Neutrophil extracellular traps enhance early inflammatory response in Sendai virus-induced asthma phenotype

Paramyxoviral infection in childhood has been linked to a significant increased rate of asthma development. In mice, paramyxoviral infection with the mouse parainfluenza virus type I, Sendai virus (Sev), causes a limited bronchiolitis followed by persistent asthma traits. We have previously shown that the absence of cysteine protease dipeptidyl peptidase I (DPPI) dampened the acute lung inflammatory response and the subsequent asthma phenotype induced by Sev. Adoptive transfer of wild type neutrophils into DPPI-deficient mice restored leukocyte influx, the acute cytokine response, and the subsequent mucous cell metaplasia that accompanied Sev-induced asthma phenotype. However, the exact mechanism by which DPPI-sufficient neutrophils promote asthma development following Sev infection is still unknown. We hypothesize that neutrophils recruited to the alveolar space following Sev infection elaborate neutrophil extracellular traps (NETs) that propagate the inflammatory cascade, culminating in the eventual asthma phenotype. Indeed, we found that Sev infection was associated with NET formation in the lung and release of cell-free DNA complexed to myeloperoxidase (MPO) in the alveolar space and plasma that peaked on day 2-post infection. Absence of DPPI significantly attenuated Sev-induced NET formation in vivo and in vitro. Furthermore, concomitant administration of DNase 1, which dismantled NETs, or inhibition of peptidylarginine deiminase 4 (PAD4), an essential mediator of NET formation, suppressed the early inflammatory responses to Sev infection. Lastly, NETs primed bone marrow derived cells to release cytokines that can amplify the inflammatory cascade

Asthma in childhood: a complex, heterogeneous disease

Asthma in childhood is a heterogeneous disease with different phenotypes and variable clinical manifestations, which depend on the age, gender, genetic background, and environmental influences of the patients. Several longitudinal studies have been conducted to classify the phenotypes of childhood asthma, on the basis of the symptoms, triggers of wheezing illness, or pathophysiological features of the disease. These studies have provided us with important information about the different wheezing phenotypes in young children and about potential mechanisms and risk factors for the development of chronic asthma. The goal of these studies was to provide a better insight into the causes and natural course of childhood asthma. It is well-known that complicated interactions between genes and environmental factors contribute to the development of asthma. Because childhood is a period of rapid growth in both the lungs and the immune system, developmental factors should be considered in the pathogenesis of childhood asthma. The pulmonary system continues to grow and develop until linear growth is completed. Longitudinal studies have reported significant age-related immune development during postnatal early life. These observations suggest that the phenotypes of childhood asthma vary among children and also in an individual child over time. Improved classification of heterogeneous conditions of the disease will help determine novel strategies for primary and secondary prevention and for the development of individualized treatment for childhood asthma

IL‐17E (IL‐25) and IL‐17RB promote respiratory syncytial virus‐induced pulmonary disease

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141555/1/jlb0809.pd

CCL20/CCR6 blockade enhances immunity to RSV by impairing recruitment of DC

Chemokines are important mediators of the immune response to pathogens, but can also promote chronic inflammatory states. Chemokine receptor 6 (CCR6) is found on immature DC and effector/memory T cells, and binds a single ligand, CCL20, with high affinity. Here, we investigated the role of CCL20 and CCR6 in a pulmonary viral infection caused by RSV, a ubiquitous virus that can cause severe pulmonary complications. Neutralization of CCL20 during RSV infection significantly reduced lung pathology and favored a Th1 effector response. CCR6-deficient animals recapitulated this phenotype, and additionally showed enhanced viral clearance when compared with WT mice. No differences were observed in migration of T cells to the lungs of CCR6 −/− animals; however, a significant reduction was observed in numbers of conventional DC (cDC), but not plasmacytoid DC, in CCR6 −/− mice. A pathogenic phenotype could be reconstituted in CCR6 −/− mice by supplying cDC into the airway, indicating that mere number of cDC dictates the adverse response. Our data suggest that blockade of the CCL20/CCR6 pathway provides an environment whereby the attenuated recruitment of cDC alters the balance of innate immune cells and mediates the efficient antiviral response to RSV.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/71373/1/1042_ftp.pd

Exposure of neonates to Respiratory Syncytial Virus is critical in determining subsequent airway response in adults

BACKGROUND: Respiratory syncytial virus (RSV) is the most common cause of acute bronchiolitis in infants and the elderly. Furthermore, epidemiological data suggest that RSV infection during infancy is a potent trigger of subsequent wheeze and asthma development. However, the mechanism by which RSV contributes to asthma is complex and remains largely unknown. A recent study indicates that the age of initial RSV infection is a key factor in determining airway response to RSV rechallenge. We hypothesized that severe RSV infection during neonatal development significantly alters lung structure and the pulmonary immune micro-environment; and thus, neonatal RSV infection is crucial in the development of or predisposition to allergic inflammatory diseases such as asthma. METHODS: To investigate this hypothesis the present study was conducted in a neonatal mouse model of RSV-induced pulmonary inflammation and airway dysfunction. Seven-day-old mice were infected with RSV (2 × 10(5 )TCID(50)/g body weight) and allowed to mature to adulthood. To determine if neonatal RSV infection predisposed adult animals to enhanced pathophysiological responses to allergens, these mice were then sensitized and challenged with ovalbumin. Various endpoints including lung function, histopathology, cytokine production, and cellularity in bronchoalveolar lavage were examined. RESULTS: RSV infection in neonates alone led to inflammatory airway disease characterized by airway hyperreactivity, peribronchial and perivascular inflammation, and subepithelial fibrosis in adults. If early RSV infection was followed by allergen exposure, this pulmonary phenotype was exacerbated. The initial response to neonatal RSV infection resulted in increased TNF-α levels in bronchoalveolar lavage. Interestingly, increased levels of IL-13 and mucus hyperproduction were observed almost three months after the initial infection with RSV. CONCLUSION: Neonatal RSV exposure results in long term pulmonary inflammation and exacerbates allergic airways disease. The early increase in TNF-α in the bronchoalveolar lavage implicates this inflammatory cytokine in orchestrating these events. Finally, the data presented emphasize IL-13 and TNF-α as potential therapeutic targets for treating RSV induced-asthma

How Exposures to Biologics Influence the Induction and Incidence of Asthma

A number of environmental factors can affect the development and severity of allergy and asthma; however, it can be argued that the most significant inhaled agents that modulate the development of these conditions are biologics. Sensitization to environmental allergens is an important risk factor for the development of asthma. Innate immune responses are often mediated by receptors on mononuclear cells whose primary ligands arise from microorganisms. Many pathogens, especially viruses, target epithelial cells and affect the host immune response to those pathogens. The acquired immune response to an allergen is influenced by the nature of the innate immune system. Products of innate immune responses to microbes promote T(H)1-acquired responses. In the absence of T(H)1 responses, T(H)2 responses can dominate. Central to T(H)1/T(H)2 balance is the composition of contaminants that derive from microbes. In this review we examine the biology of the response to allergens, viruses, and bacterial products in the context of the development of allergy and asthma

Cost effectiveness of palivizumab in Spain: an analysis using observational data

Objectives: To assess the cost effectiveness of palivizumab for prevention of severe respiratory syncytial virus (RSV) disease in high-risk infants in Spain, incorporating country-specific observational hospitalisation data. Methods: An existing decision tree model, designed using data from a large international clinical trial of palivizumab versus no prophylaxis, was updated to include Spanish observational hospitalisation data. The analysis was performed for preterm children born at or before 32 weeks gestational age, who are at high risk of developing severe RSV disease requiring hospitalisation. Data sources included published literature, official price/tariff lists and national population statistics. The primary perspective of the study was that of the Spanish National Health Service in 2006. Results: The base-case analysis included the direct medical costs associated with palivizumab prophylaxis and hospital care for RSV infections. Use of palivizumab produces an undiscounted incremental cost-effectiveness ratio (ICER) of €6,142 per quality-adjusted life-year (QALY), and a discounted ICER of €12,814/QALY. Conclusion: Palivizumab provides a cost-effective method of prophylaxis against severe RSV disease requiring hospitalisation among preterm infants in Spain

Azithromycin attenuates airway inflammation in a mouse model of viral bronchiolitis

<p>Abstract</p> <p>Background</p> <p>Viral bronchiolitis is the leading cause of hospitalization in young infants. It is associated with the development of childhood asthma and contributes to morbidity and mortality in the elderly. Currently no therapies effectively attenuate inflammation during the acute viral infection, or prevent the risk of post-viral asthma. We hypothesized that early treatment of a paramyxoviral bronchiolitis with azithromycin would attenuate acute and chronic airway inflammation.</p> <p>Methods</p> <p>Mice were inoculated with parainfluenza type 1, Sendai Virus (SeV), and treated daily with PBS or azithromycin for 7 days post-inoculation. On day 8 and 21 we assessed airway inflammation in lung tissue, and quantified immune cells and inflammatory mediators in bronchoalveolar lavage (BAL).</p> <p>Results</p> <p>Compared to treatment with PBS, azithromycin significantly attenuated post-viral weight loss. During the peak of acute inflammation (day 8), azithromycin decreased total leukocyte accumulation in the lung tissue and BAL, with the largest fold-reduction in BAL neutrophils. This decreased inflammation was independent of changes in viral load. Azithromycin significantly attenuated the concentration of BAL inflammatory mediators and enhanced resolution of chronic airway inflammation evident by decreased BAL inflammatory mediators on day 21.</p> <p>Conclusions</p> <p>In this mouse model of paramyxoviral bronchiolitis, azithromycin attenuated acute and chronic airway inflammation. These findings demonstrate anti-inflammatory effects of azithromycin that are not related to anti-viral activity. Our findings support the rationale for future prospective randomized clinical trials that will evaluate the effects of macrolides on acute viral bronchiolitis and their long-term consequences.</p

Sensitization to inhalant allergens between 4 and 8 years of age is a dynamic process: results from the BAMSE birth cohort

Allergic diseases are common in the growing population and have been increasing worldwide. Allergic sensitization, i.e. presence of Immunoglobulin E in the blood, is important for development of allergic disease and sensitization to foods often precedes sensitization to inhalant allergens. Peanut allergy is one of the most prevalent food allergies. It is rarely outgrown and is one of the major causes of fatal and near-fatal allergic reactions. However, asymptomatic peanut sensitization is common, but due to the risk of severe reactions, most peanut sensitized individuals have been regarded as peanut allergic from a clinical point of view. As a consequence, this has resulted in decreased quality of life due to fear of severe reactions. The overall aim of this thesis has been to analyse sensitization patterns to inhalant allergens over time, and to analyse birch pollen- and peanut-IgE antibodies and IgE to peanut allergen components in relation to symptoms of peanut allergy. The study populations in this thesis emanates from A) 4 089 children from a birth cohort (BAMSE) – with follow up at several time points up to eight years of age, Paper I-III and V, and from B) material from a clinical database, established during 2007-2010 of 237 consecutive children with suspected peanut or tree nut allergy, and attending the outpatient allergy clinic at Sachs’ Children’s Hospital. Of these children, 98 were included in study V based on sensitization pattern to peanut allergen components. Paper I describes the dynamic process of sensitization to inhalant allergens. Between four and eight years of age, the proportion of children sensitized to any of the inhalant allergens tested increased from 15% to 25%. At both four and eight years the prevalence of IgE to birch and cat dominated, but sensitization to timothy and dog increased relatively more during this period. In Paper II we showed that children at school age, sensitized both to birch pollen and peanut are less likely to exhibit high IgE levels to peanut and report symptoms to peanut as compared to children with sensitization to peanut, but not to birch pollen. In Paper III IgE reactivity to peanut allergen components in 200 eight-year-old children was investigated. Peanut symptoms were reported in 87% of the children with IgE reactivity to any of the storage proteins of the peanut allergen extract Ara h 1, 2 or 3. This is to be compared with 17% of children with IgE reactivity to Ara h 8 (Bet v 1 homologue), but not to Ara h 1, 2 or 3. Furthermore, symptoms were found to be more severe in children with Ara h 1, 2 or 3 IgE reactivity. Paper IV is a case report from Sachs’ Children’s Hospital, highlighting that sensitization to Ara h 6, homologous to Ara h 2, even in the absence of this latter protein component may cause severe reactions to peanut. This is likely to occur rarely. Paper V supports the suggestion that sensitization to Ara h 8 reflects mild OAS or peanut tolerance at oral peanut challenge. However, sensitization to so far unidentified determinants in peanut may in rare cases cause symptoms. In conclusion, sensitization to inhalant allergens is a dynamic process and birch sensitization dominates at the age of eight. Peanut component Ara h 1-3 sensitization is very often associated with true peanut allergy. Isolated Ara h 8 sensitization seems to indicate peanut tolerance. However, all peanut proteins related to IgE-mediated reactions may not yet have been identified and characterized