Biomedical subjects

Maria G Belvisi

Publications and source records attributed to Maria G Belvisi.

At least 19 recordsLinked to original sources

PubMed2006

Role of matrix metalloproteinases in the inflammatory response in human airway cell-based assays and in rodent models of airway disease.

Since the discovery of the first matrix metalloproteinase (MMP), this ever-growing family of proteinases has been the subject of intense research. Although it was initially believed that MMPs were solely involved in matrix turnover and degradation, there are now data suggesting MMPs are actively involved in the inflammatory process. In previous studies, we have demonstrated an increase in MMP expression in human cell-based assays and in preclinical rat models of airway inflammation. Therefore, the aim of this study was to characterize the role of MMPs in these models by profiling the impact of a broad-spectrum MMP inhibitor. In lipopolysaccharide (LPS)-stimulated THP-1 cells and primary human lung tissue macrophages, the MMP inhibitor had no significant effect on the release of tumor necrosis factor-alpha, interleukin (IL)-8, IL-1 beta, growth-regulated oncogene-alpha, macrophage inflammatory protein-1 alpha, or IL-6 whereas dexamethasone has a significant impact on all cytokines from both cell types. Similarly, in the more biologically complex LPS-driven rat model of airway inflammation, the MMP inhibitor did not have an impact on mediator release and cellular burden. The compound did, however, significantly reduce levels of lung MMP-9. Furthermore, in a "disease" model, the compound did not affect cellular inflammation but did significantly reduce elastase-induced experimental emphysema. In summary, these data demonstrate for the first time that MMPs do not play a role in the increase in inflammatory mediators or cellular burden observed in these preclinical models. However, they do appear to be involved in the elastase-driven breakdown of airway structure, which is not due to a direct effect of the stimulus.

Animals↗

PubMed2006

IkappaB kinase-2-independent and -dependent inflammation in airway disease models: relevance of IKK-2 inhibition to the clinic.

Nuclear factor kappaB (NF-kappaB) is a transcription factor believed to be central in the expression of numerous inflammatory genes and the pathogenesis of many respiratory diseases. We have previously demonstrated increased NF-kappaB pathway activation in a steroid-sensitive animal model of lipopolysaccharide (LPS)-driven airway inflammation. It is noteworthy that this phenomenon was not observed in a steroid-insensitive model of elastase-induced inflammation in the rat. The aim of this study was to gather further evidence to suggest that these similar profiles of neutrophilic inflammation can be NF-kappaB-dependent or -independent by determining the impact of an IkappaB kinase-2 (IKK-2) inhibitor, 2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide (TPCA-1). In the LPS model, TPCA-1 blocked the increase in NF-kappaB DNA binding, a marker of NF-kappaB pathway activation. This inhibition was associated with a reduction in inflammatory mediator release [tumor necrosis factor alpha (TNFalpha)/interleukin-1beta (IL-1beta)/matrix metalloproteinase-9 (MMP-9)] and lung inflammatory cell burden (neutrophilia/eosinophilia). These data were paralleled with a steroid and in human cell based assays. In the elastase-driven inflammation model, in which our group has previously failed to measure an increase in NF-kappaB DNA binding, neither TPCA-1 nor the steroid, affected mediator release (IL-1beta/MMP-9) or cellular burden (neutrophilia/lymphomononuclear cells). This is the first study to examine the effect of an IKK-2 inhibitor in well validated models that mimic aspects of the inflammatory lesion evident in diseases such as COPD. In conclusion, we have demonstrated that animal models with similar profiles of airway inflammation can be IKK-2 inhibitor/steroid-sensitive or -insensitive. If both profiles of inflammation exist in the clinic, then this finding is extremely exciting and may lead to greater understanding of disease pathology and the discovery of novel anti-inflammatory targets.

Amides↗

PubMed2006

Peroxisome proliferator-activated receptor gamma agonists as therapy for chronic airway inflammation.

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-activated transcription factor belonging to the nuclear hormone receptor superfamily. PPARgamma regulates several metabolic pathways by binding to sequence-specific PPAR response elements in the promoter region of target genes, including lipid biosynthesis and glucose metabolism. Synthetic PPARgamma agonists have been developed, such as the thiazolidinediones rosiglitazone and pioglitazone. These act as insulin sensitizers and are used in the treatment of type 2 diabetes. Recently however, PPARgamma ligands have been implicated as regulators of cellular inflammatory and immune responses. They are thought to exert anti-inflammatory effects by negatively regulating the expression of pro-inflammatory genes. Several studies have demonstrated that PPARgamma ligands possess anti-inflammatory properties and that these properties may prove helpful in the treatment of inflammatory diseases of the airways. This review will outline the anti-inflammatory effects of synthetic and endogenous PPARgamma ligands and discuss their potential therapeutic effects in animal models of inflammatory airway disease.

Animals↗

PubMed2005

Second-generation inhibitors demonstrate the involvement of p38 mitogen-activated protein kinase in post-transcriptional modulation of inflammatory mediator production in human and rodent airways.

The exact role of p38 mitogen-activated protein kinase (MAPK) in the expression of inflammatory cytokines is not clear; it may regulate transcriptionally, post-transcriptionally, translationally, or post-translationally. The involvement of one or more of these mechanisms has been suggested to depend on the particular cytokine, the cell type studied, and the specific stimulus used. Interpretation of some of the published data is further complicated by the use of inhibitors such as 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole (SB 203580) used at single, high concentrations. The aim of this study was to determine the impact of two second-generation p38 MAPK inhibitors on the expression of a range of inflammatory cytokines at the gene and protein levels in human cultured cells. Similar assessment of the impact of these compounds on inflammatory cytokine expression in a preclinical in vivo model of airway inflammation was performed. The results in THP-1 cells and primary airway macrophages clearly show that protein expression is inhibited at much lower concentrations of inhibitor than are needed to impact on gene expression. In the rodent model, both compounds, at doses that cause maximal inhibition of cellular recruitment, inhibit tumor necrosis factor alpha (TNFalpha) protein production without impacting on nuclear factor kappaB pathway activation or TNFalpha gene expression. In summary, the data shown here demonstrate that, although at high compound concentrations there is some level of transcriptional regulation, the predominant role of p38 MAPK in cytokine production is at the translational level. These data question whether the effect of p38 inhibitors on gene transcription is related to their potential therapeutic role as anti-inflammatory compounds.

Animals↗

PubMed2005

Ikappa-B kinase-2 inhibitor blocks inflammation in human airway smooth muscle and a rat model of asthma.

RATIONALE: Nuclear factor (NF)-kappaB is a transcription factor known to regulate the expression of many inflammatory genes, including cytokines, chemokines, and adhesion molecules. NF-kappaB is held inactive in the cytoplasm, bound to I-kappaB. The removal of I-kappaB, via the actions of inhibitor of kappaB (I-kappaB) kinase-2 (IKK-2), allows NF-kappaB to enter the nucleus. OBJECTIVES: To determine the impact of inhibiting IKK-2 on in vitro and in vivo models of airway inflammation. METHODS: The effect of inhibiting IKK-2 was assessed in stimulated, cultured, primary human airway smooth muscle cells and an antigen-driven rat model of lung inflammation. MEASUREMENTS: The release of cytokines from cultured cells and inflammatory cytokine expression and cellular burden in the lung were determined. MAIN RESULTS: Two structurally distinct molecules and dominant negative technology demonstrated that inhibition of IKK-2 activity completely blocked cytokine release from cultured cells, whereas the two glucocorticoid comparators had limited impact on granulocyte colony-stimulating factor, interleukin 8, and eotaxin release. In addition, in an in vivo antigen-driven model of airway inflammation, the IKK-2 inhibitor blocked NF-kappaB nuclear translocation, which was associated with a reduction in inflammatory cytokine gene and protein expression, airway eosinophilia, and late asthmatic reaction, similar in magnitude to that obtained with budesonide. CONCLUSION: This study demonstrates that inhibiting IKK-2 results in a general reduction of the inflammatory response in vitro and in vivo. Compounds of this class could have therapeutic utility in the treatment of asthma and may, in certain respects, possess a beneficial efficacy profile compared with that of a steroid.

Amides↗

PubMed2005

Preclinical profile of ciclesonide, a novel corticosteroid for the treatment of asthma.

Ciclesonide is a novel, inhaled corticosteroid under development for the treatment of asthma. Ciclesonide is activated to desisobutyryl-ciclesonide (des-CIC) in the lungs to provide potent anti-inflammatory activity. The investigations herein compared the activity of ciclesonide with fluticasone in animal models to assess efficacy/potency as an airway anti-inflammatory and the comparative side effect potential to consider the therapeutic ratio of each compound. In radioligand binding assays, des-CIC and fluticasone exhibited comparable high-affinity binding to the glucocorticoid receptor, whereas ciclesonide exhibited 100-fold less binding affinity. In the Brown Norway rat model of antigen-induced airway eosinophilia and in a model of Sephadex-induced lung edema, ciclesonide and fluticasone exhibited comparable efficacy. Interestingly, following 7-day intratracheal administration, ciclesonide elicited adrenal involution with a potency that was 44-fold less than fluticasone. Furthermore, ciclesonide was 22-fold less active than fluticasone in eliciting hypoplasia of the femoral growth plate. These data support the concept that ciclesonide acts as a parent compound that, when delivered to the airways, can be transformed into the active metabolite des-CIC, resulting in local high anti-inflammatory activity. Furthermore, ciclesonide possesses equivalent anti-inflammatory efficacy through pulmonary activation with a significantly improved safety profile in preclinical animal models compared with fluticasone.

Adrenal Glands↗

PubMed2005

Steroid-resistant inflammation in a rat model of chronic obstructive pulmonary disease is associated with a lack of nuclear factor-kappaB pathway activation.

RATIONALE: Emphysema is one component of chronic obstructive pulmonary disease (COPD), a respiratory disease currently increasing in prevalence worldwide. The mainstay therapy adopted to treat patients with COPD is glucocorticoids; unfortunately, this treatment has limited impact on disease symptoms or underlying airway inflammation. OBJECTIVE: There is an urgent need to develop therapies that modify both the underlying inflammation, thought to be involved in disease progression, and the structural changes in the emphysematous lung. METHODS: We have characterized an elastase-driven model of experimental emphysema in the rat that demonstrates COPD-like airway inflammation and determined the impact of a clinically relevant glucocorticoid. MEASUREMENTS AND MAIN RESULTS: We observed an increase in lung neutrophils, lymphomononuclear cells, mucus production, and inflammatory cytokines. Also present were increases in average air space area, which are associated with emphysema-like changes in lung function, such as increased residual volume and decreased flow; these increases in area were maintained for up to 10 weeks. In addition, we observed that elastase-induced airway neutrophilia is steroid resistant. Interestingly, the inflammation observed after elastase administration was found to be temporally associated with a lack of nuclear factor-kappaB pathway activation. This apparent nuclear factor-kappaB-independent inflammation may explain why treatment with a glucocorticoid was ineffective in this preclinical model and could suggest parallels in the steroid-resistant human disease. CONCLUSION: We believe that this model, in addition to its suitability for testing therapies that may modify existing emphysema, could be useful in the search for new therapies to reduce the steroid-resistant airway inflammation evident in COPD.

Algorithms↗

PubMed2005

Prostanoid receptor expression by human airway smooth muscle cells and regulation of the secretion of granulocyte colony-stimulating factor.

The prostanoid receptors on human airway smooth muscle cells (HASMC) that augment the release by IL-1beta of granulocyte colony-stimulating factor (G-CSF) have been characterized and the signaling pathway elucidated. PCR of HASM cDNA identified products corresponding to EP(2), EP(3), and EP(4) receptor subtypes. These findings were corroborated at the protein level by immunocytochemistry. IL-1beta promoted the elaboration of G-CSF, which was augmented by PGE(2). Cicaprost (IP receptor agonist) was approximately equiactive with PGE(2), whereas PGD(2), PGF(2alpha), and U-46619 (TP receptor agonist) were over 10-fold less potent. Neither SQ 29,548 nor BW A868C (TP and DP(1) receptor antagonists, respectively) attenuated the enhancement of G-CSF release evoking any of the prostanoids studied. With respect to PGE(2), the EP receptor agonists 16,16-dimethyl PGE(2) (nonselective), misoprostol (EP(2)/EP(3) selective), 17-phenyl-omega-trinor PGE(2) (EP(1) selective), ONO-AE1-259, and butaprost (both EP(2) selective) were full agonists at enhancing G-CSF release. AH 6809 (10 microM) and L-161,982 (2 microM), which can be used in HASMC as selective EP(2) and EP(4) receptor antagonists, respectively, failed to displace to the right the PGE(2) concentration-response curve that described the augmented G-CSF release. In contrast, AH 6809 and L-161,982 in combination competitively antagonized PGE(2)-induced G-CSF release. Augmentation of G-CSF release by PGE(2) was mimicked by 8-BrcAMP and abolished in cells infected with an adenovirus vector encoding an inhibitor protein of cAMP-dependent protein kinase (PKA). These data demonstrate that PGE(2) facilitates G-CSF secretion from HASMC through a PKA-dependent mechanism by acting through EP(2) and EP(4) prostanoid receptors and that effective antagonism is realized only when both subtypes are blocked concurrently.

Adolescent↗

PubMed2004

Theobromine inhibits sensory nerve activation and cough.

Cough is a common and protective reflex, but persistent coughing is debilitating and impairs quality of life. Antitussive treatment using opioids is limited by unacceptable side effects, and there is a great need for more effective remedies. The present study demonstrates that theobromine, a methylxanthine derivative present in cocoa, effectively inhibits citric acid-induced cough in guinea-pigs in vivo. Furthermore, in a randomized, double-blind, placebo-controlled study in man, theobromine suppresses capsaicin-induced cough with no adverse effects. We also demonstrate that theobromine directly inhibits capsaicin-induced sensory nerve depolarization of guinea-pig and human vagus nerve suggestive of an inhibitory effect on afferent nerve activation. These data indicate the actions of theobromine appear to be peripherally mediated. We conclude theobromine is a novel and promising treatment, which may form the basis for a new class of antitussive drugs.

Adult↗

PubMed2004

E-ring 8-isoprostanes are agonists at EP2- and EP4-prostanoid receptors on human airway smooth muscle cells and regulate the release of colony-stimulating factors by activating cAMP-dependent protein kinase.

8-Isoprostanes are bioactive lipid mediators formed via the nonenzymatic peroxidation of arachidonic acid by free radicals and reactive oxygen species. However, their cognate receptors, biological actions, and signaling pathways are poorly studied. Here, we report the effect of a variety of E- and Falpha-ring 8-isoprostanes on the release of granulocyte/macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) from human airway smooth muscle (HASM) cells stimulated with interleukin-1beta (IL-1beta). The elaboration of GM-CSF and G-CSF by IL-1beta was inhibited and augmented, respectively, in a concentration-dependent manner by 8-iso-prostaglandin (PG) E(1) and 8-iso-PGE(2), but not by 8-iso-PGF(1alpha), 8-iso-PGF(2alpha), and 8-iso-PGF(3)alpha. AH 6809 (6-isopropoxy-9-oxoxanthine-2-carboxylic acid), an EP(1)-/EP(2)-/DP-receptor blocking drug, antagonized the inhibitory effect of 8-iso-PGE(1) and 8-iso-PGE(2) on GM-CSF output with an affinity consistent with an interaction at prostanoid receptors of the EP(2)-subtype. In contrast, the facilitation by 8-iso-PGE(1) and 8-iso-PGE(2) of G-CSF release was unaffected by AH 6809 and the selective EP(4)-receptor antagonist L-161,982 [4'-[3-butyl-5-oxo-1-(2-trifluoromethyl-phenyl)-1,5-dihydro-[1,2,4]triazol-4-ylmethyl]-biphenyl-2-sulfonic acid (3-methyl-thiophene-2-carbonyl)-amide]. However, when used in combination, AH 6809 and L-161,982 displaced 5-fold to the right the 8-iso-PGE and 8-iso-PGE concentration-response curves. The opposing (1)effect of E-ring (2)8-isoprostanes on GM-CSF and G-CSF release was mimicked by 8-bromo-cAMP and abolished in cells infected with an adenovirus vector encoding an inhibitor protein of cAMP-dependent protein kinase (PKA). Together, these data demonstrate that E-ring 8-isoprostanes regulate the secretion of GM-CSF and G-CSF from HASM cells by a cAMP- and PKA-dependent mechanism. Moreover, antagonist studies revealed that 8-iso-PGE(1) and 8-iso-PGE(2) act solely via EP(2) -receptors to inhibit GM-CSF release, whereas both EP(2)- and EP(4)-receptor subtypes positively regulate G-CSF output.

Adolescent↗

PubMed2004

Nitric oxide as a noninvasive biomarker of lipopolysaccharide-induced airway inflammation: possible role in lung neutrophilia.

Lipopolysaccharide (LPS) is known to generate nitric oxide (NO) in the airway through the activation of nitric-oxide synthase (NOS). The functional consequences of this on the inflammatory response are not clear, with conflicting data published. In the clinic, exhaled NO (ex-NO) is used as a noninvasive biomarker to assess the extent of airway inflammation. It is proposed that monitoring levels of ex-NO could be a useful guide to determining the effectiveness of disease modifying therapies. The aim was, using pharmacological tools, to determine the role of NO in an aerosolized LPS-driven animal model of airway inflammation by assessment of ex-NO, neutrophilia, and inflammatory biomarkers, using a nonselective NOS inhibitor, N(G)-nitro-l-arginine methyl ester (l-NAME), and a selective inducible NOS (iNOS) inhibitor, N-3 (aminomethyl)benzyl)acetamidine (1400W). Real-time mRNA analysis of the lung tissue indicated an increased gene expression of iNOS following LPS challenge with minimal impact on constitutive NOS isoforms. LPS induced an increase in ex-NO, which appeared to correlate with the increase in iNOS gene expression and airway neutrophilia. Treatment with l-NAME and 1400W resulted in comparable reductions in ex-NO, a reduction in airway neutrophilia, but had little impact on a range of inflammatory biomarkers. This study indicates that the LPS-induced rise in ex-NO is due to enhanced iNOS activity and that NO has a role in airway neutrophilia. Additionally, it appears using ex-NO as a guide to monitoring airway inflammation may have some use, but data should be interpreted with caution when assessing therapies that may directly impact on NO formation.

Amidines↗

PubMed2004

Identification in human airways smooth muscle cells of the prostanoid receptor and signalling pathway through which PGE2 inhibits the release of GM-CSF.

1. The prostanoid receptor(s) on human airways smooth muscle (HASM) cells that mediates the inhibitory effect of PGE(2) on interleukin (IL)-1 beta-induced granulocyte/macrophage colony-stimulating factor (GM-CSF) release has been classified. 2. IL-1 beta evoked the release of GM-CSF from HASM cells, which was suppressed by PGE(2), 16,16-dimethyl PGE(2) (nonselective), misoprostol (EP(2)/EP(3)-selective), ONO-AE1-259 and butaprost (both EP(2)-selective) with pIC(50) values of 8.61, 7.13, 5.64, 8.79 and 5.43, respectively. EP-receptor agonists that have selectivity for the EP(1)-(17-phenyl-omega-trinor PGE(2)) and EP(3)-receptor (sulprostone) subtypes as well as cicaprost (IP-selective), PGD(2), PGF(2 alpha) and U-46619 (TP-selective) were poorly active or inactive at concentrations up to 10 microM. 3. AH 6809, a drug that can be used to selectively block EP(2)-receptors in HASM cells, antagonised the inhibitory effect of PGE(2), 16,16-dimethyl PGE(2) and ONO-AE1-259 with apparent pA(2) values of 5.85, 6.09 and 6.1 respectively. In contrast, the EP(4)-receptor antagonists, AH 23848B and L-161,982, failed to displace to the right the concentration-response curves that described the inhibition of GM-CSF release evoked by PGE(2) and ONO-AE1-259. 4. Inhibition of GM-CSF release by PGE(2) and 8-Br-cAMP was abolished in cells infected with an adenovirus vector encoding an inhibitor protein of cAMP-dependent protein kinase (PKA) but not by H-89, a purported small molecule inhibitor of PKA. 5. We conclude that prostanoid receptors of the EP(2)-subtype mediate the inhibitory effect of PGE(2) on GM-CSF release from HASM cells by recruiting a PKA-dependent pathway. In addition, the data illustrate that caution should be exercised when using H-89 in studies designed to assess the role of PKA in biological processes.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed2004

E-ring 8-isoprostanes inhibit ACh release from parasympathetic nerves innervating guinea-pig trachea through agonism of prostanoid receptors of the EP3-subtype.

1. In the present study, we examined the effect of E-ring 8-isoprostanes on cholinergic neurotransmission in guinea-pig trachea and identified the receptor(s) involved. As isoprostanes are isomeric with prostaglandins, PGE(2) and sulprostone (a selective EP(3)-receptor agonist) were examined in parallel. 2. 8-Iso-PGE(1), 8-iso-PGE(2) (0.1 nm-1 microM), sulprostone (1 nm-1 microM) and PGE(2) (1 microM) suppressed EFS-evoked [(3)H]ACh release from guinea-pig trachea in a concentration-dependent manner, producing 39.5, 53.9, 61.2 and 59.9% inhibition, respectively, at 1 microM. It should be noted that an established maximum effective concentration was not determined. 3. Neither SQ 29,548 (1 microm; a TP-receptor antagonist) nor AH 6809 (10 microM; an EP(1)-/EP(2)-/DP-receptor antagonist) reversed the inhibitory effect of these compounds. 4. L-798,106, a novel and highly selective EP(3)-receptor antagonist, produced a parallel shift to the right of the concentration-response curves that described the inhibitory action of sulprostone on EFS-evoked contractile responses in guinea-pig vas deferens (an established EP(3)-receptor-expressing tissue), from which a mean pA(2) of 7.48 was derived. On guinea-pig trachea, L-798,106 also antagonised sulprostone-induced inhibition of EFS-induced twitch responses, with similar potency (mean pA(2)=7.82). 5. The inhibitory effects of 8-iso-PGE(1), 8-iso-PGE(2), sulprostone and PGE(2) on EFS-induced [(3)H]ACh release was blocked by L-798,106 at a concentration (10 microM) that binds only weakly to human recombinant EP(1)-, EP(2)- and EP(4)-receptor subtypes expressed in HEK 293 cells. 6. These data suggest that E-ring 8-isoprostanes, PGE(2) and sulprostone inhibit EFS-evoked [(3)H]ACh release from cholinergic nerves innervating guinea-pig trachea, by interacting with prejunctional prostanoid receptors of the EP(3)-subtype.

Acetylcholine↗

PubMed2004

Regulation of inflammatory cell function by corticosteroids.

Different inflammatory cell profiles are observed in the lungs of patients with asthma versus those with chronic obstructive pulmonary disease (COPD). In asthma, several key mediators have been implicated, including tumor necrosis factor-alpha and interleukin (IL)-1beta, together with cytokines derived from type 2 T-helper lymphocytes, such as IL-4, IL-5, and IL-13. In fact, inhibitors of IL-4 and IL-5 show promise as therapeutic agents. In COPD, the predominant inflammatory cell types are CD8(+) T lymphocytes, macrophages, and neutrophils. Glucocorticoids inhibit eosinophils in asthma, neutrophils in COPD and severe asthma, mast cells and basophils in asthma and COPD, and macrophages in COPD. However, it is generally assumed that neutrophils are less sensitive to glucocorticoids than are eosinophils and T cells, and that macrophages from patients with COPD are less sensitive to steroid treatment under certain circumstances. These differences in the responsiveness of activated inflammatory cells may help to explain why inhaled corticosteroid treatment has been more beneficial for patients with asthma than for patients with COPD.

Administration, Inhalation↗

PubMed2004

New anti-inflammatory therapies and targets for asthma and chronic obstructive pulmonary disease.

Asthma and chronic obstructive pulmonary disease (COPD) are diseases of the airways with an underlying inflammatory component. The prevalence and healthcare burden of asthma and COPD is still rising and is predicted to continue to rise in the foreseeable future. Beta-agonists and corticosteroids form the basis of the therapies available to treat asthma. However, the treatments available for COPD, corticosteroids and anticholinergics, reduce the number and severity of exacerbations, but have a limited effect on slowing the progression of the disease. The inflammatory processes underlying the pathology of asthma have received a great deal of attention and more recently, those underlying COPD have begun to be elucidated. This has resulted in the identification of new targets that will allow the development of novel approaches by the pharmaceutical industry, which will be able to focus its efforts in an attempt to provide new and improved therapies to treat these debilitating diseases. The resultant therapies should impinge on the underlying development of these diseases rather than providing symptomatic relief or palliative treatment alone. This review will outline new targets and novel approaches currently under investigation, which may provide opportunities for novel anti-inflammatory therapeutic interventions that slow or halt disease progression in asthma and COPD.

Animals↗

PubMed2004

New advances and potential therapies for the treatment of asthma.

Asthma is a disease of the airways with an underlying inflammatory component. The prevalence and healthcare burden of asthma is still rising and is predicted to continue to rise in the current century. Inhaled beta(2)-adrenoceptor agonists and corticosteroids form the basis of the treatments available to alleviate the symptoms of asthma. There is a need for novel, safe treatments to tackle the underlying inflammation that characterizes asthma pathology. Furthermore, there is a requirement for new treatments to be developed as oral therapy in order to alleviate patient compliance issues, especially in children. A multitude of new approaches and new targets are being investigated, which may provide opportunities for novel therapeutic interventions in this debilitating disease. For simplicity, these approaches can be divided into two categories. The first comprises therapies directed against specific components or steps seen in allergic asthma. By 'components' we mean the key inflammatory cells (T cells [in particular T(h)2], B cells, eosinophils, mast cells, basophils and antigen presenting cells [APC]) and mediators (immunoglobulin E [IgE], cytokines, histamines, leukotrienes and prostanoids) believed to be involved in the chronic inflammation seen in asthma. By 'steps' we mean the allergic response, such as antigen processing and presentation, T(h)2-cell activation, B-cell isotype switching, mast cell involvement and airway remodeling. The other category of novel approaches to disease modification in asthma encompasses general anti-inflammatory therapies including phosphodiesterase 4 (PDE4) inhibitors, p38 mitogen-activated protein kinase (MAPK) inhibitors, peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists, and lipoxins.

Adrenal Cortex Hormones↗

PubMed2003

Inhibition of guinea-pig and human sensory nerve activity and the cough reflex in guinea-pigs by cannabinoid (CB2) receptor activation.

1. There is considerable interest in novel therapies for cough, since currently used agents such as codeine have limited beneficial value due to the associated side effects. Sensory nerves in the airways mediate the cough reflex via activation of C-fibres and RARs. Evidence suggests that cannabinoids may inhibit sensory nerve-mediated responses. 2. We have investigated the inhibitory actions of cannabinoids on sensory nerve depolarisation mediated by capsaicin, hypertonic saline and PGE2 on isolated guinea-pig and human vagus nerve preparations, and the cough reflex in conscious guinea-pigs. 3. The non-selective cannabinoid (CB) receptor agonist, CP 55940, and the selective CB2 agonist, JWH 133 inhibited sensory nerve depolarisations of the guinea-pig vagus nerve induced by hypertonic saline, capsaicin and PGE2. These responses were abolished by the CB2 receptor antagonist SR144528, and unaffected by the CB1 antagonist SR141716A. Similarly, JWH 133 inhibited capsaicin-evoked nerve depolarisations in the human vagus nerve, and was prevented by SR144528. 4. Using a guinea-pig in vivo model of cough, JWH 133 (10 mg kg-1, i.p., 20 min) significantly reduced citric acid-induced cough in conscious guinea pigs compared to those treated with the vehicle control. 5. These data show that activation of the CB2 receptor subtype inhibits sensory nerve activation of guinea-pig and human vagus nerve, and the cough reflex in guinea-pigs, suggesting that the development of CB2 agonists, devoid of CB1-mediated central effects, will provide a new and safe antitussive treatment for chronic cough.

Animals↗

PubMed2003

Dissociation by steroids of eosinophilic inflammation from airway hyperresponsiveness in murine airways.

BACKGROUND: The link between eosinophils and the development of airway hyperresponsiveness (AHR) in asthma is still controversial. This question was assessed in a murine model of asthma in which we performed a dose ranging study to establish whether the dose of steroid needed to inhibit the eosinophil infiltration correlated with that needed to block AHR. METHODS: The sensitised BALB/c mice were dosed with vehicle or dexamethasone (0.01-3 mg/kg) 2 hours before and 6 hours after each challenge (once daily for 6 days) and 2 hours before AHR determination by whole-body plethysmography. At 30 minutes after the AHR to aerosolised methacholine the mice were lavaged and differential white cell counts were determined. Challenging with antigen caused a significant increase in eosinophils in the bronchoalveolar lavage (BAL) fluid and lung tissue, and increased AHR. RESULTS: Dexamethasone reduced BAL and lung tissue eosinophilia (ED50 values of 0.06 and 0.08 mg/kg, respectively), whereas a higher dose was needed to block AHR (ED50 of 0.32 mg/kg at 3 mg/ml methacholine. Dissociation was observed between the dose of steroid needed to affect AHR in comparison with eosinophilia and suggests that AHR is not a direct consequence of eosinophilia. CONCLUSION: This novel pharmacological approach has revealed a clear dissociation between eosinophilia and AHR by using steroids that are the mainstay of asthma therapy. These data suggest that eosinophilia is not associated with AHR and questions the rationale that many pharmaceutical companies are adopting in developing low-molecular-mass compounds that target eosinophil activation/recruitment for the treatment of asthma.

Administration, Inhalation↗