COX inhibitors for airway inflammation

INTRODUCTION: The cyclooxygenase (COX) enzyme, which is responsible for the production of prostaglandins (PGs), key mediators of inflammation, may have the potential to become an attractive target for anti-inflammatory therapy. COX catalyzes the conversion of arachidonic acid (AA) into PGs, which play a significant role in disease. PGs are lipid mediators of central importance in the regulation of inflammation and smooth muscle tone. Airway-resident inflammatory cells release PGs: PGD2 and PDF2a amplify smooth muscle contraction and airway inflammation. Following its conversion from membrane phospholipids by phospholipase, AA enters the prostanoid pathway via COX, which catalyzes the conversion of AA to PGH2. PGH2 is then converted to biologically active PGs by cell-specific PG synthases. As COX is the rate limiting step in the PG pathway, the regulation of this enzyme is of critical importance in PG production. AREAS COVERED: This review addresses the opportunities and challenges of COX inhibitors as therapeutic targets in airway inflammation. The review covers literature from the past 20 years. EXPERT OPINION: Current literature favors COX inhibitors as potential targets for airway diseases. However, from the information available, it is not clear whether the COX enzyme by itself can serve as a target in drug development for asthma and COPD. Therefore, additional research is required to elucidate the mechanisms of action of COX metabolites before it can be considered as a target.     

Aurora激酶及其抑制剂研究状态综述

Aurora激酶家族是苏氨酸/丝氨酸激酶,在有丝分裂的染色体排列,分离和胞质分裂中起重要作用。最近的研究发现,Aurora激酶在大量人类实体瘤和血液恶性肿瘤中过表达,表明其是开发抗肿瘤药物的重要靶点。本文就近几年国内外对Aurora激酶的研究,对Aurora激酶的生物学功能、与肿瘤的关系及其抑制剂的研究进展进行综述。     

Heterocyclic compounds as inflammation inhibitors

Clinical use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with significant toxicity particularly in the gastrointestinal tract and kidney. Various approaches such as formulation co-administration (of agents to protect the stomach), chemical manipulation and synthesis of new safer anti-inflammatory drugs reported in the literature to overcome the toxicity of NSAIDs have been summarized. As far as synthesis of new more effective and safer anti-inflammatory drugs is concerned, we have reported recent findings in the area of synthesis of heterocyclic compounds such as pyrimidines, imidazole, benzimidazole, thiazole, thiazolidine, acridine, thiourea, alkanoic acid derivatives and other related heterocyclic compounds and their role as inflammation inhibitors.     

Mepacrine alleviates airway hyperresponsiveness and airway inflammation in a mouse model of asthma

Asthma is a multifactorial respiratory disease. Though its incidence is increasing rapidly all over the world, the available therapeutic strategies are neither sufficient nor safe for long term use. Mepacrine, a known antimalarial drug, has been shown to possess antioxidant, anti-inflammatory, platelet anti-aggregant, and PLA2 inhibitory activities. However, its possible use in asthma has not been studied yet. The objective of this study was to investigate the anti-asthmatic property of mepacrine using a mouse model of asthma. To accomplish this, male BALB/c mice were sensitized and challenged with ovalbumin and treated with increasing concentrations of mepacrine. Airway hyperresponsiveness (AHR) to methacholine was assessed using unrestrained whole body plethysmography. Mepacrine (1 mg/kg) has shown marked attenuation of AHR. Cytokines such as IL-4, IL-5, IL-13 and IFN-gamma and OVA-specific IgE levels were measured in BAL (bronchoalveloar lavage) fluid and sera, respectively. Mepacrine effectively reduced the rise in IL-4, IL-5, IL-13, and OVA-specific IgE and restored IFN-gamma levels. Mepacrine also significantly prevented the increase of sPLA2 (secretory phospholipase A2) activity in BAL fluid supernatant and Cys-LT (cysteinyl leukotrienes) in lung tissue homogenates of asthmatic mice. In addition, mepacrine treatment reduced BAL fluid eosinophilia and signs of allergic airway inflammation such as perivascular and peribronchial distribution of inflammatory cells. These findings indicate that mepacrine reduces the asthmatic features in ovalbumin induced asthma by acting on PLA2-Cys-LT axis. Thus, it could be useful for the development of better asthma therapy.     

Local inflammation in chronic upper airway disease

Chronic Rhinosinusitis (CRS), a chronic upper airway inflammation, is an inflammation of the nose and the paranasal cavities and is highly prevalent. Chronic rhinosinusitis is currently classified as CRS with nasal polyps or CRS without nasal polyps. This review highlights the pathophysiological differences in CRS on remodeling and on T-cell patterns. Nasal polyps have a high co-morbidity with the lower airway inflammatory disease, asthma. Evidence is accumulating for the role of superantigens, Staphylococcus aureus enterotoxins, in CRS with nasal polyps and asthma, both T helper 2 -biased diseases. Until today there are no biomarkers involved in the diagnosis of CRS or the treatment follow-up. Further differentiation of the phenotype of the disease is needed, which will reflect in the development of new biomarkers and in new innovative treatment options. Defining and predicting response to therapy in individual CRS patients is a challenge for future research.     

Novel immunomodulatory oligonucleotides prevent development of allergic airway inflammation and airway hyperresponsiveness in asthma

Oligodeoxynucleotides containing unmethylated CpG motifs (CpG oligos) have been shown to prevent development of allergic airway inflammation and airway hyperresponsiveness (AHR) in mouse models of asthma. Recently, we reported immunomodulatory oligonucleotides (IMOs) containing novel structures (immunomers) and synthetic immunostimulatory CpR (R=2'-deoxy-7-deazguanosine) motifs show potent stimulatory activity with distinct cytokine secretion profiles. Since type 2 T cells predominate in asthma and increase in type 1 cells can prevent the differentiation of na?ve T lymphocytes to a type 2 phenotype, we hypothesized that IMOs can prevent the development of allergic airway inflammation and AHR in the ovalbumin (OVA)-sensitized and challenged mouse model. We found that co-administration of novel IMOs during OVA-sensitization abrogated both early and late allergic responses (LARs). AHR to methacholine was also blocked with IMO treatment. Analysis of bronchoalveolar lavage (BAL) fluid of mice treated with IMOs demonstrated complete reduction in eosinophils, with concomitant decreases in both serum and BAL fluid IL-4, IL-5, and IL-6 levels. In addition, there was a significant reduction in serum IL-10 levels. IMOs, in general, significantly attenuated the rise in serum IgE levels. In comparison, IMOs showed a significantly more potent effect on early and late allergic response than a conventional CpG oligo in this model. These data suggest that the treatment with these novel IMOs prevents OVA-induced allergic airway inflammation and AHR in asthma in the mouse and may provide a useful agent in the treatment of human asthma.     

Reactive nitrogen and oxygen species in airway inflammation.

The free radical nitric oxide (NO) is an important mediator of many biological processes. Interestingly, the molecule appears to be a two-edged sword. Apart from NO having a function as a paracrine messenger, NO-derived oxidants are important weapons against invading pathogens. The role of NO in the airways is similarly ambiguous. Besides the task as a bronchodilator, NO and its derivatives play a role in the pathophysiology of asthma via their putative damaging effects on the airways. This deleterious effect can be increased by a nitrosative response to respiratory tract infections, since both the infectious agent and the host may suffer from the consequent nitrosative stress. Interestingly, respiratory infections can also compromise the beneficial (bronchodilator) effects of NO. This paper gives an overview on NO and its derivatives in the pathophysiology of airway inflammation.     

Mepacrine treatment attenuates allergic airway remodeling segregated from airway inflammation in mice

Asthma is a chronic airway disease characterized by increased airway hyperresponsiveness, airway inflammation, and airway remodeling including collagen deposition in subepithelial regions. We have shown earlier that mepacrine has anti-inflammatory activity and decreased the features of airway remodeling in a subacute model of asthma, when administered during the inflammatory phase. But it was not clear whether the reduction of airway remodeling by mepacrine was a direct effect or indirectly related to the reduction in the airway inflammation. In this study, we determined the effect of mepacrine on airway remodeling and airway hyperresponsiveness (AHR) in a chronic model of asthma which showed the features of airway inflammation in the initial stage (inflammation predominant stage) and airway remodeling with mild airway inflammation in a later stage (remodeling predominant stage). Mepacrine was administered only in the later stage that more accurately simulates human asthma, where airway remodeling already exists at the time of diagnosis. The remodeling predominant stage was associated with high levels of Th2 cytokines like IL-4 and IL-13, increase in the levels of profibrotic mediators such as arginase and TGF-β, and increased collagen deposition. These were efficiently attenuated by mepacrine treatment and led to a significant reduction in AHR. Thus, we conclude from this study that mepacrine has direct effects on established airway remodeling independent of its anti-inflammatory effects.     

Effects of combination therapy with montelukast and carbocysteine in allergen-induced airway hyperresponsiveness and airway inflammation

Background and purpose:

Montelukast and S-carbocysteine have been used in asthmatic patients as an anti-inflammatory or mucolytic agent respectively. S-carbocysteine also exhibits anti-inflammatory properties.

Experimental approach:

Ovalbumin (OVA) sensitized BALB/c mice were challenged with OVA for 3 days followed by single OVA re-challenge (secondary challenge) 2 weeks later. Forty-eight hours after secondary challenge, mice were assessed for airway hyperresponsiveness (AHR) and cell composition in bronchoalveolar lavage (BAL) fluid. Suboptimal doses of 10 mg·kg⁻¹ of S-carbocysteine by intraperitoneal injection (ip), 20 mg·kg⁻¹ of montelukast by gavage, the combination of S-carbocysteine and montelukast or 3 mg·kg⁻¹ of dexamethasone as a control were administered from 1 day before the secondary challenge to the last experimental day. Isolated lung cells were cultured with OVA and montelukast to determine the effects on cytokine production.

Key results:

Treatment with S-carbocysteine or montelukast reduced both AHR and the numbers of eosinophils in BAL fluid. Neutralizing IFN-γ abolished the effects of S-carbocysteine on these airway responses. Combination of the two drugs showed further decreases in both AHR and eosinophils in the BAL fluid. Goblet cell metaplasia and Th2-type cytokines, interleukin (IL)-4, IL-5 and IL-13, in BAL fluid were decreased with montelukast treatment. Conversely, S-carbocysteine increased Th1-type cytokines, IFN-γ and IL-12 in BAL fluid.

Conclusions and inplications:

The combination of two agents, montelukast and S-carbocysteine, demonstrated additive effects on AHR and airway inflammation in a secondary allergen model most likely through independent mechanisms of action.     

Sulphur dioxide-induced airway hyperreactivity and pulmonary inflammation in dogs

Anaesthetised Beagle dogs were exposed to sulphur-dioxide (SO2) for 2 h and the pulmonary effects studied up to 24 h using bronchoalveolar lavage (BAL) and lung mechanics measurements. SO2-induced hyperreactivity to histamine was associated with epithelial cell shedding, an increase in airway permeability to plasma proteins and an increase in BAL PGE2 content. Leukotrienes were not recovered in BAL. Ibuprofen reduced hyperreactivity at 24 h post SO2 but not immediately after SO2 and had no effect on BAL cells at anytime. These results suggest that 2 phases of hyperreactivity exist--an immediate effect which may involve epithelial cell loss and a later phase which may be inflammatory.     

Kinase inhibitors: not just for kinases anymore

Kinase inhibitors are widely employed as biological reagents and as leads for drug design. Their use is often complicated by their lack of specificity. Although binding conserved ATP sites accounts for some of their nonspecificity, some compounds inhibit proteins not known to bind ATP. It has been found that promiscuous hits from high-throughput screening may act as aggregates. To explore whether this mechanism might explain the action of widely used nonspecific kinase inhibitors, 15 such compounds were studied. Eight of these, rottlerin, quercetin, K-252c, bisindolylmaleimide I, bisindolylmaleimide IX, U0126, indirubin, and indigo, inhibited three diverse non-kinase enzymes. Inhibition was time-dependent and sensitive to enzyme concentration; by light scattering, the compounds formed particles of 100-1000 nm diameter. These observations suggest that these eight kinase inhibitors, at least at micromolar concentrations, are promiscuous and act as aggregates. Results obtained from the use of these compounds at micromolar or higher concentrations against individual enzymes should be interpreted cautiously.     

Phospholipase A2 inhibitors in inflammation

The key reaction of the arachidonic acid cascade is the liberation of arachidonic acid from membrane phospholipids by a phospholipase A₂ (PLA₂). An excessive stimulation of this biochemical pathway leads to the formation of pathophysiological concentrations of lipid mediators like prostaglandins, leukotrienes, lysophospholipids and platelet activating factor, which are implicated in the development of inflammatory conditions. Thus, inhibitors of PLA₂ are expected to be a new treatment option for such diseases. One problem associated with the in vitro search for PLA₂ inhibitors is the selection of the appropriate enzyme, since many different PLA₂s are present in the mammalian organism. This paper discusses which of these PLA₂s is most likely to play the major role in the generation of the pro-inflammatory lipid mediators. Furthermore, patents claiming inhibitors of PLA₂s for the prevention and treatment of inflammation are reviewed for the period January 1997 to December 2000.     

Synthesis and biological evaluation of neutrophilic inflammation inhibitors

In several non-infectious human diseases, such as ulcerous colitis, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), the extravasal recruitment of neutrophils plays a crucial role in the development of tissue damage, which, when persistent, can lead to the irreversible organ dysfunction. The neutrophil activation is controlled by a number of intracellular pathways, particularly by a cAMP-dependent protein kinase A (PKA) which also acts on phosphodiesterase IV (PDE4) gene stimulating the synthesis of this enzyme, able to transform cAMP to inactive AMP. PDE4 inhibitors enhance intracellular cAMP and decrease inflammatory cell activation. Several 3-cyclopentyloxy-4-methoxybenzaldehyde and 3-cyclopentyloxy-4-methoxybenzoic acid derivatives were synthesized and studied by us to evaluate their ability to inhibit the superoxide anion production in human neutrophils. These compounds were found able to inhibit the neutrophil activation and some of them increased the cAMP level on tumor necrosis factor-alpha-stimulated neutrophils. Moreover, they also inhibited selectively the human PDE4 enzyme, although they are less potent than the reference compound Rolipram. We report here synthesis, biological studies and some SAR considerations concerning the above mentioned compounds.     

Continued inhalation of lidocaine suppresses antigen-induced airway hyperreactivity and airway inflammation in ovalbumin-sensitized guinea pigs

It is unclear whether inhaled lidocaine is effective against airway hyperreactivity and inflammation in asthma. The aim of this study was to investigate the effects of inhaled lidocaine on airway hyperreactivity and inflammation. Airway reactivity to inhaled histamine, cellular composition of bronchoalveolar lavage (BAL) fluid, plasma substance P (SP), and isolated lung tissue were evaluated in ovalbumin (OVA)-sensitized guinea pigs 7 days after OVA challenge. The effects of inhaled lidocaine on this model were also evaluated. Treatment with lidocaine was administered in two fashions: as single inhalation or inhalation bid for 7 consecutive days, for comparison with a saline-inhaled control group. Airway hyperreactivity to histamine, increase in number of total cells and increased proportion of eosinophils in BAL fluid, and marked eosinophil infiltration in airway walls were noted even 7 days after OVA challenge in the control group. Plasma SP level was also significantly increased. Although treatment with single lidocaine inhalation did not affect airway hyperreactivity, continued inhalation (bid for 7 days) attenuated airway hyperreactivity. Continued, but not single, inhalation of lidocaine also suppressed infiltration of eosinophils in BAL fluid and in airway walls. In addition, plasma SP levels were significantly reduced by continued but not by single inhalation. It appears possible that lidocaine when inhaled suppresses eosinophilic inflammation of the airway and SP-induced neurogenic inflammation, leading to alleviation of airway hyperreactivity.     

Expression and role of sugar chains on airway mucus in induction and exacerbation of airway inflammation

Human bronchial mucins, such as MUC5AC, have traditionally been defined as a family of high-molecular weight glycoproteins. Changes in the contents of sugar chains on MUC5AC are among the fundamental features in inflammatory respiratory disease. The changes have been shown to lead to unfavorable alterations in the viscosity of mucus, resulting in impairment of mucociliary transport, vulnerability to viral/bacterial infection as sugar chains play an important role in adhesion of some viruses and bacteria to the epithelium, and finally inflammatory cell infiltration in the airway. Recently, we found that expression of some glycosyltransferases associated with the contents and structure of sugar chains is regulated by phosphatidylinositol-phospholipase (PI-PL) C signaling in cells. L-Carbocisteine, a mucoregulatory drug, normalized or balanced fucosylated and sialylated sugar chains, such as sialyl Lewis x through inhibition of PI-PL C signaling. We prepared MUC5AC fusion protein with tandem repeats associated with MUC5AC, and confirmed that L-carbocisteine inhibited the increases in viscosity associated with sialyl Lewis x expression levels. In addition, the clinical study (2008) noted that L-carbocisteine reduced the frequency of common colds and exacerbation of symptoms in patients with COPD. These favorable effects in patients may be due to normalization of sugar chain contents on mucins. We suggest that the inhibitory effect on infection of airway epithelial cells by rhinoviruses, respiratory syncytial virus, and influenza viruses by treatment with L-carbocisteine may also be based on the regulation of sugar chain contents or structures on mucins.     

Microvascular remodelling in chronic airway inflammation in mice

1. Chronic inflammation is associated with blood vessel remodelling, including vessel proliferation and enlargement, and changes in vessel phenotype. We sought to characterize these changes in chronic airway inflammation and to determine whether corticosteroids that inhibit inflammation, such as dexamethasone, can also reduce microvascular remodelling. 2. Chronic airway inflammation was induced in C3H mice by infection with Mycoplasmapulmonis and the tracheal vessels treatment also decreased the immunoreactivity for P-selectin and the number of adherent leucocytes (595 +/- 203 vs 2,024 +/- 393 cells/ mm2 in treated and non-treated infected mice, respectively). 6. We conclude that microvascular enlargement and changes in vessel phenotype are features of some types of chronic inflammation and, furthermore, that dexamethasone reverses the microvascular enlargement, changes in vessel phenotype and leucocyte influx associated with chronic inflammatory airway disease.