Persistent Airway Inflammation Research Articles

Pentoxifylline and its active metabolite lisofylline attenuate transforming growth factor β1-induced asthmatic bronchial fibroblast-to-myofibroblast transition

Bronchial asthma is characterized by persistent airway inflammation and airway wall remodeling. Among many different cells and growth factors triggering changes in bronchi structure, transforming growth factor β1-induced fibroblast to myofibroblast transition is believed to be very important. The aim of this study was to evaluate whether theophylline (used in asthma therapy) and two other methylxanthines (pentoxifylline and its active metabolite lisofylline), may affect transforming growth factor β1-induced fibroblast to myofibroblast transition in bronchial fibroblasts derived from asthmatic patients. We show here for the first time that selected methylxanthines effectively reduce transforming growth factor β1-induced myofibroblast formation in asthmatic bronchial fibroblast populations. PTX was found to be the most effective methylxanthine. The number of differentiated myofibroblasts after PTX, LSF and THEO administration was reduced at least twofold. Studies on the use of methylxanthines opens a new perspective in the development of novel strategies in asthma therapy through their two-pronged, anti-inflammatory and anti-fibrotic action. In the future they can be considered as promising anti-fibrotic drugs.

NK cells contribute to persistent airway inflammation and AHR during the later stage of RSV infection in mice.

RSV can lead to persistent airway inflammation and AHR and is intimately associated with childhood recurrent wheezing and asthma, but the underlying mechanisms remain unclear. There are high numbers of NK cells in the lung, which not only play important roles in the acute stage of RSV infection, but also are pivotal in regulating the pathogenesis of asthma. Therefore, in this study, we assumed that NK cells might contribute to persistent airway disease during the later stage of RSV infection. Mice were killed at serial time points after RSV infection to collect samples. Leukocytes in bronchoalveolar lavage fluid (BALF) were counted, lung histopathology was examined, and airway hyperresponsiveness (AHR) was measured by whole-body plethysmography. Cytokines were detected by ELISA, and NK cells were determined by flow cytometry. Rabbit anti-mouse asialo-GM-1 antibodies and resveratrol were used to deplete or suppress NK cells. Inflammatory cells in BALF, lung tissue damage and AHR were persistent for 60days post-RSV infection. Type 2 cytokines and NK cells were significantly increased during the later stage of infection. When NK cells were decreased by the antibodies or resveratrol, type 2 cytokines, the persistent airway inflammation and AHR were all markedly reduced. NK cells can contribute to the RSV-associated persistent airway inflammation and AHR at least partially by promoting type 2 cytokines. Therefore, therapeutic targeting of NK cells may provide a novel approach to alleviating the recurrent wheezing subsequent to RSV infection.

Research progress of home environment prevention and control in children with dust mite allergic asthma

The dust mite-induced asthma in children is more common.Dust mite allergens generate persistent airway inflammation by the inhalation route into the airway.Dust mites easily stay in mattresses and pillows which are warm and humid. Home environment is the main place of children′s daily activities.Children who were exposed to dust mites in the home environment can be caused the occurrence and development of asthma.Family environment control, to a certain extent, can isolate allergens exposure. Parents are the defenders of family environment, so the parents with house dust mite allergen related knowledge, attitude and behavior will help to control the indoor dust mite levels.This article makes a brief review on dust mites related knowledge, children room environment dust mite exposure, parents with home environment control knowledge, attitude and behavior studies in recent years. Key words: Dust mite; Allergy; Childhood asthma; Home environment; Intervention; Literature review

Regulatory CD4+CD25+ T Cells Dampen Inflammatory Disease in Murine Mycoplasma Pneumonia and Promote IL-17 and IFN-γ Responses.

Mycoplasmas cause respiratory diseases characterized by persistent infection and chronic airway inflammation. Mycoplasma lung disease is immunopathologic, with CD4+ Th cells determining both disease severity and resistance to infection. Th2 cell responses promote immunopathology, while Th1 cells confer resistance to infection. However, regulatory CD4+ T cells may also have a role in the pathogenesis of mycoplasma respiratory diseases. We hypothesized Treg cells control the severity of the inflammatory lesions and may also promote persistence of infection. To examine this, BALB/c mice were depleted of CD25+ cells, and had increased disease severity due to Mycoplasma pulmonis infection. Increases in mycoplasma antibody responses and lymphocyte infiltration into lungs also occurred after CD25+ cell depletion. CD4+CD25+ regulatory T cells promoted IFN-γ and IL-17 mycoplasma-specific CD4+ T cell responses in vitro and in vivo, while dampening IL-13+ Th responses. Neither IL-10 nor TGF-ß expression was detected in CD4+CD25+ T cells from lymph nodes. Thus, a regulatory T cell population plays an important role in controlling damaging immune responses in mycoplasma respiratory disease but does not contribute to persistence of infection. It appears that a regulatory T cell population preferentially dampens Th2 cell-mediated inflammatory responses to mycoplasma through a mechanism independent of IL-10 or TGF-ß characteristic of “classic” Treg cells.

Airway bacteria drive a progressive COPD-like phenotype in mice with polymeric immunoglobulin receptor deficiency.

Mechanisms driving persistent airway inflammation in chronic obstructive pulmonary disease (COPD) are incompletely understood. As secretory immunoglobulin A (SIgA) deficiency in small airways has been reported in COPD patients, we hypothesized that immunobarrier dysfunction resulting from reduced SIgA contributes to chronic airway inflammation and disease progression. Here we show that polymeric immunoglobulin receptor-deficient (pIgR−/−) mice, which lack SIgA, spontaneously develop COPD-like pathology as they age. Progressive airway wall remodelling and emphysema in pIgR−/− mice are associated with an altered lung microbiome, bacterial invasion of the airway epithelium, NF-κB activation, leukocyte infiltration and increased expression of matrix metalloproteinase-12 and neutrophil elastase. Re-derivation of pIgR−/− mice in germ-free conditions or treatment with the anti-inflammatory phosphodiesterase-4 inhibitor roflumilast prevents COPD-like lung inflammation and remodelling. These findings show that pIgR/SIgA deficiency in the airways leads to persistent activation of innate immune responses to resident lung microbiota, driving progressive small airway remodelling and emphysema.

IL-17A induces chromatin remodeling promoting IL-8 release in bronchial epithelial cells: Effect of Tiotropium

AimsIL-17A plays a key role in the persistence of airway inflammation, oxidative stress, and reduction of steroid-sensitivity in COPD. We studied the effect of IL-17A on chromatin remodeling and IL-8 production. Main methodsWe measured the levels of IL-8 and IL-17A in induced sputum supernatants (ISS) from healthy controls (HCs), healthy smokers (HSs), and COPD patients by enzyme-linked immunosorbent assay (ELISA). A human bronchial epithelial cell line (16HBE) was stimulated with ISS from HCs, HSs, or COPD subjects. IL-8 was evaluated in 16HBE by Western blot and real-time polymerase chain reaction (PCR). Histone deacetylase 2 (HDAC2), acetyl histone H3 (Ac-His H3) (k9) and inhibitor kappa kinase alpha (IKKα) levels were evaluated in the nuclear extract by Western blot. Finally, we evaluated the effect of IL-17A depletion in ISS, the silencing of IKKα, and the anti-inflammatory effects of Tiotropium Spiriva® (100nM) on 16HBE. Key findingsIL-8 and IL-17A levels were higher in ISS from COPD patients and HSs than from HCs. IL-8 protein and messenger RNA (mRNA) levels were increased in 16HBE stimulated with ISS from COPD patients compared with untreated cells. Furthermore, ISS from COPD patients reduced the nuclear levels of HDAC2 while increasing the activity of both Ac-His H3 (k9) and IKKα in stimulated 16HBE. IL-17A depletion in ISS and the IKKα silencing in 16HBE significantly increased the nuclear levels of HDAC2, reduced Ac-His H3 (k9), and promoted IL-8 synthesis in stimulated 16HBE. Tiotropium controls the proinflammatory activity generated by ISS from COPD patients in 16HBE. SignificanceIL-17A present in the airway of COPD patients, which induces chromatin remodeling, promotes the release of IL-8 in the bronchial epithelium. Tiotropium is able to control this proinflammatory activity.

CLINICAL AND IMMUNOLOGICAL EFFECTS OF CARBOCYSTEINE IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Background: Chronic obstructive pulmonary disease (COPD) is one of the commonest diseases characterized by persistent distal airways inflammation. Thus, anti-inflammatory therapy should be the basis of COPD treatment. There is only limited evidence supporting the efficacy of mucolytics like carbocysteine in the preventing COPD exacerbations in inhaled corticosteroid-naive patients. Aim: To study clinical and immunological effects of carbocysteine in COPD. Materials and methods: During first 2 months, 30 patients with stage II COPD (mean age 55.9±1.2 years old) were treated with inhaled glucocorticosteroids and beta2-adrenoceptor agonists ‘as required’. Thereafter, the standard therapy was continued in 15 patients; in other 15 patients carbocysteine 1500 mg/day was added. Immune status was studied bi-monthly in all patients: to detect lymphocytes with expression of CD3, CD4, CD8, CD72-antigens and CD23, CD71, CD95 and HLA-DR activation markers, monoclonal antibodies were used. Quality of life was assessed using adapted Russian version of St. George’s Respiratory Questionnaire (SGRQ). Results: Compared with the anti-inflammatory therapy, adding carbocysteine to standard therapy of COPD was associated with significantly better quality of life after 4 months of therapy (less negative changes of symptoms and activity scores and improvement of psycho-social function: changes of relevant SGRQ scores were -3.4 and -8.0; -1.9 and -3.8; 0.4 and -0.76, respectively). After 4 months, carbocysteine-treated patients demonstrated better improvements in shortness of breath, cough and sputum scores compared with the control group (2 and 2.2; 1.5 and 1.9; 0.8 and 1.2, respectively). In carbocysteine group, clinical symptoms improvement correlated with positive changes of immunological status. The patients demonstrated greater significant elevation of total T-lymphocytes (especially CD8+-cells), decreased B-cells and increased expression of CD95-antigen compared with the standard therapy group. Conclusion: Carbocysteine may be recommended as an obligate part of therapy in COPD patients.

Persistent airway inflammation and high exacerbation rate in asthma that starts at menopause

Asthma that begins around the time of menopause is frequently characterised by marked clinical severity and poor response to treatment. We sought to assess the clinical characteristics, bronchial responsiveness, perception of induced bronchoconstriction and airway inflammation in women with menopausal asthma, as compared to women of a similar age with pre-existing asthma. Nine women with pre-existing asthma were selected for clinical severity (symptoms, lung function and medication requirements) similar to that in 11 women with menopausal asthma. Anti-asthmatic treatment in all of the study patients included high dose inhaled (with or without oral) corticosteroids. The women with menopausal asthma demonstrated less atopy, more chronic recurrent sinusitis, similar airway responsiveness, and similar perception of induced bronchoconstriction, but a significantly higher sputum eosinophil count (19.5 +/- 10.8 versus 3.3 +/- 4.3%; p < 0.001) and a higher severe exacerbation rate during the 1-year follow-up period (5.09 +/- 4.85 versus 0.78 +/- 0.97; p < 0.05). Sputum eosinophil count and severe asthma exacerbation rate correlated well in both groups considered as a whole (r = 0.65; p < 0.005). The eosinophilic airway inflammation present in women with menopausal asthma is poorly responsive to anti-inflammatory treatment with corticosteroids and predisposes to frequent severe exacerbations. Airway inflammation should be monitored in women with menopausal asthma.

Monoclonal Antibodies for the Management of Severe Asthma.

Asthma is a heterogeneous inflammatory disease. Most patients respond to current standard of care, i.e., bronchodilators, inhaled glucocorticosteroids and other anti-inflammatory drugs, but in some adequate asthma control cannot be achieved with standard treatments. These difficult-to-treat patients would be the target population for new biological therapies. At present, omalizumab is the only biological agent approved for the treatment of early-onset, severe IgE-dependent asthma. It is safe, effective, and well tolerated. Also, discovery of asthma subtypes suggests new treatments. Half of patients with severe asthma have T-helper type 2 (Th-2) inflammation and they are expected to benefit from monoclonal antibody-based treatments. The efficacy of the investigational monoclonal antibody mepolizumab which targets IL-5 has been well documented in late onset non-atopic asthma with persistent eosinophilic airway inflammation. Anti-IL-4 and IL-13 agents (dupilumab, lebrikizumab, and tralokinumab) which block different Th-2 inflammatory pathways and agents targeting the Th-17 inflammatory pathway in severe refractory asthma are under development. In clinical trials, these drugs reduce disease activity and improve lung function, asthma symptoms, and quality of life. However, studies on larger groups of patients are needed to confirm their safety and efficacy.

Pulmonary C Fibers Modulate MMP-12 Production via PAR2 and Are Involved in the Long-Term Airway Inflammation and Airway Hyperresponsiveness Induced by Respiratory Syncytial Virus Infection.

Children with acute respiratory syncytial virus (RSV) infection often develop sequelae of persistent airway inflammation and wheezing. Pulmonary C fibers (PCFs) are involved in the generation of airway inflammation and resistance; however, their role in persistent airway diseases after RSV is unexplored. Here, we elucidated the pathogenesis of PCF activation in RSV-induced persistent airway disorders. PCF-degenerated and intact mice were used in the current study. Airway inflammation and airway resistance were evaluated. MMP408 and FSLLRY-NH2 were the selective antagonists for MMP-12 and PAR2, respectively, to investigate the roles of MMP-12 and PAR2 in PCFs mediating airway diseases. As a result, PCF degeneration significantly reduced the following responses to RSV infection: augmenting of inflammatory cells, especially macrophages, and infiltrating of inflammatory cells in lung tissues; specific airway resistance (sRaw) response to methacholine; and upregulation of MMP-12 and PAR2 expression. Moreover, the inhibition of MMP-12 reduced the total number of cells and macrophages in bronchiolar lavage fluid (BALF), as well infiltrating inflammatory cells, and decreased the sRaw response to methacholine. In addition, PAR2 was upregulated especially at the later stage of RSV infection. Downregulation of PAR2 ameliorated airway inflammation and resistance following RSV infection and suppressed the level of MMP-12. In all, the results suggest that PCF involvement in long-term airway inflammation and airway hyperresponsiveness occurred at least partially via modulating MMP-12, and the activation of PAR2 might be related to PCF-modulated MMP-12 production. Our initial findings indicated that the inhibition of PCF activity would be targeted therapeutically for virus infection-induced long-term airway disorders. The current study is critical to understanding that PCFs are involved in long-term airway inflammation and airway resistance after RSV infection through mediating MMP-12 production via PAR2, indicating that the inhibition of PCF activity can be targeted therapeutically for virus infection-induced long-term airway disorders.

The use of corticosteroids in patients with COPD or asthma does not decrease lung squamous cell carcinoma.

BackgroundAsthma and COPD (chronic obstructive pulmonary disease) lead to persistent airway inflammation and are associated with lung cancer. The objective of the study was to assess the relationship between inhaled (ICS) and oral corticosteroid (OCS) use, and risk of lung squamous cell carcinoma (SqCC).MethodsThis study was a nested case–control study. Patients with newly diagnosed asthma or COPD between 2003 and 2010 were identified from the National Health Insurance Database. Cases were defined as patients diagnosed with SqCC after enrollment. For each case, four control individuals who were randomly matched for sex and age and date diagnosis of asthma or COPD were selected.ResultsFrom the 1,672,455 eligible participants, 793 patients with SqCC were matched with 3,172 controls. The odds ratios (ORs) of SqCC in men who received high and low-dose ICS were 2.18 (95 %CI, 1.56–3.04) and 1.77 (1.22–2.57), respectively. Similarly, the ORs were 1.46 (95 %CI, 1.16–1.84) and 1.55 (95 %CI, 1.22–1.98) for men who were placed on low and high dose OCS. However, there was no significant association between cumulative ICS and/or OCS and risk of SqCC in women. Recent dose increase in corticosteriod was significantly associated with risk of SqCC. Specifically, among men, the ORs for SqCC were 8.08 (95 %CI, 3.22–20.30) for high-dose ICS + OCS, 4.49 (95 % CI, 2.05–9.85) for high-dose ICS, and 3.54 (95 % CI, 2.50–5.01) for high-dose OCS treatments, respectively. The OR for SqCC in women who received high-dose OCS was 6.72 (95 %CI, 2.69–16.81).ConclusionCorticosteroid use did not decrease SqCC in patients with asthma or COPD. Recent dose increase in corticosteroids was associated with SqCC.

Involvement of fibrocytes in asthma and clinical implications.

Bloodborne fibrocytes are bone marrow-derived cells that participate in immune responses and exhibit pro-inflammatory and matrix remodelling properties. In patients with asthma receiving an adequate treatment, the blood fibrocyte count is very low and comparable to that obtained in healthy individuals. In these patients, a transient increase in fibrocyte numbers in the peripheral blood and in the airways occurs in concomitance with increased bronchial inflammation and reflects disease worsening and the need for more intensive treatment. Persistently elevated numbers of fibrocytes in the peripheral blood and in the bronchial mucosa are observed in chronically undertreated or corticosteroid-resistant asthma and are associated with persistent airway inflammation and ongoing remodelling of the bronchial wall. The asthmatic bronchial epithelium is the main source of fibrocyte chemoattractants in asthma and contributes with T helper type 2 lymphocytes and eosinophils to promote the proliferation and pro-remodelling function of recruited fibrocytes. The presence of elevated numbers of fibrocytes in the bronchial mucosa of allergic patients with undertreated or treatment-resistant asthma may also increase the risk of acute exacerbations because these cells can amplify T helper type 2 lymphocyte-driven inflammation on every exposure to the clinically relevant allergen and can promote further inflammation on rhinovirus infections by allowing viral replication and releasing additional pro-inflammatory factors. Improved methods for the isolation and functional analysis of pure populations of viable circulating fibrocytes have allowed a better understanding of the effector role of these cells. A reliable and clinically applicable assay has been developed to measure blood fibrocyte counts as outcome measure in future clinical trials. New therapeutic agents are needed to block both persistent inflammation and fibrocytosis in corticosteroid-resistant asthma.

Nuclear Receptor Nur77 Attenuates Airway Inflammation in Mice by Suppressing NF-κB Activity in Lung Epithelial Cells.

Allergic asthma is characterized by persistent chronic airway inflammation, which leads to mucus hypersecretion and airway hyperresponsiveness. Nuclear receptor Nur77 plays a pivotal role in distinct immune and inflammatory cells and is expressed in eosinophils and lung epithelium. However, the role of Nur77 in allergic airway inflammation has not been studied so far. In the present study, we determined the role of Nur77 in airway inflammation using a murine model of OVA-induced allergic airway inflammation. We found that OVA-challenged Nur77 knockout (KO) mice show significantly enhanced infiltration of inflammatory cells, including eosinophils and lymphocytes, and aggravated mucus production. The infiltration of macrophages is limited in this model and was similar in wild-type and Nur77 KO mice. Higher levels of Th2 cytokines were found in bronchoalveolar lavage fluid and draining lymph node cells of Nur77-KO mice, as well as increased serum IgG1 and IgG2a levels. Knockdown of Nur77 in human lung epithelial cells resulted in a marked increase in IκBα phosphorylation, corresponding with elevated NF-κB activity, whereas Nur77 overexpression decreased NF-κB activity. Consistently, Nur77 significantly decreased mRNA levels of inflammatory cytokines and Muc5ac expression and also attenuated mucus production in lung epithelial cells. To further corroborate these findings, we searched for association of single nucleotide polymorphisms in Nur77 gene with asthma and with the severity of bronchial hyperresponsiveness. We identified three Nur77 single nucleotide polymorphisms showing association with severity of bronchial hyperresponsiveness in asthma patients. Collectively, these findings support a protective role of Nur77 in OVA-induced airway inflammation and identify Nur77 as a novel therapeutic target for airway inflammation.

The Three A's in Asthma - Airway Smooth Muscle, Airway Remodeling & Angiogenesis.

Asthma affects more than 300 million people worldwide and its prevalence is still rising. Acute asthma attacks are characterized by severe symptoms such as breathlessness, wheezing, tightness of the chest, and coughing, which may lead to hospitalization or death. Besides the acute symptoms, asthma is characterized by persistent airway inflammation and airway wall remodeling. The term airway wall remodeling summarizes the structural changes in the airway wall: epithelial cell shedding, goblet cell hyperplasia, hyperplasia and hypertrophy of the airway smooth muscle (ASM) bundles, basement membrane thickening and increased vascular density. Airway wall remodeling starts early in the pathogenesis of asthma and today it is suggested that remodeling is a prerequisite for other asthma pathologies. The beneficial effect of bronchial thermoplasty in reducing asthma symptoms, together with the increased potential of ASM cells of asthmatics to produce inflammatory and angiogenic factors, indicate that the ASM cell is a major effector cell in the pathology of asthma. In the present review we discuss the ASM cell and its role in airway wall remodeling and angiogenesis.

Resveratrol suppresses persistent airway inflammation and hyperresponsivess might partially via nerve growth factor in respiratory syncytial virus-infected mice

Respiratory syncytial virus (RSV) infection is involved in persistent and recurrent wheezing. There are no effective and safe drugs for the sequelae of persistent wheezing after early bronchiolitis. In this study, we investigated the effect of resveratrol on persistent airway inflammation and airway hyperresponsiveness (AHR) induced by RSV infection. RSV-infected mice were sacrificed at serial time points after infection to collect samples and measure the number of inflammatory cells and levels of interferon-gamma (IFN-γ), nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF). Airway inflammation, AHR, and the levels of NGF and BDNF were detected after resveratrol administration. Furthermore, Ab-NGF was used to investigate the role of NGF in RSV-induced prolonged airway inflammation and AHR. We found that RSV RNA remained detectable in the lungs of RSV-infected mice on day 60, accompanying persistent airway inflammation and AHR for 60 days. IFN-γ levels in BALF were increased on day 7 but reduced to normal levels by day 14 post-RSV infection, while NGF and BDNF levels gradually increased from day 14 to 60. Furthermore, after resveratrol treatment, the total number of cells in BALF was reduced; the number of inflammatory cells infiltrating the lungs was also lower. Resveratrol attenuated the airway response to methacholine and significantly decreased NGF levels in BALF without affecting BDNF levels. Moreover, airway inflammation and AHR associated with RSV persistence were attenuated after Ab-NGF administration. In all, resveratrol suppresses persistent airway inflammation and AHR might partially through reducing the levels of NGF after RSV infection.

Afzelin attenuates asthma phenotypes by downregulation of GATA3 in a murine model of asthma.

Asthma is a serious health problem causing significant mortality and morbidity globally. Persistent airway inflammation, airway hyperresponsiveness, increased immunoglobulin E (IgE) levels and mucus hypersecretion are key characteristics of the condition. Asthma is mediated via a dominant T-helper 2 (Th2) immune response, causing enhanced expression of Th2 cytokines. These cytokines are responsible for the various pathological changes associated with allergic asthma. To investigate the anti-asthmatic potential of afzelin, as well as the underlying mechanisms involved, its anti-asthmatic potential were investigated in a murine model of asthma. In the present study, BALB/c mice were systemically sensitized using ovalbumin (OVA) followed by aerosol allergen challenges. The effect of afzelin on airway hyperresponsiveness, eosinophilic infiltration, Th2 cytokine and OVA-specific IgE production in a mouse model of asthma were investigated. It was found that afzelin-treated groups suppressed eosinophil infiltration, allergic airway inflammation, airway hyperresponsiveness, OVA-specific IgE and Th2 cytokine secretion. The results of the present study suggested that the therapeutic mechanism by which afzelin effectively treats asthma is based on reduction of Th2 cytokine via inhibition of GATA-binding protein 3 transcription factor, which is the master regulator of Th2 cytokine differentiation and production.

Hemoptisis masiva en fibrosis quística tratada con Amplatzer Plug IV

The hemoptysis is a complication commonly reported in patients diagnosed with cystic fibrosis and affects approximately 9% of the population. It may be in limited quantity to massive events that threaten the patient's life. Its pathogenesis is complex, but the most commonly accepted cause is persistent airway inflammation asso- ciated with neovascularization with damage to the vasculature of the bronchial arteries. The case of a 22 year old with confirmed diagnosis of cystic fibrosis in whom control of hemoptysis was achie- ved through embolization of bronchial arteries and placement PLUG IV Occluder device percutaneously successfully described.

Correlations between Cu, Zn- Superoxide dismutase and Macrophages or MUC5AC in Human Eosinophilic Chronic Rhinosinusitis

Background: Chronic rhinosinusitis with eosinophilic infiltration (ECRS) has been noted a severe and intractable type of rhinosinusitis, which is often associated with asthma. Macrophages as well as eosinophilic infiltration have been reported to take part in the processes of severe asthma. Mucus hypersecretion and persistent airway inflammation results from the increased expression of mucin gene (MUC5AC). Oxidants are well known to induce the characteristic features that aggravate asthma. Superoxide dismutase (SOD), a cytoprotective enzyme against oxidants, has been extensively studied in airway diseases. From the viewpoint of “One way one disease”, we examined whether SOD could be associated with infiltrating macrophages, MUC5AC and other factors that exacerbate the rhinosinusitis. Methods: Parts of each specimen derived from the nasal polyps of ECRS and chronic rhinosinusitis without eosinophilic infiltration (non-ECRS) were divided and fixed in 10 % phosphate buffered formalin, embedded in paraffin, processed routinely and then prepared as semi-thin sections (3.5 μm). We immunohistochemically observed copper/zinc-superoxide dismutase (Cu, Zn-SOD) and macrophages by using CD68 and IL-17A as factors that promoteMUC5AC. Results: The mean numbers of macrophages (CD68 positive cells) and IL-17A positive cells in the ECRS were significantly greater than in non-ECRS. The mean percentage of epithelial cells with Cu, Zn-SOD positive reaction in non-ECRS was significantly greater than in ECRS. There were significant negative correlations in all cases between Cu, Zn-SOD and CD 68, IL-17A or MUC5AC. Conclusions: Our study suggests that loss of Cu, Zn-SOD in epithelia of ECRS could increase both IL-17 A and MUC5AC, resulting in the infiltration of macrophages and mucus over production.

Impaired CD8+ T cell immunity after allogeneic bone marrow transplantation leads to persistent and severe respiratory viral infection

RationaleBone marrow transplant (BMT) recipients experience frequent and severe respiratory viral infections (RVIs). However, the immunological mechanisms predisposing to RVIs are uncertain. Therefore, we hypothesized that antiviral T cell immunity is impaired as a consequence of allogeneic BMT, independent of pharmacologic immunosuppression, and is responsible for increased susceptibility to RVI. MethodsBone marrow and splenocytes from C57BL/6(H2b) mice were transplanted into B10.BR(H2k) (Allo) or C57BL/6(H2b) (Syn) recipients. Five weeks after transplantation, recipient mice were inoculated intranasally with mouse parainfluenza virus type 1 (mPIV-1), commonly known as Sendai virus (SeV), and monitored for relevant immunological and disease endpoints. Main resultsSevere and persistent airway inflammation, epithelial injury, and enhanced mortality are found after viral infection in Allo mice but not in control Syn and non-transplanted mice. In addition, viral clearance is delayed in Allo mice as evidenced by prolonged detection of viral transcripts at Day 15 post-inoculation (p.i.) but not in control mice. In concert with these events, we also detected decreased levels of total and virus-specific CD8+ T cells, as well as increased T cellexpression of inhibitory receptor programmed death-1 (PD-1), in the lungs of Allo mice at Day 8 p.i. Adoptive transfer of CD8+ T cells from non-transplanted mice recovered from SeV infection into Allo mice at Day 8 p.i. restored normal levels of viral clearance, epithelial repair, and lung inflammation. ConclusionsTaken together these results indicate that allogeneic BMT results in more severe RVI based on the failure to develop an appropriate pulmonary CD8+ T cell response, providing an important potential mechanism to target in improving outcomes of RVI after BMT.

Benralizumab, an anti-interleukin 5 receptor α monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: a phase 2b randomised dose-ranging study

Persistent eosinophilic airway inflammation in asthma increases the risk of exacerbations. In a phase 2b dose-ranging study, we aimed to assess the efficacy and safety of benralizumab, an anti-interleukin 5 receptor α monoclonal antibody that depletes blood and airway eosinophils, in adults with uncontrolled eosinophilic asthma. We did a randomised, controlled, double-blind, dose-ranging phase 2b study. Eligible participants were adults aged 18-75 years with uncontrolled asthma using medium-dose or high-dose inhaled corticosteroids and longacting β agonists, with two to six exacerbations in the past year. Current or former smokers were excluded. We used the ELEN index (an algorithm to predict elevated sputum eosinophils) or baseline fraction of exhaled nitric oxide to stratify patients by eosinophilic status, and with an interactive web-voice response system randomly assigned eosinophilic individuals in a 1:1:1:1 ratio to receive placebo, 2 mg benralizumab, 20 mg benralizumab, or 100 mg benralizumab, and non-eosinophilic individuals in a 1:1 ratio to receive placebo or 100 mg benralizumab. Study drugs were given as two subcutaneous injections every 4 weeks for the first three doses, then every 8 weeks, for 1 year. Patients, treating physicians, and study investigators were masked to treatment allocation. The primary endpoint was annual exacerbation rate in eosinophilic individuals after 1 year of follow-up. Analysis was by modified intention to treat. This study was designed with a two-sided α of 0·2 and powered at 78% for the primary outcome in the eosinophilic population. This study is registered with ClinicalTrials.gov, number NCT01238861. Between Jan 3, 2011, and March 6, 2012, we randomly assigned 324 eosinophilic individuals to placebo (n=80) or benralizumab 2 mg dose (n=81), 20 mg dose, (n=81), or 100 mg dose (n=82), and 285 non-eosinophilic individuals to 100 mg benralizumab (n=142, 140 included in analysis) or placebo (n=143, 142 included in analysis). In eosinophilic individuals, benralizumab reduced exacerbation rates compared with placebo in the 100 mg group (0·34 vs 0·57, reduction 41%, 80% CI 11 to 60, p=0·096) but not in the 2 mg group (0·65 vs 0·57, difference -9%, 80% CI -59 to 26, p=0·781) or the 20 mg group (0·37 vs 0·57, reduction 36%, 80% CI 3 to 58, p=0·173). In patients with a baseline blood eosinophil cutoff of at least 300 cells per μL, exacerbation rates in the benralizumab 20 mg group (n=70) and 100 mg group (n=97) were lower than in the placebo group (n=83; 0·30 vs 0·68, reduction 57%, 80% CI 33 to 72, p=0·015 for 20 mg dose; 0·38 vs 0·68, difference 43%, 80% CI 18 to 60, p=0·049 for 100 mg dose). Our findings suggested that benralizumab 20 mg and 100 mg resided at the dose-response plateau. Treatment-emergent adverse events occurred in 277 (72%) of 385 participants receiving any benralizumab dose compared with 143 (65%) of 221 receiving placebo. Nasopharyngitis (44 [11%] patients receiving benralizumab vs 13 [6%] patients receiving placebo) and injection site reactions (60 [16%] vs eight [4%]) occurred more frequently with benralizumab than with placebo. Benralizumab at 20 mg and 100 mg doses seemed to reduce asthma exacerbations in adults with uncontrolled eosinophilic asthma and baseline blood eosinophils of at least 300 cells per μL, possibly due to targeting of the interleukin 5 receptor rather than interleukin 5 ligand. Further investigation of benralizumab treatment in phase 3 studies is warranted. MedImmune.