Chronic Inflammatory Asthma Research Articles

Platelet aggregation, secretion, and coagulation changes in children with asthma.

The chronic inflammation in asthma evolves by cells including eosinophils, mast cells and lymphocytes. Despite their principal function in hemostasis, platelets contribute to pathogenesis of asthma that activation of platelets occurs following antigen provocation and during asthma attack. Our aim was to evaluate the platelet functions and other hemostatic features of children with asthma, both during symptom-free period and asthma attack. We enrolled patients with asthma attack (n = 33), mild intermittent asthma (n = 18), mild persistent asthma (n = 15) and healthy children (n = 20). Demographic characteristics and disease-related features were noted. Platelet aggregation and secretion tests (expressed as ATP release) were performed by lumiaggregometer method by stimulation with collagen, epinephrine, ADP, thrombin, ristocetin and arachidonic acid. Plasma levels of D-dimer, factor VIII (FVIII) and von Willebrand factor (vWF) were assessed. There were no differences in platelet aggregation induced by agonists between study groups. ATP release from platelets of patients with asthma exacerbation induced by ADP was lower compared with mild intermittent asthma (P < 0.001). Epinephrine-stimulated ATP secretion was also lower in patients with asthma attack than mild intermittent (P = 0.039) and mild persistent asthma (P = 0.011) and controls (P = 0.018). vWF measurements were higher in children with asthma attack than other study groups (P = 0.001). However, FVIII was increased in patients with severe asthma attack. Asthma is a disease in which many immune cells play a role, one of which is the platelet. Distinctions in platelet secretion profiles and plasma levels of vWF and FVIII provide evidence that coagulation mechanisms might be critical for asthma pathogenesis.

DOES ADEQUATE TREATMENT OF BRONCHIAL ASTHMA (BA) CAN PREVENT THE EXCESS DECLINE OF PULMONARY FUNCTION OVER TIME AMONG ELITE ATHLETES?

BackgroundIt is known that the pulmonary function shows a decline over time. There is the potential for an increase of airway damage among athletes who have higher ventilation compared with...

Effect of mesenchymal stem cells on inhibiting airway remodeling and airway inflammation in chronic asthma

Previous studies proved that bone marrow-derived mesenchymal stem cells (BMSCs) could improve a variety of immune-mediated disease by its immunomodulatory properties. In this study, we investigated the effect on airway remodeling and airway inflammation by administrating BMSCs in chronic asthmatic mice. Forty-eight female BALB/c mice were randomly distributed into PBS group, BMSCs treatment group, BMSCs control group, and asthmatic group. The levels of cytokine and immunoglobulin in serum and bronchoalveolar lavage fluid were detected by enzyme-linked immunosorbent assay. The number of CD4(+) CD25(+) regulatory T cells and morphometric analysis was determined by flow cytometry, hematoxylin-eosin, immunofluorescence staining, periodic-acid Schiff, and masson staining, respectively. We found that airway remodeling and airway inflammation were evident in asthmatic mice. Moreover, low level of IL-12 and high levels of IL-13, IL-4, OVA-specific IgG1, IgE, and IgG2a and the fewer number of CD4(+) CD25(+) regulatory T cells were present in asthmatic group. However, transplantation of BMSCs significantly decreased airway inflammation and airway remodeling and level of IL-4, OVA-specific IgE, and OVA-specific IgG1, but elevated level of IL-12 and the number of CD4 + CD25 + regulatory T cells in asthma (P < 0.05). However, BMSCs did not contribute to lung regeneration and had no significant effect on levels of IL-10, IFN-Y, and IL-13. In our study, BMSCs engraftment prohibited airway inflammation and airway remodeling in chronic asthmatic group. The beneficial effect of BMSCs might involved the modulation imbalance cytokine toward a new balance Th1-Th2 profiles and up-regulation of protective CD4 + CD25 + regulatory T cells in asthma, but not contribution to lung regeneration.

IL-2 and IL-4 Stimulate MEK1 Expression and Contribute to T Cell Resistance against Suppression by TGF-β and IL-10 in Asthma

The T cell-driven airway inflammation in chronic asthma is uninhibited and sustained. We examined the resistance of T cells from asthmatic patients against suppression by TGF-β, IL-10 and glucocorticoids and explored its signaling mechanism. CD4(+)CD25(-) T cells from allergic asthmatic subjects demonstrated increased TCR-stimulated proliferation as compared with healthy and chronic obstructive pulmonary disease controls. This proliferation was resistant to inhibition by TGF-β, IL-10, and dexamethasone and to anergy induction. CD4 T cells from asthmatic patients, but not chronic obstructive pulmonary disease, allergic rhinitis, and healthy subjects, showed increased expression of MEK1, heightened phosphorylation of ERK1/2, and increased levels of c-Fos. IL-2 and IL-4 stimulated the expression of MEK1 and c-Fos and induced T cell resistance. The inhibition of MEK1 reversed, whereas induced expression of c-Fos and JunB promoted T cell resistance against TGF-β- and IL-10-mediated suppression. We have uncovered an IL-2- and IL-4-driven MEK1 induction mechanism that results in heightened ERK1/2 activation in asthmatic T cells and make them resistant to certain inhibitory mechanisms.

The role of cyclophilins in regulating leukocyte recruitment in chronic allergic asthma. (35.14)

Abstract Chronic allergic asthma is an airway disease characterized by persistent inflammation. Elevated numbers of eosinophils, activated lymphocytes, and mast cells, as well as increased levels of IL-5, are detectable in the airways and lung tissues of asthmatic patients even in the absence of allergen challenge. The factors regulating this persistent inflammation are not known. While classical chemokines such as eotaxins 1-3, RANTES, MIP-1α, and MCP-1 are highly elevated after acute allergen challenge, they return to baseline levels by 24h after exposure. Although better known as intracellular chaperone proteins or as the target of the immunosuppressive drug cyclosporine A, extracellular cyclophilins are also potent chemoattractants that are elevated during lung inflammation. We propose that extracellular cyclophilins could function as important chemoattractants regulating the leukocyte recruitment and persistence observed during the chronic phase of allergic asthma. To test this possibility, we made use of a mouse model of chronic asthma and inhibited the function of cyclophilins during the chronic phase of the disease using the drug NIM811, a non-immunosuppressive analog of cyclosporine A (provided by Novartis). Mice treated with NIM811 demonstrated a significant reduction (~50%) in airway and tissue inflammation upon acute allergen challenge. These findings suggest a potential role for cyclophilins in maintaining inflammation in chronic asthma.

Levels of soluble human leukocyte antigen-G are increased in asthmatic airways

To the Editors: Human leukocyte antigen-G (HLA-G) is a non-classical, class Ib, major histocompatibility complex antigen, encoded by a gene on chromosome 6p21 within the HLA complex 1. HLA-G is constitutively expressed during pregnancy where it has a critical role in maintaining immune tolerance toward the allogenic fetus and placenta 2, 3, but has also been associated with inflammatory diseases such as psoriasis, multiple sclerosis, and ulcerative colitis, and with solid-organ transplantation 3, 4. We recently reported associations between variation in HLA-G and risk for asthma in Chicago-area asthma families, in multigenerational Dutch asthma families and in a birth cohort at high risk for developing asthma 1, 5. A role for HLA-G in asthma pathogenesis was further suggested by the demonstration of expression of a soluble isoform of HLA-G, sHLA-G5, in airway epithelial cells 1 and of increased circulating plasma levels of sHLA-G in children with atopic asthma 6. Because airway inflammation in asthma involves a T-helper cell (Th) type 2-skewing of lymphocytes similar to pregnancy, HLA-G is an attractive candidate molecule for promoting the immune profile characteristic of asthma. Localisation of HLA-G to airway epithelium suggests that its dysregulation could contribute to airway inflammation in chronic asthma. To evaluate this further, we hypothesised that HLA-G abundance would be increased in asthmatic airways. To test this hypothesis, we measured concentrations of sHLA-G in bronchoalveolar lavage (BAL) fluid obtained from 12 non-asthmatic control subjects and 15 subjects with mild persistent asthma. The use of human subjects was approved by the University of Chicago Institutional Review Board (Chicago, IL, USA). Asthma was diagnosed using National Asthma Education and Prevention Program guidelines. …

構造生物学研究の新展開 ２．基礎研究から応用展開に向けて（ｃ）応用志向型研究 システインロイコトリエン研究の新知見

Cysteinyl leukotriene has been known to be a major component of SRS-A (Slow Reacting Substance of Anaphylaxis). Inhibitors affecting on its biosynthesis and antagonists of its G-protein coupled receptor are therapeutic agents for acute inflammatory diseases, such as bronchial asthma and rhinitis. Latest findings in pathobiology of asthma suggest that cysteinyl leukotriene would take a key role in not only acute but also chronic inflammation of asthma. The structure basis of biosynthesis of cysteinyl leukotriene was revealed by crystallographic analysis of human membrane protein leukotriene C4 synthase.

Asthma phenotypes

The many roads leading to the syndrome of asthma have proven to be intricately interconnected. The chronic inflammation of asthma is characterized by airway hyperreactivity and variable reversibility. Past classification systems relied on assessment of daily impairment and the distinction between intrinsic (nonallergic) and extrinsic (allergic). With more precise asthma phenotypes, association studies likely will have greater significance. In addition, patients at higher risk for severe disease can be more effectively managed, and treatments can be directed to responders. In this review, we look at eight identified phenotypes: atopic and nonatopic status, pre-asthma wheezing, inflammatory mediator predominance, aspirin-sensitive, exercise-induced, severe, and flare-prone asthma. Although significant overlap exists among the distinctions, any future phenotype classification system will need to incorporate these eight clinical asthmatic populations.

Inhibition of allergen-induced airway remodelling by tiotropium and budesonide: a comparison

Chronic inflammation in asthma and chronic obstructive pulmonary disease drives pathological structural remodelling of the airways. Using tiotropium bromide, acetylcholine was recently identified as playing a major regulatory role in airway smooth muscle remodelling in a guinea pig model of ongoing allergic asthma. The aim of the present study was to investigate other aspects of airway remodelling and to compare the effectiveness of tiotropium to the glucocorticosteroid budesonide. Ovalbumin-sensitised guinea pigs were challenged for 12 weeks with aerosolised ovalbumin. The ovalbumin induced airway smooth muscle thickening, hypercontractility of tracheal smooth muscle, increased pulmonary contractile protein (smooth-muscle myosin) abundance, mucous gland hypertrophy, an increase in mucin 5 subtypes A and C (MUC5AC)-positive goblet cell numbers and eosinophilia. It was reported previously that treatment with tiotropium inhibits airway smooth muscle thickening and contractile protein expression, and prevents tracheal hypercontractility. This study demonstrates that tiotropium also fully prevented allergen-induced mucous gland hypertrophy, and partially reduced the increase in MUC5AC-positive goblet cell numbers and eosinophil infiltration. Treatment with budesonide also prevented airway smooth muscle thickening, contractile protein expression, tracheal hypercontractility and mucous gland hypertrophy, and partially reduced MUC5AC-positive goblet cell numbers and eosinophilia. This study demonstrates that tiotropium and budesonide are similarly effective in inhibiting several aspects of airway remodelling, providing further evidence that the beneficial effects of tiotropium bromide might exceed those of bronchodilation.

Inhaled Corticosteroids for Asthma

1. Edward W. Fong, MD* 2. Robert H. Levin, PharmD† 1. *Pediatric Pulmonologist, Children's Hospital and Research Center Oakland, Oakland, Calif., and California Pacific Medical Center, San Francisco, Calif 2. †Professor Emeritus of Clinical Pharmacy, University of California San Francisco School of Pharmacy, San Francisco, Calif Asthma is an inflammatory disease of the respiratory tract. It is the most common chronic disorder in children and adolescents, with more than 3 million asthma attacks occurring in more than 5% of all children each year. Asthma creates significant morbidity and is the leading cause of school absences. Costs attributed to asthma are in the billions of dollars each year. All levels of persistent asthma require daily anti-inflammatory treatment, and the safest, most effective treatment for patients who have persistent asthma is inhaled corticosteroids (ICSs). Although steroids may be given orally or parenterally, and numerous nonsteroidal medications are available for treating persistent asthma, ICSs are the treatment of choice. Even when ICSs are given daily over a long period of time, they have less toxicity than oral or parenteral steroids administered only occasionally. This article reviews the currently available ICSs, devices and techniques for optimal administration, and potential adverse effects. The data and recommendations are based on the National Asthma Education and Prevention Program (NAEPP) guidelines (1991 and 1997) and Update 2002, which are available at http://www.nhlbi.nih.gov/guidelines/asthma. Asthma is a complex disorder whose pathogenesis is not fully understood. Current thinking is that susceptible individuals develop asthma because of an imbalance between the T-helper (Th)1 and Th2 lymphocytes. Th1 cells produce interleukin-2 (IL-2) and interferon-gamma, which act as a cellular defense mechanism, and Th2 cells produce cytokines (IL-4, IL-5, IL-6, IL-9, and IL-13), which mediate allergic inflammation. According to this current “hygiene hypothesis,” the Th1 cellular defense mechanism is reduced, while Th2 cellular activity increases. This imbalance predisposes the individual to episodes of chronic inflammatory asthma. Whatever triggers the pathogenesis sets up an inflammatory process in which many cellular components participate, including mast cells, T lymphocytes, eosinophils, neutrophils, and epithelial cells. The result is inflammation, hyperresponsiveness (bronchospasm), and in …

Neuro–immune interaction in allergic asthma: role of neurotrophins

The nature of persistent airway hyperreactivity and chronic inflammation in asthma remains unclear. It has been suggested that bi-directional neuro-immune interaction plays an important role in the pathogenesis of this disease, leading to enhanced airway narrowing after contact with unspecific stimuli, as well as infiltration, activation and degranulation of several immune cell subtypes. Important mediators in neuro-immune cross-talk are neurotrophins, which are produced by cells at the site of inflammation. In addition to modulating the function of several leucocyte subsets, they play an important role in the synthesis of neuropeptides by sensory nerve cells. Neuropeptides have been shown to cause smooth-muscle contraction and, in addition, modulate the production of pro-inflammatory molecules by leucocytes. The aim of the present review is to provide an overview of the molecular mechanisms by which neurotrophins and neuropeptides are involved in neuro-immune cross-talk in allergic asthma.

The use of computed tomography to assess asthma severity

Chronic inflammation in asthma can also lead to airway remodeling, which contributes to airway narrowing. It may be possible to assess and quantify the extent of airway remodeling in vivo using computed tomography. This review examines recent developments in the evaluation of asthma severity using computed tomography, and the effect of treatment assessed by computed tomography. Asthma patients have thicker airways on computed tomography scans than do healthy control individuals, and the degree of thickening is related to the severity of disease, airflow obstruction, and airway reactivity. Recent studies have indicated that patients with severe asthma and irreversible airflow obstruction had longer disease duration, a greater inflammatory process and more airway abnormalities, assessed by high-resolution computed tomography, suggestive of airway remodeling. Other studies have shown that high-resolution computed tomography lung density correlates with airflow limitation and lung volume (but not with lung transfer factor), and also correlates with patient age and severity of asthma. More recently, two publications demonstrated the effect of treatment on airway wall thickness and lung density assessed by computed tomography in patients with asthma. High-resolution computed tomography is one of the most useful tools for imaging airways and parenchyma. Computed tomography scanning may be useful in determining which patients might benefit from more or less treatment. With additional advances in technology, it is likely that quantitative assessment by computed tomography will ultimately be a valuable tool for the study and treatment of chronic airway diseases.

Clinical significance of measurement of interleukin 4 and interleukin 5 serum concentrations in bronchial asthma

Cytokines IL-4 and IL-5 participate in the chronic inflammation process in the atopic airway diseases. Our study is aimed at determining correlation between IL-4 and IL-5 serum concentrations and severity of the disease in patients with bronchial asthma. The total of 65 patients with asthma is classified into three groups: 1. patients with mild, 2. moderate and 3. severe asthma. The control group comprised 10 healthy individuals. Measurement of IL-4 and IL-5 serum concentrations was performed according to ELISA method. Minimal detectable concentrations of IL-4 and IL-5 were 0.27 pg/mL and 4 pg/mL, respectively. IL-4 (Z = 2.245, p = 0.025) and IL-5 (Z = 2.139, p = 0.032) serum concentrations are significantly lower in healthy individuals in comparison to the individuals with asthma. Comparison of the study results between the groups (mild, moderate and severe asthma) evidenced that IL-4 serum concentrations in the group with moderate (Z = 2.604, p = 0.009) and severe asthma (Z= 2.658, p = 0.008) were statistically significantly higher in comparison to the group with mild asthma. IL-5 serum concentrations in the group with moderate (Z = 3.910, p = 0.000) and severe asthma (Z = 4.037, p = 0.000) were statistically significantly higher in comparison to the group with mild asthma. Further studies on the role of IL-4 and IL-5 in the process of chronic inflammation in asthma are needed.

Current and emerging therapies for the management of chronic inflammation in asthma

The pathophysiology of asthma, current treatment guidelines, and emerging immunomodulating treatments are reviewed. Asthma is a chronic disease of inflammation, which left untreated, may result in irreversible lung damage. Inhaled antigens elicit a T-helper cell type-2 response, leading to the production of immunoglobulin E (IgE) and eosinophil sensitization. Eosinophil infiltration into the airway is thought to play an important role in chronic inflammation and increases several weeks before an acute exacerbation in moderate to severe asthma. The updated guidelines from the National Asthma Education and Prevention Program and the National Institutes of Health focus on the use of daily antiinflammatory treatment in patients with persistent asthma. Inhaled corticosteroid (ICS) therapy remains the cornerstone for controlling mild and moderate asthma, but when used in higher doses for moderate-to-severe asthma it may cause long-term adverse effects, including osteoporosis and glaucoma. Step-up therapy should be the combination of a long-acting beta-agonist (LABA) and an ICS. Leukotriene modifiers may provide additional symptom control in patients with moderate to severe asthma but have not been shown to be as cost-effective as monotherapy. Newer entities focus on direct immune modulation and include monoclonal antibodies targeting various inflammatory-response receptors (IgE, interleukin [IL]-2, IL-4, and IL-5). Phosphodiesterase-4 (PDE-4) inhibitors may be effective for chronic obstructive pulmonary disease, but have not delivered consistent results for controlling asthma. Cytokine-receptor antagonists and leukocyte-suppressing antiinflammatory drugs (LSAIDs) are currently under investigation and have yielded promising preliminary results as alternatives for the treatment of asthma. Current and emerging therapies for the management of chronic inflammation in asthma include ICSs, LABAs, leukotriene modifiers, monoclonal antibodies, PDE-4 inhibitors, cytokine-receptor antagonists, and LSAIDs.

Current and emerging therapies for the management of chronic inflammation in asthma

Current and emerging therapies for the management of chronic inflammation in asthma

Use of Macrolide Antibiotics in the Treatment of Asthm

PURPOSE: Chronic infections such as Mycoplasma pneumoniae and Chlamydia pneumoniae can maintain inflammatory response in chronic asthma. Macrolide antibiotics have both antimicrobial and anti-inflammatory effects that can potentially alter the course of inflammation in chronic asthma.

Relationship between airway inflammation, hyperresponsiveness, and obstruction in asthma

Background: Although the role of eosinophils in airway inflammation in chronic asthma has been extensively studied, a role for neutrophils has not been well characterized. Furthermore, prior studies have not systematically sought or controlled for factors that might confound the relationship between cellular markers of inflammation and physiologic measures of airway function. Objective: The purpose of this study was to determine whether eosinophilic and neutrophilic inflammation independently contribute to abnormalities of airway function in asthma. Methods: Multivariate analysis of data collected during screening and enrollment of 205 asthmatic adults for clinical trials was conducted to examine the relationships between cellular inflammation in induced sputum and FEV1 and methacholine responsiveness (PC20) while confounding factors were controlled for. Results: We found that age, sex, ethnicity, and use of inhaled corticosteroids were important confounding factors of the relationship between cellular inflammation and airway function. When these factors were controlled for, multivariate analysis showed that eosinophil percentage in induced sputum is independently associated with lower FEV1 and lower PC20 (P = .005 and P = .005, respectively). In the same models, increased sputum neutrophil percentage is independently associated with lower FEV1 (P = .038) but not with PC20 (P = .49). Conclusions: These results suggest that both eosinophilic inflammation and neutrophilic inflammation independently contribute to abnormalities of FEV1 in asthma. Therapies directed specifically at control of neutrophilic inflammation might be useful in improving airway caliber in patients with chronic asthma. (J Allergy Clin Immunol 2001;108:753-8.)

Airway remodeling in asthma

Airway remodeling is the term given to a series of structural changes characterized by chronic, irreversible airway obstruction. Structural changes in the airway wall caused by chronic inflammation of asthma. Evidence for asthma airway remodeling demonstrating an accelerated decline of lung function that cannot be completely reversed with therapy. Combination therapy produced at least as much protection against inflammation as theuse of the higher dose of the inhaled corticosteroid.

Antileukotriene agents.

The antileukotriene agents, the first new class of asthma medications introduced in two decades, represent a promising new alternative in the continuing search for effective and safe therapy for chronic inflammation in asthma. The leukotrienes are inflammatory mediators whose effects on asthma include bronchoconstriction, increased vascular permeability, and increased mucus production. In chronic asthma, regular use of either leukotriene synthesis inhibitors or leukotriene receptor antagonists has improved pulmonary function and clinical symptoms significantly. Antileukotriene agents appear to be safe and well tolerated, although long-term studies will be needed to confirm this.

The leukotrienes: mediators of chronic inflammation in asthma

The leukotrienes: mediators of chronic inflammation in asthma