Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory airway disease in which persistent airway inflammation leads to incomplete reversible airflow limitation and destruction of lung structures, so controlling airway inflammation is the key to COPD treatment. Among the drugs used in the treatment of chronic airway inflammatory diseases, glucocorticoids (GC) are the most powerful drugs known for their anti-inflammatory activity, and their value and status in the treatment of bronchial asthma (asthma) are well recognized. However, in the treatment of COPD, numerous studies have shown that hormones are not effective in controlling progressive airway inflammation and in reversing the decline in lung function due to airway inflammation, resulting in the so-called hormone therapy insensitivity [1]. Therefore, understanding the mechanisms underlying the occurrence of insensitivity to hormone therapy in COPD and exploring measures to effectively control airway inflammation in COPD will contribute to the prevention and treatment of the disease.
I. The status of glucocorticoids in the treatment of COPD
Chronic inflammation is the main cause of COPD disease progression and lung function decline. Unfortunately, however, there is no anti-inflammatory therapy that can effectively reverse the decline in lung function. Although inhaled and oral hormones are effective in controlling airway inflammation in asthma, they are not as effective in the treatment of airway inflammation in COPD, and thus the role of hormones in the treatment of stable COPD is limited. More previous studies have suggested that regular inhaled hormones do not stop the decline in lung function in the long run. However, recent studies have shown that for COPD patients with pulmonary function FEV1 < 60%, regular use of inhaled hormones can slow the rate of lung function decline, reduce the number of acute exacerbations in COPD patients, reduce the severity of the disease, improve wheezing symptoms, and improve the quality of life of patients [2]. The benefits are especially evident in patients with severe, very severe, and recurrent acute exacerbations of COPD. Of course, inhaled hormone therapy increases the incidence of pneumonia in patients and does not reduce overall mortality.
Earlier studies have suggested that the response to short-term oral hormones is predictive of the long-term efficacy of hormones on FEV1. Therefore, short-term oral hormones (2 weeks) were recommended in the old Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines to assess whether patients would benefit from long-term inhaled or oral hormone therapy. However, recent studies have shown that short-term oral hormones do not accurately predict the efficacy of long-term inhaled hormones in COPD patients. Therefore, the updated GOLD guidelines do not recommend therapeutic trials of oral hormones for patients with moderate, severe, and very severe COPD who do not respond well to inhaled bronchodilators.
In the treatment of acute exacerbations of COPD, patients can benefit from oral hormones in terms of improved treatment success, reduced need for additional therapy and shorter hospital stays. However, the benefits of oral hormones in the treatment of stable COPD lack sufficient evidence, not to mention the insignificant improvement in lung function and the side effects of long-term oral hormones [3]. In the acute exacerbation period either inhaled hormone or oral hormone therapy has better efficacy, the former can prevent acute exacerbation and the latter can reverse acute exacerbation.
Second, the mechanism of insensitivity of glucocorticoid therapy for COPD
Airway inflammation in COPD is insensitive to hormone therapy compared to asthma, as evidenced by the fact that inhaled hormones have no effect on the decline of lung function, and very limited effect on the number of inflammatory cells and the release of pro-inflammatory mediators in the lungs of COPD patients. It has also been demonstrated in vitro that hormones do not inhibit the release of pro-inflammatory mediators from alveolar macrophages in the alveolar lavage fluid of COPD patients [4]. Although the mechanisms underlying the insensitivity to hormone therapy in COPD are still unclear, the following are the main aspects in terms of the available knowledge.
(i) Molecular mechanism
GC acts by binding to the intracytoplasmic GC receptor (GR) to form a complex that is activated and then enters the nucleus. In the nucleus, GC either binds to DNA to turn on the expression of anti-inflammatory genes or acts by indirectly inhibiting the activity of, for example, nuclear factor кB (NF-кB) and activating protein factor-1 (AP-1), affecting many different signaling pathways. The latter requires the involvement of co-blockers; factors such as reduced GR expression, reduced GC binding to GR, enhanced activity of inflammatory pathways or lack of co-blocker activity can lead to insensitivity to hormones, and these factors are influenced by oxidative stress, among others, leading to clinical insensitivity to hormone therapy in COPD [5].
The vast majority of infiltrating inflammatory cells in COPD respond to hormones, but neutrophils are an exception. Neutrophils are not only present in stable COPD, but are also the main infiltrating inflammatory cells in acute exacerbations. The exact mechanism of the decreased inflammatory effect of hormones on neutrophils remains unknown, and the relationship with the expression of GRβ, a subtype of GR (whether high or low), is controversial. It is also unclear whether the hormone insensitivity in acute exacerbations of COPD is an extension of the hormone insensitivity already present in the stable phase or whether there is a nonresponse mediated by the rapidly increasing number of neutrophils in the acute exacerbation.
Measurement of the level of GRβ expression in COPD revealed no significant change in GRβ expression despite a decrease in GRα expression [6]. Thus a possible explanation is that the higher ratio of GRβ/GRα in inflammatory cells of COPD patients may impair GRα function enough to cause insensitivity to hormones. But few studies have been done to determine what the exact ratio of GRα and GRβ expression is? Importantly, even if an increased proportion of GRβ is measured, the functional impact of this is difficult to clarify the role of GRβ in the development of hormone insensitivity. In some in vitro studies, oxidative stress was able to impair
GRα translocation, but there is a lack of evidence in vivo for the role of impaired GRα translocation in COPD hormone response [7].
(ii) Genetic mechanisms
Many studies have linked genetic mutations to the mechanism of occurrence of hormone insensitivity because in asthma, there is a role of genetic factors in the mechanism of occurrence of relative hormone insensitivity [8]. In COPD, the direct relationship between genetic mutations and the mechanism of occurrence of hormone insensitivity is not clear. However, there is evidence that genetic susceptibility may play an important role in the mechanism of COPD development. Studies of the antioxidant capacity of the lungs of COPD patients and smokers suggest that patients who develop COPD have a lower capacity for antioxidant defense, which may partially explain the development of COPD in a small proportion (about 20%) of smokers (but not all of them) [9]. Of concern is the glycine variant of extracellular superoxide dismutase 3 (SOD3, an antioxidant) at its 213th position (occurring in about 2% of the general population), which increases plasma SOD3 levels up to 10-fold, which is associated with its prevention of COPD development in smokers [10].
(iii), oxidative stress and decrease in the activity of histone deacetylases (HDACs)
Both exogenous factors (e.g., pollution, smoking) and endogenous factors (e.g., respiratory burst of pro-inflammatory response cells such as macrophages and neutrophils) can increase the oxidative load in COPD patients. Oxidative stress interferes with GC nuclear translocation and blocks the binding of GC-GR complexes to DNA, thus limiting its inflammatory antagonistic effects, or GC resistance, which can block the inflammatory signaling process through mechanisms such as competition for binding sites and enhanced HDAC activity. However, due to the persistence of oxidative stress, not only the nuclear translocation of GC-GR complex is reduced, blocking the anti-inflammatory response effect of GC, but more importantly, the activity of HDAC enzymes in lung tissue is also significantly reduced, the histone acetylation/deacetylation balance is disrupted, histone molecules are deacetylated, and the transcription of inflammatory protein genes and the synthesis of inflammatory proteins are enhanced. The increase in inflammatory mediators and the self-reinforcement and amplification of the inflammatory response ultimately lead to the long-term persistence and progressive exacerbation of airway inflammation in COPD [11].
Oxidative stress reduces HDAC-2 expression and decreases its activity.The reduction in HDAC-2 expression and activity is significantly associated with oxidant-mediated covalent bonding alterations, including hyperphosphorylation, nitration and carbonylation. The covalent bonding alterations impair protein activity and accelerate proteasomal degradation [12].
The oxidant-mediated loss of HDAC-2 activity and the resulting imbalance in histone acetylation status can lead to an enhanced inflammatory response to the disease. HDAC-2 expression and activity are reduced in the peripheral lungs of COPD patients and correlate with the severity of the disease [13]. Furthermore, since HDAC-2 activity underlies the transcriptional function of the pro-inflammatory response gene GRα, a reduction in its activity and expression impairs hormone function and consequently leads to a reduced response to hormones. In models with diminished HDAC-2 activity, hormone function is also reduced; if HDAC-2 activity is restored or protected, this is when hormone sensitivity is also restored [14]. Thus, there is definite evidence that the reduced HDAC-2 activity and expression in COPD patients is an important factor in the mechanism of their hormone insensitivity. In addition, because of the presence of reduced expression of other HDACs including HDAC-3, 5 and 8 in COPD, it should be considered that alterations in the expression and/or activity of other HDACs may also play an important role in the impaired hormone function. Smoking leads to a decrease in macrophage HDAC-1, 2 and 3 [15]. However, the role of these HDACs in COPD lung and inflammatory cells is unclear and further studies are needed to elucidate their role in GR function and disease.
(iv) Kinase signaling pathway
Kinase signaling pathways may also play an important role in the development of hormone therapy insensitivity in COPD. Compared to the smoking population, p38 mitogen-activated protein kinase (MAPK) is elevated in peripheral lung tissue and alveolar macrophages in patients with mild to moderate COPD, and its activity is negatively correlated with a decrease in FEV1 and FEV1/FVC [16]. To some extent increased GRα phosphorylation leading to decreased ligand binding is associated with elevated p38MAPK. Dexamethasone induced decreased MKP-1 expression and enhanced p38 activity in severe asthma compared to non-severe asthma [17]. However, in COPD, there are no studies to investigate the hormone-mediated induction of MKP-1 expression, and therefore it is not clear the relationship between MKP-1 expression, activity or signaling pathways and hormone insensitivity in COPD.
There is evidence that other kinases and signaling pathways, including glycogen synthase kinase 3β, extracellular signal-regulated kinase-1/2, and c-Jun amino-terminal kinase directly regulate GRα activity through phosphorylation, which may also affect gene specificity [18].
Oxidative stress also activates different kinase pathways, including the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. It has been shown that both PI3Kδ and Akt activities are elevated in peripheral lung macrophages of COPD patients. Selective inhibition of the PI3Kδ/Akt pathway, compared with normal lung function in a smoking population, may repair the ability of hormones to inhibit the expression of inflammatory mediators in COPD patients [19]. It is unclear how the PI3Kδ/Akt pathway comes to influence HDAC-2 activity and the expression of other co-blockers during oxidative stress and its role in hormone treatment insensitivity.
III. Countermeasures against hormone therapy insensitivity in COPD
(A) Repair GC function
Oxidative stress reduces HDAC activity, which is one of the main causes of hormone insensitivity in COPD patients. Some studies have shown that low-dose theophylline can reverse the hormone resistance caused by oxidative stress through direct activation of HDAC, thus improving the anti-inflammatory effect of hormones. Therefore, inhaled hormones plus theophylline can significantly reduce the inflammatory response in COPD than inhaled hormones alone [20]. Increased production of reactive nitrogen during oxidative stress is also a major mechanism in the pathogenesis of COPD, and one study found that theophylline significantly reduced the production of reactive nitrogen and reduced neutrophil infiltration compared to hormones, which did not reduce neutrophil infiltration [21].
Theophylline may also repair GC function by inhibiting PI3Kδ activation during oxidative stress, thereby increasing its anti-inflammatory effects when hormone therapy is not sensitive in COPD [22]. High concentrations of theophylline do inhibit many PI3K subunits. Thus, selective PI3Kδ inhibitors may repair GC function through protection of HDAC-2 and or restoration of HDAC-2 activity, thereby reducing inflammatory mediator expression. PI3Kδ, γ are leukocyte-specific related subunits that are central to intrinsic, acquired immunity, including recruitment of neutrophils, involvement in high-affinity receptor IgE receptor signaling (FcεRI), chemokine signaling pathways. Therefore, selective PI3Kδ/γ inhibitors are of great interest and are being developed as anti-inflammatory agents, especially for applications in anti-allergic diseases.
Turmeric, similar to theophylline, has been shown in vitro to repair GC function by protecting HDAC-2 expression and active action [23]. The specific mechanisms of antioxidant, anti-inflammatory, and GC protection of turmeric are not yet clear.
(ii), Selective anti-inflammatory factors
Tumor necrosis factor-α (TNF-α) is an important inflammatory mediator in the inflammatory response of COPD, but studies on patients with moderate and severe COPD with anti-TNF-α antibodies have found no benefit to patients, but instead there are many side effects causing lung cancer and lung infections [24]. Selective p38MAPKα inhibitors have the effect of inhibiting the release of pro-inflammatory mediators (e.g., TNF-α, CXCL8) associated with the inflammatory response in COPD in vitro, while inhibiting oxidative stress, suggesting that the anti-inflammatory properties of p38MAPKα inhibitors are not affected by oxidative stress. p38MAPK expression is elevated in the lungs of COPD patients, and selective p38MAPK inhibitors reduced the expression of inflammatory markers in the blood of COPD patients [25]. It is suggested that selective p38MAPK inhibitors may be another option for COPD insensitive to GC therapy.
(iii) Pro-inflammatory elimination strategies
The persistence of inflammatory response in COPD is related to its own lack of ability to eliminate inflammatory response and self-regulation. The impairment of inflammation elimination ability is one of the important reasons for the insensitivity of GC treatment for COPD.
GC not only fails to inhibit the inflammatory response of neutrophils, but also disrupts the apoptosis of neutrophils, which leads to the continuous release of inflammatory mediators, superoxide and neutrophil elastase by neutrophils, which in turn leads to tissue damage and the persistence of the inflammatory response. Neutrophil apoptosis is central to the elimination of inflammation, which can lead to a shift in the function of macrophages, i.e., from initially promoting the inflammatory response to releasing mediators that promote the elimination of inflammation (prostaglandin E2, IL-10) [26].
Cigarettes impair the phagocytosis of macrophages, which in turn decreases the clearance of apoptotic neutrophils.In COPD patients treated with GC, the apoptosis of their neutrophils is delayed in vitro, which not only leads to longer survival of neutrophils and release of more inflammatory mediators, but also exacerbates lung damage due to the inflammatory response caused by the intracellular components of necrotic neutrophils as a result of the decreased phagocytosis of macrophages. Studies on inflammation elimination in COPD are scarce, so information on the effect of inflammation elimination on GC function is also scarce, but this area of inflammation elimination will provide help in the search for effective and new anti-inflammatory drugs for the treatment of COPD.
PI3Ks not only have a repair function for GC but may also play a role in inflammation elimination. PI3K inhibitors enhance the eosinophil-induced inflammatory response by inhibiting Akt activity and enhancing apoptosis, which eliminates antigen-induced eosinophils. Studies in transgenic mice and selective inhibitors have confirmed that PI3Kβ is required for Fcr receptor-mediated phagocytosis of macrophages [27]. Therefore, in addition to its anti-inflammatory effects, selective PI3K inhibitors may also promote the elimination of inflammation, which may also be a new therapeutic avenue. Some other small molecule inhibitors (including cell cycle protein-dependent kinase inhibitors) can promote neutrophil apoptosis and inflammation elimination. Therefore, selective inhibitors that promote neutrophil apoptosis are also a new therapeutic pathway.
In conclusion, although GC plays an important role in COPD treatment, the presence of factors such as decreased activity of HDACs due to oxidative stress makes COPD appear insensitive to GC therapy. Therefore, the combination of GC with drugs that can repair GC function (including agents with antioxidant and pro-inflammatory elimination effects) will play a more important role in controlling the inflammatory response in COPD, slowing down the decline in lung function and disease progression, and reducing mortality.