology ; Extracellular Matrix ; immunology ; Fibronectins ; metabolism ; Glucocorticoids ; administration & dosage ; pharmacology ; Guinea Pigs ; Immunohistochemistry ; Lung ; drug effects ; immunology ; Male ; Ovalbumin ; administration & dosage ; immunology
6.Attenuation of airway inflammation by simvastatin and the implications for asthma treatment: is the jury still out?.
Jing Nan LIU ; Dong Hyeon SUH ; Eun Mi YANG ; Seung Ihm LEE ; Hae Sim PARK ; Yoo Seob SHIN
Experimental & Molecular Medicine 2014;46(9):e113-
Although some studies have explained the immunomodulatory effects of statins, the exact mechanisms and the therapeutic significance of these molecules remain to be elucidated. This study not only evaluated the therapeutic potential and inhibitory mechanism of simvastatin in an ovalbumin (OVA)-specific asthma model in mice but also sought to clarify the future directions indicated by previous studies through a thorough review of the literature. BALB/c mice were sensitized to OVA and then administered three OVA challenges. On each challenge day, 40 mg kg-1 simvastatin was injected before the challenge. The airway responsiveness, inflammatory cell composition, and cytokine levels in bronchoalveolar lavage (BAL) fluid were assessed after the final challenge, and the T cell composition and adhesion molecule expression in lung homogenates were determined. The administration of simvastatin decreased the airway responsiveness, the number of airway inflammatory cells, and the interleukin (IL)-4, IL-5 and IL-13 concentrations in BAL fluid compared with vehicle-treated mice (P<0.05). Histologically, the number of inflammatory cells and mucus-containing goblet cells in lung tissues also decreased in the simvastatin-treated mice. Flow cytometry showed that simvastatin treatment significantly reduced the percentage of pulmonary CD4+ cells and the CD4+/CD8+ T-cell ratio (P<0.05). Simvastatin treatment also decreased the expression of the vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 proteins, as measured in homogenized lung tissues (P<0.05) and human epithelial cells. The reduction in the T cell influx as a result of the decreased expression of cell adhesion molecules is one of the mechanisms by which simvastatin attenuates airway responsiveness and allergic inflammation. Rigorous review of the literature together with our findings suggested that simvastatin should be further developed as a potential therapeutic strategy for allergic asthma.
Animals
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Anti-Inflammatory Agents/*therapeutic use
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Asthma/*drug therapy/immunology
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Bronchoalveolar Lavage Fluid/immunology
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CD4-Positive T-Lymphocytes/drug effects/immunology
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CD8-Positive T-Lymphocytes/drug effects/immunology
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Female
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Humans
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Hydroxymethylglutaryl-CoA Reductase Inhibitors/*therapeutic use
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Inflammation/*drug therapy/immunology
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Interleukins/analysis/immunology
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Lung/*drug effects/immunology
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Mice, Inbred BALB C
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Simvastatin/*therapeutic use
7.Study Progression on Non-small Cell Lung Cancer with EGFR Mutation Treated by Immune Checkpoint Inhibitors.
Rilan BAI ; Naifei CHEN ; Jiuwei CUI
Chinese Journal of Lung Cancer 2018;21(8):641-648
In recent years, epidermal growth factor receptor tyrosine kinase inhibitors have been recommended by many guidelines as first-line drugs for advanced non-small cell lung cancer (NSCLC) with EGFR gene mutations and no resistance. However, with the prolongation of medication time, most appear acquired resistance. In recent years, breakthroughs in inhibitors of programmed death-1 (PD-1) and its ligand (PD1 ligand, PD-L1) have rapidly changed the therapeutic model of NSCLC. Recent studies have shown that the efficacy of immune checkpoint inhibitors in EGFR-mutant NSCLC patients is not satisfactory, which might be caused by low PD-L1 expression, inhibitory immune microenvironment and low tumor mutation load. This review will elaborate the immune microenvironment of NSCLC patients with EGFR mutation, the latest study progression of immune checkpoint inhibitors and its combined with TKI, expecting to bring new hopes for the treatment of EGFR-mutant NSCLC patients.
.
Carcinoma, Non-Small-Cell Lung
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drug therapy
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genetics
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immunology
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ErbB Receptors
;
genetics
;
Humans
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Immune System
;
drug effects
;
immunology
;
Lung Neoplasms
;
drug therapy
;
genetics
;
immunology
;
Molecular Targeted Therapy
;
methods
;
Mutation
8.Combined effects of neonatal Bacillus Calmette-Guerin vaccination and respiratory syncytial infection on experimental asthma in mice.
Rui LI ; En-mei LIU ; Xi-qiang YANG ; Li-jia WANG
Chinese Journal of Pediatrics 2006;44(6):420-424
OBJECTIVENeonatal Bacillus Calmette-Guerin (BCG) vaccination could decrease asthma prevalence in human according to "hygiene hypothesis". The authors proposed a hypothesis that effect of BCG vaccination on inhibiting asthma in human might be reversed by respiratory virus infection. The objective of this study was to observe combined effects of neonatal BCG vaccination and respiratory syncytial virus (RSV) infection on experimental asthma in mice.
METHODSNeonatal BALB/c mice were divided into five groups. Control and ovalbumin (OVA) groups were mock-vaccinated at birth and mock-infected at 3 weeks of age. BCG + OVA group was BCG-vaccinated and mock-infected. RSV + OVA group was mock-vaccinated and RSV-infected. BCG + RSV + OVA group was BCG-vaccinated and RSV-infected. Except for control group, all the other groups underwent ovalbumin (OVA) sensitization and challenge. Airway responsiveness to inhaled methacholine was measured and bronchoalveolar lavage (BAL) was performed after the last challege. Cells in BAL fluid (BALF) were counted. Cytokines in BALF and serum OVA-specific IgE were detected by ELISA and inflammatory characteristics of lungs was scored by staining with hematoxylin and eosin.
RESULTS(1) The numbers of total white cells, lymphocytes, monocytes, neutrophils, and eosinophils in the BALF from all OVA-sensitized/challenged groups were significantly greater than those in control (P < 0.01), and BCG + OVA group had significantly lower total white cells, lymphocytes and eosinophils as compared with other OVA-sensitized/challenged groups (P < 0.05 or 0.01). (2) All OVA-sensitized/challenged groups had significantly lower IFNgamma (P < 0.05) and higher IL-4 (P < 0.05) level in BALF as compared with control, but there was no significant difference among all OVA sensitized/challenged groups. There was no significant difference in IL-10 level between all experimental groups. (3) All OVA-sensitized/challenged groups showed significantly higher serum OVA-specific IgE titers than control (P < 0.05 or 0.01), but no significant difference was found among all OVA sensitized/challenged groups. (4) RSV + OVA and BCG + RSV + OVA groups displayed the highest airway resistance and subsequently in order as follows: OVA group, BCG + OVA group and control group in severity of airway hyperreactivity (AHR), but no significant difference was found between RSV + OVA and BCG + RSV + OVA groups. (5) Histological score of peribronchiolitis, perivasculitis, alveolitis, and peribronchial eosinophilia in all OVA-sensitized/challenged groups was significantly higher than that in control. BCG + OVA group had significantly milder peribronchiolitis and peribronchial eosinophilia than the other OVA-sensitized/challenged groups (P < 0.05) and significantly milder alveolitis than OVA and BCG + RSV + OVA groups (P < 0.05).
CONCLUSIONNeonatal BCG vaccination decreased asthmatic inflammation and AHR and RSV infection could reverse anti-asthma effect of neonatal BCG vaccination in OVA-sensitized/challenged mouse model.
Animals ; Animals, Newborn ; Asthma ; immunology ; prevention & control ; BCG Vaccine ; administration & dosage ; immunology ; pharmacology ; Bronchoalveolar Lavage Fluid ; Disease Models, Animal ; Enzyme-Linked Immunosorbent Assay ; Eosinophils ; drug effects ; immunology ; secretion ; Immunoglobulin E ; analysis ; immunology ; Interferon-gamma ; analysis ; immunology ; Interleukin-10 ; analysis ; immunology ; Interleukin-4 ; analysis ; immunology ; Leukocytes ; drug effects ; immunology ; secretion ; Lung ; drug effects ; immunology ; Mice ; Mice, Inbred BALB C ; Ovalbumin ; administration & dosage ; immunology ; toxicity ; Respiratory Syncytial Virus Infections ; immunology ; Respiratory Syncytial Viruses ; immunology ; pathogenicity ; Treatment Outcome
9.Carnosic acid enhances the anti-lung cancer effect of cisplatin by inhibiting myeloid-derived suppressor cells.
Wen LIU ; Tian-Cong WU ; Dong-Mei HONG ; Yue HU ; Ting FAN ; Wen-Jie GUO ; Qiang XU
Chinese Journal of Natural Medicines (English Ed.) 2018;16(12):907-915
Cisplatin and other platinum-based drugs are used frequently for treatment of lung cancer. However, their clinical performance are usually limited by drug resistance or toxic effects. Carnosic acid, a polyphenolic diterpene isolated from Rosemary (Rosemarinus officinalis), has been reported to have several pharmacological and biological activities. In the present study, the combination effect of cisplatin plus carnosic acid on mouse LLC (Lewis lung cancer) xenografts and possible underlying mechanism of action were examined. LLC-bearing mice were treated with intraperitoneal injection with cisplatin, oral gavage with carnosic acid, or combination with cisplatin and carnosic acid, respectively. Combination of carnosic acid and cisplatin yielded significantly better anti-growth and pro-apoptotic effects on LLC xenografts than drugs alone. Mechanistic study showed that carnosic acid treatment boosted the function of CD8 T cells as evidenced by higher IFN-γ secretion and higher expression of FasL, perforin as well as granzyme B. In the meantime, the proportion of MDSC (myeloid-derived suppressor cells) in tumor tissues were reduced by carnosic acid treatment and the mRNA levels of iNOS2, Arg-1, and MMP9, which are the functional markers for MDSC, were reduced. In conclusion, our study proved that the functional suppression of MDSC by carnosic acid promoted the lethality of CD8 T cells, which contributed to the enhancement of anti-lung cancer effect of cisplatin.
Abietanes
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administration & dosage
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Animals
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Antineoplastic Agents
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administration & dosage
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CD8-Positive T-Lymphocytes
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drug effects
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immunology
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Carcinoma, Lewis Lung
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drug therapy
;
genetics
;
immunology
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Cell Line, Tumor
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Cisplatin
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administration & dosage
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Drug Synergism
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Humans
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Interferon-gamma
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genetics
;
immunology
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Lung Neoplasms
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drug therapy
;
genetics
;
immunology
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Matrix Metalloproteinase 9
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genetics
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Mice
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Mice, Inbred C57BL
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Myeloid-Derived Suppressor Cells
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drug effects
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immunology
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Plant Extracts
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administration & dosage
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Rosmarinus
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chemistry
10.Feiji Recipe inhibits the growth of lung cancer by modulating T-cell immunity through indoleamine-2,3-dioxygenase pathway in an orthotopic implantation model.
Bin LUO ; Zu-Jun QUE ; Zhi-Yi ZHOU ; Qing WANG ; Chang-Sheng DONG ; Yi JIANG ; Bing HU ; Hui SHI ; Yu JIN ; Jian-Wen LIU ; He-Gen LI ; Lin WANG ; Jian-Hui TIAN
Journal of Integrative Medicine 2018;16(4):283-289
OBJECTIVEEscape from the body's immune response is a basic characteristic of lung cancer, and indoleamine-2,3-dioxygenase (IDO) plays a key role in mediating immune escape of non-small-cell lung cancer, which leads to recurrence and metastasis. Feiji Recipe, a compound Chinese herbal medicine, has the effect of stabilizing lesions and prolonging survival in patients with lung cancer. The purpose of this study was to investigate the mechanisms underlying the anticancer properties of Feiji Recipe.
METHODSAn orthotopic transplant model of mouse Lewis lung cancer, with stable expression of IDO gene, was established in C57BL/6 mice. Optical imaging was used to observe the effects of Feiji Recipe in the treatment of lung cancer in vivo. The effects of Feiji Recipe on the proliferation of mouse Lewis lung cancer cell line 2LL, 2LL-enhanced green fluorescent protein (2LL-EGFP) and 2LL-EGFP-IDO were investigated, and the apoptosis of T-cells was examined by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide using flow cytometry. Chemical composition of Feiji Recipe was validated by high-performance liquid chromatography.
RESULTSCompared to the control group, the survival of animals treated with Feiji Recipe was significantly prolonged (P = 0.0074), and the IDO protein level decreased (P = 0.0072); moreover, the percentages of CD4CD25 T-cells and Foxp3 T-cells were significantly decreased (P < 0.05). The molecular mechanism of Feiji Recipe against lung cancer may relate to the regulation of immune cells, such as T-cells and regulatory T-cells.
CONCLUSIONThe molecular mechanism of Feiji Recipe in treatment of lung cancer is to restore the function of T-cells in the cancer microenvironment through interfering with the IDO pathway.
Animals ; Apoptosis ; drug effects ; Carcinoma, Lewis Lung ; drug therapy ; enzymology ; immunology ; physiopathology ; Cell Proliferation ; drug effects ; Disease Models, Animal ; Drugs, Chinese Herbal ; administration & dosage ; Growth Inhibitors ; administration & dosage ; Humans ; Indoleamine-Pyrrole 2,3,-Dioxygenase ; genetics ; immunology ; Lung Neoplasms ; drug therapy ; enzymology ; immunology ; physiopathology ; Male ; Mice ; Mice, Inbred C57BL ; T-Lymphocytes, Regulatory ; drug effects ; immunology