Estrogen as a new therapeutic target for asthma and chronic obstructive pulmonary disease

Asthma and chronic obstructive pulmonary disease (COPD) affect the lives of a large portion of the population and can lead to morbidity and mortality. In many women, the incidence and severity of asthma exacerbations vary along their menstrual cycle. Estrogen, a natural occurring hormone, affects differently many of the cell types that are involved in asthma, including macrophages, eosinophils, neutrophils, lymphocyte, mast cells, fibroblasts, epithelial and smooth muscle cells. By binding to its receptors on the plasma or nuclear membrane, estrogen affects the expression of a plethora of proteins that are involved in the pathogenesis of asthma and COPD. In this review we will summarize the current knowledge of the role of estrogen in the expression, production and secretion of inflammatory agents that are involved in asthma and COPD and its potential therapeutic role in these diseases.     

Interferon-gamma as a possible target in chronic asthma

The role of interferon-gamma (IFN-gamma) in asthma is controversial. However, this cytokine has been proposed to play a role both in acute severe asthma and chronic stable asthma. We have shown that in a chronic low-level challenge model of allergic asthma in mice, which replicates characteristic features of airway inflammation and remodelling, the mechanisms of airway hyperreactivity (AHR) are markedly different to those in short-term high-level challenge models. Notably, AHR is independent of various Th2 cytokines and their signalling pathways. However, administration of a neutralising antibody to IFN-gamma suppresses AHR. More recently, we have found that following chronic allergen challenge, but not acute challenge, IFN-gamma-producing CD4+ T cells are demonstrable in peribronchial lymph nodes, both in wild-type mice and in STAT6-/-mice. Treatment with anti-IFN-gamma decreases the number of IFN-gamma-producing CD4+ T cells in both wild-type and gene-targeted mice, providing a possible explanation for the ability of anti-IFN-gamma to inhibit AHR in the setting of chronic challenge. These data further strengthen the notion that the pathogenesis of the lesions of asthma, and especially of AHR, involves a co-operative interaction between Th2 and Th1 cytokines. This may be particularly relevant to acute exacerbations of asthma, in which setting there may be justification for therapeutic inhibition of IFN-gamma.     

Nitric oxide synthase (NOS) as therapeutic target for asthma and chronic obstructive pulmonary disease

In the respiratory tract, NO is produced by residential and inflammatory cells. NO is generated via oxidation of L-arginine that is catalysed by the enzyme NO synthase (NOS). NOS exists in three distinct isoforms: neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS). NO derived from the constitutive isoforms of NOS (nNOS and eNOS) and other NO-adduct molecules (nitrosothiols) are able to modulate bronchomotor tone. NO derived from the inducible isoform of NO synthase, up-regulated by different cytokines via NF-kappaB-dependent pathway, seems to be a pro-inflammatory mediator with immunomodulatory effects. The production of NO under oxidative stress conditions secondarily generates strong oxidising agents (reactive nitrogen species) that may amplify the inflammatory response in asthma and COPD. Moreover, NO can be exhaled and levels are abnormal in stable atopic asthma and during exacerbations in both asthma and COPD. Exhaled NO might therefore be a non-invasive tool to monitor the underlying inflammatory process. It is suggested that NOS regulation provides a novel target in the prevention and treatment of chronic inflammatory diseases of the airways such as asthma and COPD.     

(R)-salbutamol in the treatment of asthma and chronic obstructive airways disease

INTRODUCTION: Asthma and chronic obstructive pulmonary disease (COPD) are inflammatory disorders that have an increasing prevalence and associated morbidity and mortality. β(2)-adrenoceptor agonists (β(2)-agonists) act by stimulating the β(2)-adrenoceptor present on airway smooth muscle and other cells in the airway, resulting in bronchodilatation. β(2)-agonists are among the most commonly used drugs in the world and remain pivotal in the treatment of symptoms in patients with asthma and COPD. Salbutamol is a chiral drug with (R)- and (S)- isomers. Almost all β(2)-agonists that are used at present are racemic mixtures of (R)- and (S)-salbutamol. AREAS COVERED: In this review the authors show that (R)-salbutamol alone (generically known as levosalbutamol) provides beneficial β(2)-agonist effects at a cellular level and in experimental models of airways disease. In addition the authors demonstrate that (S)-salbutamol opposes the desirable effects of (R)-salbutamol and can actually cause features of asthma and COPD in vitro and in experimental asthma. EXPERT OPINION: Despite this strong body of experimental evidence, (R)-salbutamol has not shown consistent superiority over (S)- or racemic salbutamol in human asthma or COPD.     

Therapy of chronic obstructive airways disease

The most frequently employed measure in attempts to alleviate symptoms and improve the quality of life of patients with chronic obstructive airways disease (COAD) is to prescribe medications. However, COAD is largely an irreversible condition and no therapeutic intervention has been shown to be universally useful. Theophylline or corticosteroid are occasionally helpful but most patients will not benefit. Of the remaining options, only oxygen has been shown to be effective in selected patients and should be administered on a continuous basis. It is becoming increasingly evident that clinicians should be more discriminating when making therapeutic decisions for persons with COAD. Maintenance therapy with pharmacological agents should be entertained only after individually conducted therapeutic trials. Moreover, enormous costs can result from treating even a small fraction of the population estimated to have COAD.     

Matrix metalloproteinase-9/gelatinase B is a putative therapeutic target of chronic obstructive pulmonary disease and multiple sclerosis

Matrix metalloproteinases (MMPs) are a large family of proteolytic enzymes involved in an array of physiological and pathological processes from development, morphogenesis, reproduction, wound healing, and aging to inflammation, angiogenesis, neurological disorders, and cancer cell invasion and metastasis. The imbalance between MMP activity and the inhibitory action of tissue inhibitors of metalloproteinases (TIMPs) are implicated in multiple diseases. Secreted in the body in a latent form, upon activation MMP-9 (gelatinase B) acts on many inflammatory substrates, and thus is suspected of contributing to the progression of cardiovascular disease, rheumatoid arthritis, and the subjects of this review, chronic obstructive pulmonary disease (COPD) and multiple sclerosis (MS). COPD is the fourth most common cause of death in the United States. In COPD, increased expression of MMP-9 by inflammatory cells e.g. neutrophils and macrophages is correlated with a variety of processes that cause lung damage. MMP-9 is also important in cytokine and protease modulation; it degrades the serine protease inhibitor alpha(1)-antitrypsin, which thus may lead to lung destruction. MS affects approximately 400,000 Americans and over a million people worldwide. Upregulation of MMP-9 increases the permeability of the blood brain barrier (BBB), facilitates the infiltration of leukocytes into the central nervous system, and causes myelin sheath degradation and neuronal damage. Early stage clinical trials have shown promising results when MMP-9 is inhibited in MS. These observations lead to the hypothesis that MMP-9 is a potential drug target for both COPD and MS and further development of highly potent and specific MMP-9 inhibitors is warranted.     

Interleukin-5 as a potential target for asthma treatment

Increased accumulation of eosinophils in bronchial mucosa is a hallmark of bronchial asthma. Upon activation, these eosinophils synthesize and release an array of proinflammatory and cytotoxic products that cause edema, mucus secretion, tissue damage and airway hyperreactivity. Maturation, activation and survival of eosinophils are largely dependent on the availability of the hematopoietic cytokine interleukin-5 (IL-5), produced by activated T-helper type 2 (Th2) lymphocytes. Numerous findings obtained in animal models of asthma, utilizing IL-5 transgenic mice or anti-IL-5 antibodies, have underscored the key contribution of this cytokine to the allergic process. Clinical studies in humans have also indicated the close correlation between airway IL-5 expression, eosinophilia and asthma symptoms. Taken together, these findings have advanced IL-5 to a potentially successful target for asthma treatment. Current tactics to tackle IL-5 are neutralization of IL-5, IL-5 receptor antagonism, interference with IL-5-induced intracellular signaling and inhibition of IL-5 biosynthesis.     

Oligonucleotides: New therapeutic approaches for asthma and chronic obstructive pulmonary disease

Asthma and COPD are significant lung diseases for which anti-inflammatories, including inhaled corticosteroids and leukotriene- targeted drugs, represent a key element of current therapy. Oligonucleotides comprise a diverse family of emerging drug candidates for the treatment of these diseases. There is a commonality in the chemistry of oligonucleotide drug molecules but, importantly, individual candidates are distinct in their molecular targets and also possess different mechanisms of action. Oligonucleotides may be divided in two groups based on their main mechanism of action: (i) RNA-targeting; and (ii) protein-targeting. Antisense oligonucleotides and siRNAs, both of which belong to the RNA-targeting group, and the immunostimulatory sequence-based drugs, which are members of the protein-targeting group, are progressing through clinical trials. In principle, the development of these agents is facilitated by a series of significant advantages, such as those associated with delivery to the lung via inhalation, and targeting to the site of action, resulting in reduced levels of systemic exposure. Although no oligonucleotide-based drug has been approved for the treatment of asthma or COPD, this class of compounds holds significant promise in the treatment of these two diseases. Several oligonucleotide drug candidates have been evaluated in the clinic with no significant adverse safety findings, while clinical proof of concept based on short-term inhalation protocols in challenge models in humans has also been established.     

Evaluating revefenacin as a therapeutic option for chronic obstructive pulmonary disease

ABSTRACT

Introduction

In chronic obstructive pulmonary disease (COPD), inhaled long-acting antimuscarinic agents (LAMA) are effective maintenance therapies used across all severity stages of the disease. Most of them are administered via dry powder inhalers, but these devices require a potent inspiratory flow which cannot be effectively achieved by patients with advanced disease. In such patients, inhaled therapy via nebulization might be an option.     

CCR6 as a possible therapeutic target in psoriasis

Importance of the field: Psoriasis is a common, chronic autoimmune disease of the skin. Despite a number of effective treatments, new therapies are needed with enhanced efficacy, safety and convenience. Chemokine receptors are GPCRs that control leukocyte trafficking, and like other GPCRs, are good potential drug targets. The chemokine receptor CCR6 is expressed on the T_H17 subset of CD4⁺ T cells, which produces IL-17A/F, IL-22, TNF-α and other cytokines, and which has been implicated in the pathogenesis of psoriasis. CCR6 and its ligand, CCL20/MIP-3α, are highly expressed in psoriatic skin and CCR6 is necessary for the pathology induced in a mouse model of psoriasis-like inflammation.

Areas covered in this review: This review summarizes the evidence for the importance of the IL-23/T_H17 axis, and in particular CCR6 and CCL20 in psoriasis, dating from 2000 to the present, and discusses the possibility of inhibiting CCR6 as a treatment for the disease.

What the reader will gain: The review informs the reader of the current thinking on the mechanisms of inflammation in psoriasis and the possible roles for CCR6 (and CCL20) in disease pathogenesis.

Take home message: We conclude that CCR6 should be investigated as a potential therapeutic target in psoriasis.     

RhoA/Rho-kinase as a therapeutic target in asthma

Rho-kinase is an effector molecule of RhoA, a monomeric GTP-binding protein, and causes Ca(2+) sensitization via inactivation of myosin phosphatase. The major physiological functions of Rho-kinase include contraction, migration, and proliferation in cells. These actions are thought to be related to the pathophysiological features of asthma, i.e., airflow limitation, airway hyperresponsiveness, beta-adrenergic desensitization, eosinophil recruitment and airway remodeling. Here, the roles of RhoA/Rho-kinase in the pathophysiology and treatment of asthma were investigated. In airway smooth muscle, pre-exposure to chemical mediators released from inflammatory cells markedly enhances methacholine-induced contraction without elevating intracellular concentrations of Ca(2+). This augmented responsiveness to methacholine involves the phosphorylation of myosin phosphatase targeting protein 1 (MYPT1) via Rho-kinase, however, it is attenuated by pre-treatment with Rho-kinase inhibitors such as Y-27632 and HA-1077. Airway smooth muscle contraction due to asthma-related substances such as contractile agonists and reactive oxygen species is suppressed by these Rho-kinase inhibitors. Reduced responsiveness to beta-adrenergic receptor agonists occurs via Ca(2+) sensitization, after exposure to lysophospholipids and proteases released from inflammatory cells. This beta-adrenergic desensitization is also attenuated in the presence of Y-27632. Furthermore, the proliferation of airway smooth muscle cells is elevated by Rho-kinase, however, it is markedly suppressed by Y-27632. Antigen challenges cause hyperresponsiveness and eosinophilia in the airways; however, these reactions are markedly suppressed by these Rho-kinase inhibitors. These findings indicate that RhoA/Rho-kinase is involved in the pathophysiology of asthma, and suggest that Rho-kinase inhibitors have therapeutic potential for prohibiting these features. In conclusion, RhoA/Rho-kinase is a novel target molecule for the treatment of asthma.     

Chemokine receptors as therapeutic targets in chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is an increasing global health problem for which there are no effective disease-modifying therapies. COPD involves chronic inflammation of small airways and lung parenchyma, with the recruitment of inflammatory cells. This inflammatory-cell trafficking is orchestrated by multiple chemokines, so the blockade of chemokine receptors with selective antagonists might be an effective anti-inflammatory strategy in this disease. Several studies support the implication of several chemokines and their receptors in COPD, including chemokine receptors CXCR2 and CXCR3, with small-molecule receptor antagonists that are in development being potential anti-inflammatory therapies. Such a pharmacological strategy would provide a mechanism with which to inhibit leukocyte recruitment and, hence, reduce the inflammatory profile in COPD, which is currently unaffected by pharmacotherapy.     

PCSK9 as a therapeutic target of dyslipidemia

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9), which promotes degradation of hepatic low density lipoprotein receptor (LDLR), has a role in plasma cholesterol metabolism. Its gene is associated with the development of familial hypercholesterolemia. mRNA silencing or inhibition of PCSK9-induced degradation of LDLR may be used to treat this disease. Objective/methods: To summarize approaches proposed to reduce the levels of PCSK9 and/or its activity. Results/conclusions: mRNA knockdown approaches include the use of antisense oligonucleotides either as soluble phosphorothioates or locked nucleic acids and lipidoid nanoparticles embedded with small interfering RNAs. Passive immunization is also an option. Other strategies include inhibition of the zymogen activation of proPCSK9, or the interaction of PCSK9 with the EGF-A domain of the LDLR. The N-terminal prosegment and the C-terminal Cys-His rich domain (CHRD), are alternative targets. Annexin A2 specifically binds the CHRD and inhibits PCSK9 function, and Annexin A2 peptide mimics could pave the way for the development of novel PCSK9-inhibitory compounds.