Biomedical subjects

Simon D Message

Publications and source records attributed to Simon D Message.

5 recordsLinked to original sources

PubMed2006

An experimental model of rhinovirus induced chronic obstructive pulmonary disease exacerbations: a pilot study.

BACKGROUND: Acute exacerbations of COPD are a major cause of morbidity, mortality and hospitalisation. Respiratory viruses are associated with the majority of exacerbations but a causal relationship has not been demonstrated and the mechanisms of virus-induced exacerbations are poorly understood. Development of a human experimental model would provide evidence of causation and would greatly facilitate understanding mechanisms, but no such model exists. METHODS: We aimed to evaluate the feasibility of developing an experimental model of rhinovirus induced COPD exacerbations and to assess safety of rhinovirus infection in COPD patients. We carried out a pilot virus dose escalating study to assess the minimum dose of rhinovirus 16 required to induce experimental rhinovirus infection in subjects with COPD (GOLD stage II). Outcomes were assessed by monitoring of upper and lower respiratory tract symptoms, lung function, and virus replication and inflammatory responses in nasal lavage. RESULTS: All 4 subjects developed symptomatic colds with the lowest dose of virus tested, associated with evidence of viral replication and increased pro-inflammatory cytokines in nasal lavage. These were accompanied by significant increases in lower respiratory tract symptoms and reductions in PEF and FEV1. There were no severe exacerbations or other adverse events. CONCLUSION: Low dose experimental rhinovirus infection in patients with COPD induces symptoms and lung function changes typical of an acute exacerbation of COPD, appears safe, and provides preliminary evidence of causation.

Adult↗

PubMed2006

Role of deficient type III interferon-lambda production in asthma exacerbations.

Rhinoviruses are the major cause of asthma exacerbations, and asthmatics have increased susceptibility to rhinovirus and risk of invasive bacterial infections. Here we show deficient induction of interferon-lambdas by rhinovirus in asthmatic primary bronchial epithelial cells and alveolar macrophages, which was highly correlated with severity of rhinovirus-induced asthma exacerbation and virus load in experimentally infected human volunteers. Induction by lipopolysaccharide in asthmatic macrophages was also deficient and correlated with exacerbation severity. These results identify previously unknown mechanisms of susceptibility to infection in asthma and suggest new approaches to prevention and/or treatment of asthma exacerbations.

Asthma↗

PubMed2006

Rhinovirus replication in human macrophages induces NF-kappaB-dependent tumor necrosis factor alpha production.

Rhinoviruses (RV) are the major cause of acute exacerbations of asthma and chronic obstructive pulmonary disease (COPD). Rhinoviruses have been shown to activate macrophages, but rhinovirus replication in macrophages has not been reported. Tumor necrosis factor alpha (TNF-alpha) is implicated in the pathogenesis of acute exacerbations, but its cellular source and mechanisms of induction by virus infection are unclear. We hypothesized that rhinovirus replication in human macrophages causes activation and nuclear translocation of NF-kappaB, leading to TNF-alpha production. Using macrophages derived from the human monocytic cell line THP-1 and from primary human monocytes, we demonstrated that rhinovirus replication was productive in THP-1 macrophages, leading to release of infectious virus into supernatants, but was limited in monocyte-derived macrophages, likely due to type I interferon production, which was robust in monocyte-derived but deficient in THP-1-derived macrophages. Similar to bronchial epithelial cells, only small numbers of cells supported complete virus replication. We demonstrated RV-induced activation of NF-kappaB and colocalization of p65/NF-kappaB nuclear translocation with virus replication in both macrophage types. The infection induced TNF-alpha release in a time- and dose-dependent, RV serotype- and receptor-independent manner and was largely (THP-1 derived) or completely (monocyte derived) dependent upon virus replication. Finally, we established the requirement for NF-kappaB but not p38 mitogen-activated protein kinase in induction of TNF-alpha. These data suggest RV infection of macrophages may be an important source of proinflammatory cytokines implicated in the pathogenesis of exacerbations of asthma and COPD. They also confirm inhibition of NF-kappaB as a promising target for development of new therapeutic intervention strategies.

Asthma↗

PubMed2003

Host defense function of the airway epithelium in health and disease: clinical background.

Respiratory infection is extremely common and a major cause of morbidity and mortality worldwide. The airway epithelium has an important role in host defense against infection and this is illustrated in this review by considering infection by respiratory viruses. In patients with asthma or chronic obstructive pulmonary disease, respiratory viruses are a common trigger of exacerbations. Rhinoviruses (RV) are the most common virus type detected. Knowledge of the immunopathogenesis of such RV-induced exacerbations remains limited, but information is available from in vitro and from in vivo studies, especially of experimental infection in human volunteers. RV infects and replicates within epithelial cells (EC) of the lower respiratory tract. EC are an important component of the innate-immune response to RV infection. The interaction between virus and the intracellular signaling pathways of the host cell results in activation of potentially antiviral mechanisms, including type 1 interferons and nitric oxide, and in the production of cytokines and chemokines [interleukin (IL)-1 beta, IL-6, IL-8, IL-11, IL-16, tumor necrosis factor alpha, granulocyte macrophage-colony stimulating factor, growth-regulated oncogene-alpha, epithelial neutrophil-activating protein-78, regulated on activation, normal T expressed and secreted, eotaxin 1/2, macrophage-inflammatory protein-1 alpha], which influence the subsequent induced innate- and specific-immune response. Although this is beneficial in facilitating clearance of virus from the respiratory tract, the generation of proinflammatory mediators and the recruitment of inflammatory cells result in a degree of immunopathology and may amplify pre-existing airway inflammation. Further research will be necessary to determine whether modification of EC responses to respiratory virus infection will be of therapeutic benefit.

Adult↗

PubMed2002

Viruses in asthma.

Current evidence suggests that the overall load of infectious agents, including respiratory viruses, encountered early in life is an important factor influencing maturation of the immune system from a type 2 bias at birth towards predominantly type 1 responses, thus avoiding atopic diseases. The 'hygiene hypothesis' proposes that the relatively sterile environment present in industrialised Western countries has contributed to the recent epidemic of asthma and atopy. Whether specific infections are of greater or lesser protective value is an important question if strategies are to be derived to mimic the beneficial effects of childhood infection whilst avoiding morbidity and potential mortality of the natural pathogens. Infection by respiratory viruses is a major trigger of wheezing in infants and of exacerbations of asthma in older children. Viruses are detected in up to 85% of such episodes. Rhinovirus is common in all age groups; respiratory syncytial virus (RSV) is most important in infants and young children. Knowledge of the immunopathogenetic mechanisms of virus infection in the asthmatic airway will lead to the development of new treatments for virus-induced asthma.

Adolescent↗