Phosphodiesterase inhibitors: new perspectives on an old therapy for asthma?

Abstracts

Asthma is a chronic inflammatory disease characterized by varying degrees of airflow obstruction and diverse clinical manifestations. As knowledge of asthma pathogenesis has increased, treatment has evolved. Airway inflammation, modulated by genetic and environmental factors, results in altered airway architecture (airway remodeling). Inflammation in asthma is typically multicellular in nature, involving mast cells, neutrophils, eosinophils, and T lymphocytes, as well as muscle and epithelial cells. Various cytokines and chemokines play roles in orchestrating the inflammatory process. Recognition of the critical role played by airway inflammation, which is an indicator of the degree of asthma severity, has shifted the treatment toward either prevention or the inhibition of inflammatory markers. In light of this, new drug formulations have been considered. In addition to the beta2 agonists, theophylline, and corticosteroids currently being used, the second generation of selective phosphodiesterase inhibitors has shown promising results. Recent studies suggest that these drugs may soon offer a novel alternative in the treatment of asthma.

Phosphodiesterase inhibitors; Inflammation mediators; Asthma

A asma é uma doença inflamatória crônica com níveis variados de obstrução ao fluxo aéreo e diferentes formas de apresentação. Seu tratamento vem sendo modificado com a evolução do conhecimento sobre sua patogenia. A inflamação das vias aéreas, que é modulada por determinantes genéticos e ambientais, resulta na alteração definitiva da arquitetura da via aérea (remodelamento). O padrão inflamatório da asma é de natureza multicelular, envolvendo mastócitos, neutrófilos, eosinófilos, linfócitos T, células musculares e epiteliais. Diversas citocinas e quimiocinas contribuem para a orquestração do processo inflamatório. O reconhecimento do papel crítico da inflamação, que está associada à gravidade da doença, vem direcionando o eixo do tratamento para a prevenção ou para o bloqueio das alterações inflamatórias. Nesse sentido, além dos agentes beta2-adrenérgicos, da teofilina e dos corticosteróides, novos fármacos vêm sendo estudados. Dentre eles, os inibidores específicos de fosfodiesterases vêm apresentando resultados promissores. A partir dos resultados obtidos com a segunda geração dessas substâncias, pode-se imaginar que, em breve, elas representarão uma nova opção para o tratamento da asma.

Inibidores de fosfodiesterase; Mediadores da inflamação; Asma

REVIEW ARTICLE

Phosphodiesterase inhibitors: new perspectives on an old therapy for asthma?

Hisbello Campos^I, Debora Xisto^II, Walter A. Zin^III, Patricia R.M. Rocco^IV

^IPhysician at the Professor Hélio Fraga Reference Center, MS

^IIIntern in the Respiratory Physiology Department

^IIIProfessor Emeritus, Chief of the Respiratory Physiology Laboratory

^IVAdjunct Professor. Chief of the Pulmonary Investigation Laboratory

^{Correspondence}

ABSTRACT

Asthma is a chronic inflammatory disease characterized by varying degrees of airflow obstruction and diverse clinical manifestations. As knowledge of asthma pathogenesis has increased, treatment has evolved. Airway inflammation, which is modulated by genetic and environmental factors, results in altered airway architecture (airway remodeling). Inflammation in asthma is typically multicellular in nature, involving mast cells, neutrophils, eosinophils, and T lymphocytes, as well as muscle and epithelial cells. Various cytokines and chemokines play roles in orchestrating the inflammatory process. Recognition of the critical role played by airway inflammation, which is an indicator of the degree of asthma severity, has shifted the axis of treatment axis toward either prevention or the use of blockers for proinflammatory alterations. In light of this, new drug formulations have been considered. In addition to the b₂ agonists, theophylline, and corticosteroids currently being used, the second generation of selective phosphodiesterase inhibitors has shown promising results. Recent studies suggest that these drugs may soon offer a novel alternative in the treatment of asthma.

Key words: Phosphodiesterase inhibitors/therapeutic use. Inflammation mediators. Asthma/pathology.

Abbreviations used in this paper:

BHR – Bronchial hyperresponsiveness

BR – Bronchial remodeling

cAMP – Cyclic adenosine 3´,5´-monophosphate

cGMP – Cyclic guanosine 3´,5´-monophosphate

COPD – Chronic Obstructive Pulmonary Disease

ECM – Extracellular matrix

IFN – Interferon

IL – Interleukin

MMP – Metalloproteinase

PDE – Phosphodiesterase

TIMP – Tissue inhibitor of matrix metalloproteinases

TNF – Tumor necrosis factor

Introduction

Evolution walks hand in hand with time. However, the process of evolution sometimes involves taking a step back and looking at a past event from a new perspective. A prime example of this is found in the evaluation of medications for various diseases. Certain drugs that had been relegated to secondary roles in the treatment of a particular disease are frequently "rediscovered" due to new data regarding the pathogenic mechanisms of the disease. This is currently the case in asthma therapy. Traditionally, methylxanthine administration was the most common therapy for asthma worldwide. More recently, with the development of safer and more potent bronchodilators (inhaled b₂-agonists), methylxanthine use decreased and theophylline was favored. However, the discovery of a potential anti-inflammatory effect associated with theophylline brought methylxanthine back to the center of attention. Although theophylline has been used in asthma therapy for over 6 decades, the actual mechanism involved in its effect is still unclear. Several hypotheses have been proposed, including non-specific phosphodiesterase (PDE) inhibition, antagonism to adenosine receptors, catecholamine secretion stimulus, and altered intracellular flow of calcium.⁽¹⁾

In recent decades, the core of asthma therapy has been a regimen of inhaled corticosteroids, often combined with a long-acting inhaled b₂-agonist. When this type of therapy is used with regularity, satisfactory results are usually obtained. However, when treatment fails, there are at least 3 aspects to be considered. First, some components of the complex cellular interaction in asthma are not affected by this regimen. Second, a phobia of corticosteroid use can interfere with patient adherence to the treatment and even with the prescription of such drugs. Finally, administration via the inhalation pathway, despite being ideal for asthma treatment, is an obstacle in certain situations. Therefore, the search for effective drugs that overcome these obstacles to asthma treatment is ongoing. At the same time, understanding of asthma physiopathology has gradually been increasing, creating new alternatives for asthma therapy. In the near future (until genetic therapy becomes a viable alternative) new therapeutic formulations will certainly be based on the molecular mechanisms involved in inflammation and airway hyperresponsiveness in asthmatic patients. In light of this, phosphodiesterase-4 (PDE4) inhibitor drugs have been studied and might prove useful in asthma therapy.

In this study, aspects of the development of PDE inhibitors and their application in asthma treatment will be reviewed.

Evolution of asthma treatment

The history of asthma bronchodilator use begins in 1900 with the use of an adrenal substance extract proposed by Solis-Cohen.⁽²⁾ Although ephedrine had been known to the Chinese for over 5000 years, it was not introduced into western medicine and used as a bronchodilator until 1924. From the beginning of the 20^th century, theophylline was the bronchodilator most commonly used by asthma patients. Theophylline is a methylxanthine whose structure is similar to that of caffeine and theobromine. In 1786, William Withering suggested theophylline use in asthma therapy, recommending strong coffee as a remedy for asthma symptoms.⁽³⁾ Some time afterwards, in 1860, Dr Henry Hyde Salter, who was also asthmatic, agreed that strong coffee would be the best available therapy for asthma.⁽³⁾ In 1900, Boehringer laboratory began synthesizing theophylline. From the 1930s, theophylline was widely used in the treatment of asthma. Interestingly, even though it has been used by millions of people for decades, the mechanism of the ameliorative effect of theophylline administration in asthma patients is still unclear, as is its proper placement within the hierarchy of asthma therapies. The molecular mechanism apparently involves inhibition of PDEs, antagonism to adenosine receptors, stimulation of catecholamine secretion and inhibition of mediators involved in bronchial inflammation, as well as inhibited intracellular liberation of calcium. Theophylline is a weak and non-selective PDE inhibitor. The PDE enzymes are responsible for cyclic nucleotide degradation, which leads to increased intracellular concentrations of cyclic adenosine 3´,5´-monophosphate (cAMP) and cyclic guanosine 3´,5´-monophosphate (cGMP). However, at therapeutically tolerable concentrations of theophylline, the degree of inhibition was found to be quite small (5–10%).⁽⁴⁾ This finding inspired a search for inhibitors that would be more potent and selective when used in the treatment of asthma. The subsequent development of more potent and less toxic bronchodilators (b₂-agonists) relegated theophylline to third place in the asthma drug race. Theophylline came to be prescribed only for patients with poorly controlled asthma or for whom the cost of medication was an issue.

In 1948, Ahlquist classified adrenergic receptors into two types, alpha and beta, and observed that the latter mediated bronchodilation.⁽⁵⁾ Subsequently, the study of b-receptor specific stimulatory agents began. In 1967, Lands et al. demonstrated that there were two b-receptor classes, b₁ and b₂, and stated that the b₁ receptor was responsible for chronotropic and inotropic cardiac effects and the b₂ receptor was responsible for bronchodilation. Further studies targeted b-receptor selective stimulatory agents. In the 1970s, recognition of the role of inflammation in asthma shifted the axis of treatment toward anti-inflammatory therapy. Corticosteroids became the main pillar in asthma therapy, whereas bronchodilators were prescribed for the control of acute symptoms. The inclusion of inhaled corticosteroids in asthma therapy brought hope that the early use of these drugs would be a "modifying factor for the disease", altering its natural course and, with long-term use, leading to remission. However, a paradox began to come to light. Although inhaled corticosteroids were developed and proven to be fully effective in therapeutic trials, better asthma control was not achieved. Discrepancies between laboratory results and clinical practice were attributed to problems with patient compliance. These problems arose from patient fear of long-term corticosteroid use, the cost of the treatment and stigmas such as "inhalants harm the heart", "there is no cure for asthma", etc. Factors associated with the chronic use of medication in general were also implicated. Later, a combination of inhaled corticosteroid and inhaled long-acting b₂-agonist was recommended for almost all types of asthma. The hope was that this combination would control both the disease and its symptoms and that full remission could be expected. Unfortunately, as before, the opposite proved to be true, altering some crucial definitions and leading to further, more extensive studies of the aspects involved in treatment failure. With the novel concept of bronchial remodeling, remission began to be defined as the absence of asthma symptoms during, rather than after, corticosteroid therapy. The main reasons for asthma treatment failure were once again identified as corticosteroid phobia, negative responses to corticosteroids in certain pathogenic mechanisms, the complexity of the inhalation pathway, and the cost of the medication. Pharmaceutical companies continued the quest for new medication options to broaden the therapeutic spectrum and overcome the difficulties of treatment compliance. Some of these companies began to release newly developed anti-inflammatory drugs (mainly leukotriene receptor antagonists and PDE inhibitors) which had two clear advantages: they were administered orally and they had a much lower potential for producing adverse side effects.

New directions in asthma treatment

The growing understanding of the complex network of genetic, molecular, and cellular mechanisms involved in asthma physiopathology has provided new targets for treatment. Initially, treatment focus centered on the use of bronchodilators: first theophylline, then b₂-adrenergic drugs. Inhaled corticosteroids soon became the drug of choice, whereas bronchodilators played a secondary role. Some time later, a combination of both proved to be the ideal therapy. Prior to that time, airway inflammation and bronchospasm (cause and effect) were the targets of asthma therapy. More recently, various cytokines involved in inflammation processes and airway remodeling came to be the prime targets. Currently, more than simply aiming at cause and effect, researchers have investigated drugs that interfere with the sequence of proinflammatory events and prevent airway alterations (remodeling) from becoming chronic. However, since mechanisms responsible for the development of chronic inflammation and for remodeling may differ, anti-inflammatory drugs might not necessarily prevent or attenuate the remodeling process.

Inflammatory cytokines as a treatment target

Among the various cytokines involved in asthma pathogenesis, chemokines have deserved special attention. These are proteins that can induce migration of specific leukocyte subgroups to the site of the inflammation, causing it to spread. Since they play a critical role in provoking cellular inflammation, they are potential targets for therapeutic intervention. So far, 28 chemokines have been identified and are classified as either a - or b-type.⁽⁷⁾ The first stage in leukocyte recruitment involves the activation of integrins, which are molecules on the leukocyte membrane that mediate leukocyte adherence to endothelial cells and to extracellular matrix (ECM) proteins. After that, chemokines cause the adhered leukocytes to migrate across the endothelium and the ECM.^(8,9) In asthma patients, some b-chemokines seem to attract eosinophils, mast cells and T lymphocytes to the airways.⁽¹⁰⁾ The understanding of the roles of various cytokines in atopic diseases has become the basis for new therapeutic options involving the inhibition of these cytokines or of their effects. The main targets for this asthma therapy are proinflammatory cytokines such as the interleukins (IL-5, IL-4, and IL-13) and tumor necrosis factor alpha (TNF-a ). The therapeutic value of cytokines with anti-inflammatory effects, such as IL-10, IL-12 and interferon-gamma (IFN-g ), has also been evaluated. Other studies have been carried out involving transcription factor inhibitors,^(11-13) mitogen-activated protein kinase,⁽¹⁴⁾ cellular adhesion blockers, prostaglandin inhibitors,^(15-17) platelet-activating factor antagonists,^(18,19) phospholipase inhibitors,^(20,21) bradykinin antagonists,^(22-24) antioxidants,^(25,26) adenosine antagonists,^(27-29) nitric oxide synthase inhibitors,^(30,31) endothelin antagonists,⁽³²⁾ eosinophil basic protein inhibitors,^(33-35) or inflammatory enzyme inhibitors.^(36-38) Initial results of most studies of these cytokines do not define their therapeutic value or determine whether asthma patients would benefit from treatment with cytokines.⁽³⁹⁾

Remodeling as a treatment target

Remodeling is a dynamic process which can occur in any organ and may do more than simply return an organ to its original structure ("model again"), but may also effect profound changes. Huber and Koessler, in the 1920s, were the first to use the term bronchial remodeling (BR) to describe structural changes to the airways of asthmatic patients.⁽⁴⁰⁾ Their observations were later confirmed.⁽⁴¹⁾ However, it was only in the mid-1980s when such changes were associated with asthma severity and bronchial hyperresponsiveness (BHR).^(42-46) Lung architecture remodeling is now considered a marker for conditions such as alveolar wall destruction (in emphysema), intra-alveolar fibrosis (in idiopathic pulmonary fibrosis), bronchiectasis (in cystic fibrosis), cavitation (in tuberculosis), and sub-epithelial fibrosis (in asthma). All of these pathological changes include modifications to the lung ECM. Matrix metalloproteinases (MMPs), which are able to cleave structural proteins such as collagen fibers and elastin fibers, are involved in this process. These MMPs belong to a family of neutral proteinases that are thought to play important roles in the pathological processes of the lungs. One, MMP-9, has been studied in asthma and other lung diseases such as cancer, chronic obstructive pulmonary disease (COPD), interstitial lung disease, acute pulmonary injury, ventilator-associated lung injury, pulmonary hypertension and pneumonia. The main MMP-9 circulating inhibitor is a₂-macroglobulin, and its inhibitors in tissues are called tissue inhibitors of matrix metalloproteinases (TIMPs).⁽⁴⁷⁾ Apparently, the BR seen in asthma patients results from the interaction between TIMP-1 and MMP-9.^(48,49)

There is evidence that asthma begins in the womb. According to studies involving human cohorts, asthma susceptibility is mainly determined during fetal development and within the first 3 to 5 years of life.⁽⁵⁰⁾ Genetic and environmental factors interact during this crucial period of pulmonary development and growth, defining the structure of the lungs and the functions of the airways. Changes during this critical period make airways predisposed to airborne allergen sensitization and more susceptible to environment pollutants.⁽⁵¹⁾ The airways of asthmatic patients respond in exaggerated ways to a wide variety of environmental factors. This phenomenon is known as BHR (bronchial hyperresponsiveness) and is the result of inflammatory responses and airway structural changes (remodeling) in asthma. Epithelial injury, deposition of extracellular matrix proteins, goblet cell metaplasia, smooth muscle cell hypertrophy and hyperplasia, as well as increased vascularization and enervation of bronchi (among other abnormalities) are known collectively as BR (bronchial remodeling) and represent irreversible asthma-related changes to the airways. It is not clear yet whether BR is a consequence of the inflammatory response or whether it occurs simultaneously, but various structural elements of the airways of asthmatic patients become altered and produce cytokines, growth factors, and mediators which may amplify and prolong the inflammatory response. Even if BR is interpreted as a response to intermittent inflammatory stimuli and to the presence of a large number of active proinflammatory cells in the bronchial tubes, genetic predisposition, as well as the presence of resident and structural cells, might also take part in asthma pathogenesis. The Th2 lymphocyte and its cytokines, especially IL-4 and IL-13, make binomial distributions of inflammation and remodeling even more complex and may be responsible for some changes in the BR, including goblet cell metaplasia, hypersecretion of mucus, subepithelial fibrosis, and smooth muscle proliferation.^(52,53) It is possible that, because they modulate lung tissue properties, the mechanisms of these proteins actually help determine the asthma phenotype. This would support the theory that asthma is the result of an abnormality occurring during lung maturation, and that, due to this abnormality, T cells become polarized to the Th2 phenotype.⁽⁵⁴⁾

Role of phosphodiesterase-4 inhibitors in asthma treatment

According to some studies, asthma progresses and worsens with the passage of time.^(55,56) Since there are no long-term (> 5 years) prospective studies, the efficacy of anti-inflammatory treatment in the natural course of asthma is still being debated in the literature. There are indications that early intervention with inhaled corticosteroids is advantageous, delaying pulmonary function impairment or reducing BHR in children and adults.^(57-60) However, these effects appear to be incomplete and transitory.⁽⁶¹⁾ To date, there is no direct evidence that early intervention with anti-inflammatory therapy reduces the persistence of airway inflammation. Adults who suffered from persistent asthma in childhood present with reduced pulmonary function⁽⁶²⁾ and increased bronchial responsiveness,⁽⁶³⁾ regardless of whether asthma symptoms subside or not. Asthma may cause serious and irreversible chronic airway obstruction⁽⁶⁴⁾ and may impair lung development.⁽⁶⁵⁾

After the importance of BR in asthma was recognized, studies attempting to develop drugs to prevent BR proliferated. The effects of corticosteroids used against asthma-related BR have yet to be established.⁽⁶⁶⁾ The capacity of long-term inhaled corticoid therapy to reverse basement membrane thickening is still being questioned.^(67-70) On the other hand, inhaled corticosteroids seem to reduce tenascin in the reticular basement membrane.⁽⁷¹⁾ Such a reduction would be beneficial. Although the usefulness of corticosteroids in asthma treatment is undeniable, their role in BR prevention has not been established in the literature.

Because of the inflammatory basis of asthma and the participation of various cytokines in asthma physiopathology, many researchers have been attempting to develop new anti-inflammatory drugs as effective as, but with less side effects than, corticosteroids. In this context, PDE4 inhibitors have been studied. This enzyme degrades the cyclic nucleotides that inhibit cellular activation. It can be said that studies attempting to define the usefulness of PDE4 inhibitors in asthma treatment result from a resurgence in the popularity of theophylline; the review of an old therapy from a new perspective. Since 1957, when the properties of a certain ribonucleotide, then known as cyclic adenosine but later renamed cyclic adenosine 3´,5´-monophosphate (cAMP), were described,⁽⁷²⁾ cyclic nucleotides and PDEs have been the focus of interest in asthma treatment. As it became evident that cyclic nucleotides were important messengers of cellular signaling and also played a major role in homeostasis, PDE-inhibitor regulation of these processes was more extensively investigated.^(73,74) The immunomodulator properties of cAMP and the anti-inflammatory potential of PDE inhibitors were demonstrated. So far, at least 5 isoenzyme families have been identified, classified by substratum specificity. However, developmental studies of selective inhibitors⁽⁷⁵⁾ and studies of molecular cloning indicate that 7 other families exist. Moreover, isoenzymes modulate various genetic variants, suggesting that there may be more than 15 different PDEs,⁽⁷⁶⁾ the concentrations of which vary depending upon the type of tissue.^(77,78) Some (PDE3, PDE4 and PDE5) seem to be more important in smooth muscle relaxation.^(12,79,80) In inflammatory cells, including mast cells, eosinophils, macrophages, T lymphocytes and structural cells, PDE4 is predominant.⁽⁸¹⁾ Due to this predominance, and to higher PDE4 concentrations in the cells of atopic patients, PDE4 inhibitors that had been proven safe were targeted as possible options for asthma treatment. When PDEs are inhibited, cellular levels of cAMP increase, resulting in smooth muscle relaxation and potentiation of the bronchodilator effect of b -agonists.

Since PDE4 is the predominant PDE in inflammatory cells, it was believed that its inhibition would have an anti-inflammatory effect, which would be useful in asthma treatment. In various animal studies of asthma, some PDE4 inhibitors reduced bronchoconstriction, antigen-induced eosinophil infiltration and local cytokine production, as well as inducing eosinophil apoptosis and reducing eosinophil infiltration after allergen challenge, thereby reducing BHR.^(82-85)

Initially, most of the PDE4 inhibitors tested produced intolerable side effects, most notably nausea, vomiting, and headache (the same side effects associated with theophylline use). Due to the possibility that a particular PDE4 subgroup is being inhibited, a search has been initiated for more selective subgroup inhibitors that would be anti-inflammatory but not produce such adverse side effects. In addition, it is possible that the vomiting is a result of the inhibitor binding to a specific receptor on the enzyme.⁽⁸⁶⁾ These findings have propelled the search for new PDE4 inhibitors that are free of such side effects. Some of the second-generation PDE4 inhibiting drugs have shown promise, leading us to believe that another group of effective treatments for asthma will be available soon.^(87,88) An in vitro study involving two selective PDE4 inhibitors, namely rolipram and cilomilast, revealed that both are able to suppress fibroblast activity, effectively blocking bronchial remodeling.⁽⁸⁹⁾

A double-blind placebo-controlled trial of cilomilast showed that the drug is well tolerated and that it ensures significant clinical improvement and maintenance of pulmonary function in asthmatic patients.⁽⁹⁰⁾ Another second-generation PDE4 inhibitor, roflumilast, is also well tolerated, suppresses late asthmatic response to allergen challenge and reduces pulmonary function impairment in cases of exercise-induced asthma.^(91,92) Another second-generation PDE4 inhibitor, BAY 19-8004, has so far only been tested in animals but may also represent an advance in asthma treatment.⁽⁹³⁾

Research continues in the search for drugs that are effective against remodeling and bronchial inflammation and can be safely used. The results of this research suggest that new drugs, among them PDE inhibitors, may become available in the near future. If their positive effects on remodeling and on inflammatory cytokines are confirmed and they prove to be well tolerated, PDE inhibitors will represent an evolution in the treatment of asthma.

Referências

Submitted: 12/5/03. Accepted, after revision: 5/8/03.

* Study performed in the Respiratory Physiology Laboratory, Pulmonary Investigation Section, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro. Financial Support: Pronex-MCT (Group Excellence Program-Department of Science and Technology, CNPq (National Council of Scientific and Technological Development) and Faperj (Carlos Chagas Filho Research Support Foundation, State of Rio de Janeiro).

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Publication Dates

• Publication in this collection
  12 May 2004
• Date of issue
  Dec 2003

History

• Accepted
  05 Aug 2003
• Received
  12 May 2003