The mechanism of chronic obstructive pulmonary disease (COPD) in the treatment of glucocorticoid and Its Countermeasures

Navigation:Home > Respiratory Medicine > Asthma > The mechanism of chronic obstructive pulmonary disease (COPD) in the treatment of glucocorticoid and Its Countermeasures

Department of respiratory medicine, Nanjing General Hospital of Nanjing military command, Beijing 210002, China (Xin Xiaofeng)Chronic obstru


Department of respiratory medicine, Nanjing General Hospital of Nanjing military command, Beijing 210002, China (Xin Xiaofeng)

Chronic obstructive pulmonary disease (COPD) is a chronic airway inflammation, airway inflammation leads to persistent airflow limitation and lung structure is not completely reversible damage, so the control of airway inflammation is the key of treatment of COPD. In the treatment of chronic airway inflammatory disease, Glucocorticoid (hormone, GC) is the strongest activity of anti-inflammatory drugs currently known, it in bronchial asthma (asthma) in the treatment of the value and status of certain people. But in the treatment of COPD, a large number of studies show that airway inflammation hormone can not effectively control the progressive development, also cannot be reversed because of lung function and airway inflammation leading to decreased, so-called not sensitive to hormone therapy [1]. Therefore, it is helpful for the prevention and treatment of COPD to understand the mechanism of COPD's insensitivity to hormone therapy, and to explore the effective measures to control the airway inflammation.

The role of glucocorticoids in the treatment of COPD

Chronic inflammation is the main cause of COPD disease progression and decreased lung function. Unfortunately, there is no effective anti-inflammatory therapy to reverse the decline of lung function. Although inhaled and oral corticosteroids are effective in controlling airway inflammation in asthma, they are not satisfactory in the treatment of airway inflammation in COPD, so the role of corticosteroids in the treatment of COPD is limited. Previous studies have suggested that regular inhalation of steroids does not prevent lung function decline in the long run. But recent studies have shown that the lung function of FEV1< 60% COPD patients, regular use of inhaled corticosteroids can slow the rate of decline in lung function, reduce the number of COPD patients with acute onset, severity of disease, improve breathing symptoms, improve the quality of life of patients with [2]. Especially for patients with severe, very severe and recurrent acute exacerbation of COPD patients more significantly. Treatment with inhaled corticosteroids, of course, increases the risk of pneumonia and does not reduce overall mortality.

Earlier studies have suggested that the short-term response to oral corticosteroids may predict the long-term effects of hormone therapy on FEV1. Therefore, in the old "Global Initiative for chronic obstructive pulmonary disease (GOLD) guidelines, short-term oral (2 weeks) hormones are recommended to assess whether patients benefit from long-term inhaled or oral corticosteroid therapy. However, recent studies have shown that short-term oral corticosteroids do not accurately predict the efficacy of long-term inhaled corticosteroids in patients with COPD. Therefore, the updated GOLD guidelines do not recommend the use of oral corticosteroids in the treatment of moderate, severe, and very severe COPD in patients with poor response to inhaled bronchodilator.

In the treatment of acute exacerbation of COPD, oral hormone can benefit patients, which is to improve the success rate of treatment, reduce the need for additional treatment and shorten the length of hospital stay. However, there is a lack of sufficient evidence for the benefits of oral corticosteroids in the treatment of stable COPD, not to mention the improvement of lung function and the side effects of long-term oral administration of [3]. In the acute exacerbation period, whether inhaled or oral hormone therapy has a good effect, the former can prevent acute exacerbation, which can reverse the acute exacerbation.

Two. The mechanism of glucocorticoid insensitivity to COPD

The airway inflammation of COPD with respect to asthma is not sensitive to hormone therapy, specifically in inhaled corticosteroids in addition to no effect on lung function decline, the number of inflammatory cells and release of inflammatory mediators promote effect is also very limited to the lung in patients with COPD. In vitro, it was also confirmed that the hormone could not inhibit the release of proinflammatory mediators [4] in alveolar lavage fluid from patients with COPD. Although the mechanism of hormone insensitivity to COPD is unclear, it is mainly from the following aspects.

(1) molecular mechanism

GC forms a complex by binding to the GC receptor (GR) in the cytoplasm, and then activates into the nucleus. In the nucleus, GC or DNA combined with the open expression of anti-inflammatory genes, or by indirect inhibition such as nuclear factor kappa B (NF- K B) and activator protein -1 (AP-1) and other activities, affecting many different signaling pathways play a role. The latter requires the involvement of the repressor. The reduced expression of GR, GC and GR combined with reduced inflammatory pathway activity or corepressor activity can lead to the lack of such factors is not sensitive to the hormone, and these factors affected by oxidative stress, resulting in COPD is not sensitive to hormone therapy clinical phenomenon [5].

Most of the infiltrating inflammatory cells in COPD respond to hormones, but neutrophils are an exception. Neutrophils are not only present in the stable phase of COPD, but also in the acute exacerbation stage. The exact mechanism of the effect of hormone on the inflammatory effect of neutrophils is still unknown, and the relationship between the expression of GR subtype GR beta (high or low) is still controversial. For acute exacerbation of COPD is not sensitive to the hormone is the extension of hormone sensitivity in stable period already exist, or there is a rapid increase in acute exacerbation of neutrophil mediated brought no response, is unclear.

The expression level of GR in COPD was measured, and the expression of GR was not found to be significantly changed in [6], although the expression of GR was decreased. Therefore, the possible explanation is that a higher proportion of GR cells in patients with COPD may be able to damage the function of GR alpha, which may lead to the insensitivity of /GR. But there is little research to determine the specific proportion of GR alpha and GR beta expression? Importantly, even if the proportion of GR beta was increased, the functional effects brought about by it were difficult to define the role of GR in the development of hormone insensitivity. In some of the in vitro studies, oxidative stress can damage the translocation of GR, but there is no evidence for the role of impaired GR alpha translocation in response to COPD in vivo, [7].

(two) genetic mechanism

A number of studies have linked genetic mutations to mechanisms that are not sensitive to hormones because of the presence of genetic factors in the pathogenesis of asthma, which is relatively insensitive to hormones [8]. In COPD, the direct relationship between genetic mutations and the mechanism of hormone insensitivity is not clear. However, there is evidence that genetic susceptibility may play an important role in the pathogenesis of COPD. Study on COPD patients and smokers lung antioxidant ability that lower its ability of antioxidant defense COPD patients, which may partly explain the small part (about 20%) of smokers (but not all smokers) [9] causes COPD. Concern is that the extracellular superoxide dismutase 3 (SOD3, antioxidant) on the variation of glycine in 213rd (the rate of about 2% in the general population), the plasma level of SOD3 increased up to 10 times, and prevent the occurrence of COPD [10] in smokers.

(two) selective anti-inflammatory factor

Tumor necrosis factor alpha (TNF- alpha) are important mediators of inflammation in the inflammatory response of COPD, but the moderate severe COPD patients with anti TNF- antibody was studied, and found no benefit on the contrary, there are many side effects caused by [24] lung cancer, pulmonary infection etc.. Selective p38MAPK inhibitors inhibit inflammation and COPD inflammation in vitro (such as TNF- alpha, CXCL8) release, also can inhibit oxidative stress, that influence the anti-inflammatory properties of p38MAPK alpha inhibitors against oxidative stress. The expression of p38MAPK in the lung of patients with [25] was increased, and the selective p38MAPK inhibitor reduced the expression of inflammatory markers in the blood of COPD patients with COPD. It is suggested that selective p38MAPK inhibitors may be another option for COPD insensitivity to GC therapy.

(three) strategies to promote inflammation

The existence of COPD inflammation is related to the elimination of inflammatory response and the lack of self regulatory ability. One of the important reasons for the treatment of COPD induced by GC is the damage of inflammation elimination ability.

GC can not only inhibit the inflammatory reaction of neutrophils, apoptosis and damage of neutrophils, the neutrophil sustained release of inflammatory mediators, superoxide and neutrophil elastase, leading to tissue damage and persistent inflammation reaction. Neutrophil apoptosis is a central part of the elimination of inflammation, it can make the function of macrophages changed from the inflammation to releasing promote inflammation elimination medium (prostaglandin E2, IL-10) [26].

Cigarette can damage the phagocytic function of macrophage, and then reduce the clearance rate of neutrophil apoptosis. GC treatment of COPD patients, which delayed neutrophil apoptosis in vitro, which will not only lead to neutrophil survival time longer, more the release of inflammatory mediators, and because of the function of macrophages decreased, causing necrosis of the neutrophil intracellular components of inflammatory reactions aggravate lung injury. Little research has been done on the elimination of inflammation in COPD, so there is little information on the effects of the elimination of inflammation on GC function, but the field of inflammation elimination will be helpful in the search for effective and new anti-inflammatory drugs for the treatment of COPD.

PI3Ks not only has the repair function of GC, but also may play a role in the elimination of inflammation. Inhibition of Akt activity by PI3K inhibitors, and enhanced apoptosis, eliminated the enhanced inflammatory response induced by antigen induced eosinophils. Transgenic mice and selective inhibitors of the study confirmed that PI3K beta is a Fcr receptor mediated macrophage phagocytic function necessary for [27]. Thus, in addition to its anti-inflammatory effects, selective PI3K inhibitors may also contribute to the elimination of inflammation, which may also be a new therapeutic approach. Some other small molecule inhibitors (including cyclin dependent kinase inhibitors) can contribute to neutrophil apoptosis and inflammation. Therefore, the selective inhibitor of neutrophil apoptosis is one of the new therapeutic approaches.

In conclusion, although GC plays an important role in the treatment of COPD, the presence of oxidative stress leads to a decrease in the activity of HDACs, which makes COPD appear to be less sensitive to GC treatment. Therefore, the drug GC and can repair the GC function (including antioxidant and inflammatory agent to eliminate) combined, will play a more important role in the control of COPD inflammation and slow down the decline of pulmonary function and disease progression and mortality.


[1] Adcock IM, Marwick J, Casolari P, et al. Mechanisms of corticosteroid resistance in severe asthma and chronic obstructive pulmonary disease (COPD).Curr Pharm Des 16:3554-3573. PMID:20977420, 2010; [PubMed - indexed for MEDLINE]

[2] Celli BR, Thomas NE, Anderson JA, et al. Effect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: results from the TORCH study. Am J Respir Crit Care Med, 2008; 178:332 338 - PMID: 18511702 - indexed for MEDLINE] [PubMed

[3] Wood-Baker R, Walters J, Haydn Walters E. Systemic corticosteroids in chronic obstructive pulmonary disease: an overview of Cochrane systematic reviews. Respir Med, 2007; 101:371 - 377 PMID: 16962307 [PubMed - indexed for MEDLINE]

[4] Culpitt SV, Rogers DF, Shah P, et al. Impaired inhibition by dexamethasone of cytokine release by alveolar macrophages from patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med, 2003; 167:24 31 - PMID: 12406856 - indexed for MEDLINE] [PubMed

[5] Adcock IM, Barnes Mechanisms of Resistance.Chest, 2008; 134:394 - 401 PMID:18682458[PubMed - indexed for MEDLINE] PJ.Molecular (Corticosteroid)

[6] Marwick JA, Caramori G, Stevenson CS, et al. Inhibition of PI3Kdelta restores glucocorticoid function in smoking-induced airway inflammation in mice. Am J Respir Crit Care Med, 2009; 179:542 - 548 PMID: 19164702 [PubMed - indexed for MEDLINE]

[7] Hacker S, Lambers C, Heotzenecker K, et al., Elevated HSP27, HSP70 and HSP90 alpha in chronic obstructive pulmonary disease: markers for immune activation and tissue destruction. Clin Lab, 2009; 55:31 - 40 PMID: 19350847 [PubMed - indexed for MEDLINE]

[8] Hakonarson H, Bjornsdottir US, Halapi E, et al. Profiling of genes expressed in peripheral blood mononuclear cells predicts glucocorticoid sensitivity in asthma patients. Proc Nat Acad Sci U S A, 2005; 102 (41): 14789 - 16203992 14794.PMID: [PubMed - indexed for MEDLINE]

[9] Smolonska J, Wijmenga C, Postma DS, Boezen HM. Meta-analyses on suspected chronic obstructive pulmonary disease genes: a summary of 20 Years Am J Respir Crit 'Research. Care Med, 2009; 180:618 - 631 PMID:19608716[PubMed - indexed for MEDLINE]

[10] Juul K, Tybjaerg-Hansen A, Marklund S, Lange P, Nordestgaard BG. Genetically increased antioxidative protection and decreased chronic obstructive pulmonary disease. Am J Respir Crit Care Med, 2006; 173:858, 864 [PubMed]

[11] Rahman I, GilmourP S, JimenezLA, eta.l Oxidative stress and

TNF- induce acetylation and kappa B/AP-1 NF- activation histone in

Alveolar epithelial cells: in transcription in inflammation[J]. MolCell Biochem, 2002, 234 /235: PMID: lung [PubMed potentialmechanism indexed for MEDLINE] gene (239-248.)

[12] Meja KK, Rajendrasozhan S, Adenuga D, et al. Curcumin restores corticosteroid function in monocytes exposed to oxidants by maintaining HDAC2. Am J Respir Cell Mol Biol, 2008; 39:312 - 323 PMID: 18421014 [PubMed - indexed for MEDLINE]

[13] Ito K, Ito M, Elliott WM, et al. Decreased histone deacetylase activity in chronic obstructive pulmonary disease. N Engl J Med, 2005; 352:1967 - 1976 PMID: 15888697 [PubMed - indexed for MEDLINE]

[14] Cosio BG, Tsaprouni L, Ito K, Jazrawi E, Adcock IM, Barnes PJ. Theophylline restores histone deacetylase activity and steroid responses in COPD macrophages. J Exp Med, 2004; 200:689 - 695 PMID: 15337792 [PubMed - indexed for MEDLINE]

[15] Yang SR, Chida AS, Bauter MR, et al. Cigarette smoke induces proinflammatory cytokine release by activation of NF-kappaB and posttranslational modifications of histone deacetylase in macrophages. Am J Physiol Lung Cell Mol Physiol, 2006; 291: L46 - L57. PMID: 16473865 [PubMed - indexed for MEDLINE]

[16] Renda T, Baraldo S, Pelaia G, et al. activation p38 in Eur Respir J, 2008; 31:62 - 69 PMID:17959643[PubMed - indexed for MEDLINE] Increased (MAPK) of

[17] Bhavsar P, Hew M, Khorasani N, et al. Relative corticosteroid insensitivity of alveolar macrophages in severe asthma compared with non-severe asthma. Thorax, 2008; 63:784 - 790 PMID: 18492738 [PubMed - indexed for MEDLINE]

[18] Galliher-Beckley AJ, Cidlowski JA. Emerging roles of glucocorticoid receptor phosphorylation in modulating glucocorticoid hormone action in health and disease. IUBMB Life, 2009; 61:979 - 986 PMID: 19787703 [PubMed - indexed for MEDLINE]

[19] Marwick JA, Caramori G, Casolari P, et al. A role for phosphoinositol 3-kinase Delta in the impairment of glucocorticoid responsivness in patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol, 2010; PMID: 20381852 125:1146 - 1153 [PubMed - indexed for MEDLINE]

[20] Ford PA, Durham AL, Russell RE, et al.Treatment Effects of Low-Dose Theophylline Combined With an Inhaled Corticosteroid in COPD. Chest, 2010; 137:1338 - 1344 PMID: 20299628 [PubMed - indexed for MEDLINE]

[21] T Hirano, T Yamagata, M Gohda, et al. Inhibition of reactive nitrogen species production in COPD airways: comparison of inhaled corticosteroid and oral theophylline. Thorax, 2006; 61: 761 - 766 PMID: 16936236 [PubMed - indexed for MEDLINE]

[22] To Y, Ito K, Kizawa Y, et al.Targeting Phosphoinositide-3-Kinase-d with Theophylline Reverses Corticosteroid Insensitivity in Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med, 2010; 182:897 - 904 PMID: 20224070 [PubMed - indexed for MEDLINE]

[23] Meja KK, Rajendrasozhan S, Adenuga D, et al. Curcumin restores corticosteroid function in monocytes exposed to oxidants by maintaining HDAC2. Am J Respir Cell Mol Biol, 2008; 39:312 - 323 PMID: 18421014 [PubMed - indexed for MEDLINE]

[24] Rennard SI, Fogarty C, Kelsen S, et al. The safety and efficacy of infliximab in moderate to severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med, 2007; 175:926 - 934 PMID: 17290043 [PubMed - indexed for MEDLINE]

[25] Singh D, Smyth L, Borrill Z, Sweeney L, Tal-Singer R., A randomized, placebo-controlled study of the effects of the p38 MAPK inhibitor SB-681323 on blood biomarkers of inflammation in COPD patients. J Clin Pharmacol, 2010; 50:94 - 100 PMID: 19880675 [PubMed - indexed for MEDLINE]

[26] Serhan CN, Savill J. of the programs end. Nat Immunol, 2005; 6:1191 - 1197 PMID: - 16369558 [PubMed - indexed for MEDLINE] inflammation: (beginning) the

[27] Leverrier Y, Okkenhaug K, Sawyer C, et al. Class I phosphoinositide 3-kinase p110beta is required for apoptotic cell and Fcgamma receptor-mediated phagocytosis by macrophages. J Biol Chem, 2003; 278:38437 - 38442 PMID: 12869549 [PubMed - indexed for MEDLINE]


Premature Ejaculation,Tumour,Hypertension,Depression,Tumour,Andrology Diseases,Tumour,Arthritis,Pain,Deaf,。 Cure999 

Cure999 @ 2018