Glucocorticoid Efficacy in Asthma: Is Improved Tissue Remodeling Upstream of Anti-Inflammation

Article · October 2009with31 Reads
DOI: 10.2310/JIM.0b013e3181b91654 · Source: PubMed
Abstract
Synthetic glucocorticoids (GCs), such as prednisone, are among the most widely prescribed drugs worldwide and are used to treat many acute and chronic inflammatory conditions. The current paradigm of GC efficacy is that they are potent anti-inflammatory agents. Decreased inflammation in many disorders is thought to lead to decreased pathological tissue remodeling. However, this model has never been validated. In particular, improvements in inflammation have not been shown to improve the rate of lung function decline in asthma. Herein, we present an alternative paradigm, where GC efficacy is mediated through more successful tissue remodeling, with reduction in inflammation secondary to successful regeneration.
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    • Initial experiments evaluated whether VBP15 restores mitotic synchrony in ALI-differentiated asthmatic airway epithelial cell cultures. This is a relevant question for the asthmatic condition because epithelial mitotic asynchrony is an important biological feature of the disease [8, 10, 18]. Importantly, similar to the effects seen with the traditional glucocorticoid, dexamethasone, VBP15 improved epithelial mitosis in asthmatic airway epithelial cells and promoted appropriate airway epithelial mitotic synchrony after mechanical injury.
    [Show abstract] [Hide abstract] ABSTRACT: Background Mitotic synchrony is the synchronous progression of a population of cells through the cell cycle and is characteristic of non-diseased airway epithelial cells. However, we previously showed that asthmatic airway epithelial cells are characterized by mitotic asynchrony and are pro-inflammatory as a result. Glucocorticoids can induce mitotic synchrony that in turn suppresses the pro-inflammatory state of diseased cells, suggesting a novel anti-inflammatory mechanism of action. Herein, we benchmarked traditional glucocorticoids against the ability of a new clinical-stage dissociative steroidal drug, VBP15, for mitotic resynchronization and associated anti-inflammatory activity in asthmatic airway epithelial cells. Methods Primary airway epithelial cells differentiated at air-liquid interface were exposed to VBP15, dexamethasone or vehicle following in vitro mechanical injury. Basolateral cytokine secretions (TGF-β1, IL-6, IL-10, IL-13, and IL-1β) were analyzed at different time points using cytometric bead assays and mitosis was examined by flow cytometry. Results VBP15 improved mitotic synchrony of proliferating asthmatic cells in air-liquid interface cultures compared to vehicle-exposed cultures. VBP15 also significantly reduced the basolateral secretion of pro-inflammatory (i.e. IL-1β) and pro-fibrogenic cytokines (i.e. TGF-β1) in air-liquid interface-differentiated asthmatic epithelial cultures following mechanical injury. Conclusion VBP15 improves mitotic asynchrony and injury-induced pro-inflammatory and fibrogenic responses in asthmatic airway epithelial cultures with efficacy comparable to traditional glucocorticoids. As it is predicted to show superior side effect profiles compared to traditional glucocorticoids, VBP15 holds potential for treatment of asthma and other respiratory conditions.
    Full-text · Article · Dec 2015
    • In addition, the asthmatic epithelium is inherently inflammogenic and upon injury (e.g. tobacco smoke, viral exposure, mechanical wounding) can release pro-inflammatory cytokines in the absence of inflammatory cells [11,12,13,14,15,16]. Glucocorticoids are among the most prescribed drugs for therapeutic management of a wide variety of acute and chronic inflammatory conditions including lupus, myositis, rheumatoid arthritis, muscular dystrophy, and asthma [17,18,19,20]. Despite their effectiveness, long-term treatment with glucocorticoids is limited by severe side effects including glaucoma, adrenal insufficiency, osteoporosis, cardiomyopathies, short stature, and mood or sleep disturbances [21,22,23,24,25].
    [Show abstract] [Hide abstract] ABSTRACT: Asthma is a chronic inflammatory condition of the lower respiratory tract associated with airway hyperreactivity and mucus obstruction in which a majority of cases are due to an allergic response to environmental allergens. Glucocorticoids such as prednisone have been standard treatment for many inflammatory diseases for the past 60 years. However, despite their effectiveness, long-term treatment is often limited by adverse side effects believed to be caused by glucocorticoid receptor-mediated gene transcription. This has led to the pursuit of compounds that retain the anti-inflammatory properties yet lack the adverse side effects associated with traditional glucocorticoids. We have developed a novel series of steroidal analogues (VBP compounds) that have been previously shown to maintain anti-inflammatory properties such as NFκB-inhibition without inducing glucocorticoid receptor-mediated gene transcription. This study was undertaken to determine the effectiveness of the lead compound, VBP15, in a mouse model of allergic lung inflammation. We show that VBP15 is as effective as the traditional glucocorticoid, prednisolone, at reducing three major hallmarks of lung inflammation-NFκB activity, leukocyte degranulation, and pro-inflammatory cytokine release from human bronchial epithelial cells obtained from patients with asthma. Moreover, we found that VBP15 is capable of reducing inflammation of the lung in vivo to an extent similar to that of prednisone. We found that prednisolone-but not VBP15 shortens the tibia in mice upon a 5 week treatment regimen suggesting effective dissociation of side effects from efficacy. These findings suggest that VBP15 may represent a potent and safer alternative to traditional glucocorticoids in the treatment of asthma and other inflammatory diseases.
    Full-text · Article · May 2013
    • It is also worth noting that most animal studies use more-continuous delivery methods (drinking water, chow, subcutaneous pellet) than do clinical studies, and this continuous administration may be more deleterious than the single-dose therapies used clinically in human patients. Recent evidence has shown that pulsed steroids can resynchronize cell cycling and cytokine signaling, leading to decreased inflammation after injury in an asthma cell culture model [18]. Perhaps an optimal GC dosing schedule could help minimize inflammation, whereas other GC dosing schedule would increase it.
    [Show abstract] [Hide abstract] ABSTRACT: Dmd(mdx) (mdx) mice are used as a genetic and biochemical model of dystrophin deficiency. The long-term consequences of glucocorticoid (GC) treatment on dystrophin-deficient skeletal and heart muscle are not yet known. Here we used systematic phenotyping to assess the long-term consequences of GC treatment in mdx mice. Our investigation addressed not only the effects of GC on the disease phenotype but also the question of whether GCs can be used as a positive control for preclinical drug evaluations. We performed nine pre-clinical efficacy trials (treated N = 129, untreated N = 106) of different durations in 9-to-50-week-old dystrophic mdx mice over a 3-year time period using standardized methods. In all these trials, we used either 1 mg/kg body weight of prednisone or 5 mg/kg body weight of prednisolone as positive controls to compare the efficacy of various test drugs. Data from untreated controls and GC-treated mice in the various trials have been pooled and analyzed to assess the effects of GCs on dystrophin-deficient skeletal and cardiac muscles of mdx mice. Our results indicate that continuous GC treatment results in early (e.g., at 50 days) improvements in normalized parameters such as grip strength, motor coordination and maximal in vitro force contractions on isolated EDL muscle, but these initial benefits are followed by a progressive loss of muscle strength after 100 days. We also found a significant increase in heart fibrosis that is reflected in a significant deterioration in cardiac systolic function after 100 days of treatment. Continuous administration of prednisone to mdx mice initially improves skeletal muscle strength, but further therapy result in deterioration of muscle strength and cardiac function associated with enhanced cardiac fibrosis. These results suggest that GCs may not serve as an appropriate positive control for long-term mdx mouse preclinical trials.
    Full-text · Article · Apr 2012
    • The estimated amount of RA in the methanol extract was 0.2%, corroborating a previously published study [12]. An ethnopharmacology survey conducted by our research group, describing plant species used in the folk medicine to treat allergies [7], identified O. gratissimum as one of these plants. To date, however, no scientific study has confirmed this activity.
    [Show abstract] [Hide abstract] ABSTRACT: Allergic asthma has emerged as an important public health problem of urban populations in developed countries. Very often herbal medicine is used to treat this widespread disease, due to the lack of efficacy and the important side effects related to the classical drugs in use. Along this line, Ocimum gratissimum (Og) is a plant widely used in Brazilian folk medicine to treat inflammatory disorders, such as asthma. In the present study we evaluated the immunomodulatory effects of Og and rosmarinic acid (RA, a polyphenolic compound) in a murine model of respiratory allergy induced by the Blomia tropicalis (Bt) mite. The respiratory allergy was induced in A/J mice by administration of Bt extract and the treatment was done using 25, 50 or 100mg/kg of an Og methanolic extract or using 2, 20 or 200mg/kg of RA. We then evaluated the changes induced by these drugs on immunological parameters related to the allergic process, which are up-regulated in this allergic model. The treatment of animals with 100mg/Kg Og and 200mg/Kg RA led to a significant reduction in the numbers of leukocytes/eosinophils in bronchoalveolar lavage (BAL); eosinophil peroxidase activity in BAL; presence of mucus in respiratory tract, histopathological changes in the lung, and IL-4 in BAL. These results suggest that the methanolic extract of Og and the polyphenol RA have therapeutic potential in this murine model of respiratory allergy to a clinically relevant human sensitizer allergen.
    Article · Mar 2012
    • Our results are supported by the findings of Ito et al. [42] that high concentrations dexamethasone (>10 -8 M) produce a time-and concentration-dependent increase in histone acetylation in A549 cells, resulting in the recruitment of the activated transcription complex, and the subsequent increase in the expression of several genes. The direct effect of glucocorticoids on transcript activation occurs through binding and activation glucocorticoid receptors (GR), which results in the translocation of glucocorticoid-receptor complexes to the nucleus and binding to glucocorticoid response elements (GREs) in the promoter region of target genes [43]. GREs are short sequences of DNA within the promoter that are able to bind glucocorticoid-receptor complexes and therefore regulate gene transcription.
    [Show abstract] [Hide abstract] ABSTRACT: "Phosphatase and tensin homolog deleted on chromosome 10" (PTEN) is mostly considered to be a cancer-related gene, and has been suggested to be a new pathway of pathogenesis of asthma. The purpose of this study was to investigate the effects of the glucocorticoid, dexamethasone, on PTEN regulation. OVA-challenged mice were used as an asthma model to investigate the effect of dexamethasone on PTEN regulation. Immunohistochemistry was used to detect expression levels of PTEN protein in lung tissues. The human A549 cell line was used to explore the possible mechanism of action of dexamethasone on human PTEN regulation in vitro. A luciferase reporter construct under the control of PTEN promoter was used to confirm transcriptional regulation in response to dexamethasone. PTEN protein was found to be expressed at low levels in lung tissues in asthmatic mice; but the expression was restored after treatment with dexamethasone. In A549 cells, human PTEN was up-regulated by dexamethasone treatment. The promoter-reporter construct confirmed that dexamethasone could regulate human PTEN transcription. Treatment with the histone deacetylase inhibitor, TSA, could increase PTEN expression in A549 cells, while inhibition of histone acetylase (HAT) by anacardic acid attenuated dexamethasone-induced PTEN expression. Based on the data a new mechanism is proposed where glucocorticoids treat asthma partly through up-regulation of PTEN expression. The in vitro studies also suggest that the PTEN pathway may be involved in human asthma.
    Full-text · Article · Apr 2011
  • [Show abstract] [Hide abstract] ABSTRACT: Despite the continuous increase in the prevalence of asthma in the most underdeveloped parts of the world, nowadays, we can generally speak of a better understanding and management of this disease. The remarkable role played by the inflammatory process in asthmatic patients is well known. The aim of most asthma guidelines is to suppress inflammatory process with a combination of anti-inflammatory drugs and immunotherapy. The management of asthma in children is a challenge because of their inability to express warning signs and seek medical attention in a timely manner. Unlike adults, asthmatic children must rely on their parents or caregivers for the administration of asthma medications. This inability to carry and self-administer asthma drugs may increase the risk of non-compliance. Glucocorticosteroids, the most important drugs for patients with asthma, are associated with an increased level of side effects and compliance issues mostly in children. In an attempt to solve that dilemma, emphasis is being placed on the modification of current management tactics and the introduction of other drugs. This review presents more recent patent therapies for the management of asthma in children.
    Article · Jan 2011
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