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Asthma is characterised by airway inflammation and airway hyperresponsiveness, resulting in reversible;e airway obstruction and paroxysmal coughing. The mechanisms by which viral infections exacerbate asthma are very complex. Recently there have been considerable advances in our understanding of asthma exacerbation at the cellular level and also the mechanisms of airway hyperresponsiveness.

Aggravation of Airway Inflammation and Cytokine Production
Many studies have investigated the mechanisms of virus induced exacerbation in airway inflammation. Eosinophils are very important effector cells in asthma, and are increased in the bronchial mucosa of asthmatic patients. Experimentally induced rhinovirus infection have been found to increase the infiltration of epithelial eosinoplhils. This persists into the convalescent period in subjects with asthma, but not in non asthmatics.Increased eosinophil products have also been observed in induced sputum supernatans from asthmatics subjects. Eosinophils from patients with RSV bronchiolitis produce more ECP in nasopharyngeal samples, supporting the hypothesis that eosinophils play a role in the development of asthma following RSV bronchiolitis. These data suggest that eosinophil infiltration is likely to be a crucial element in the pathology leading to the clinical exacerbation of asthma.

During experimental colds, CD3+, CD4+ and CD8+ T-lympho-cyte infiltration was also observed in the airway epithelium and submucosa. In asthmatic subjects, type 2 helper T-cells (Th2 cells) producing IL-4, which promotes isotype swithcing if IgE, are more increased relative to Th1 cells, which orduce IFN-y and IL-2. The Th2 cells producing IL-5, which promote eosinophil differtiation relative to Th1 cells. Cytotoxic CD8+ lymphocytes can be divided into type 1 cytotoxic T-cells (Tc1) cells which produce Th1-like cytokines, and Tc2 cells which produce Th1-like cytokines, and Tc2 cells which produce Th2-like cytokines. Respiratory viral infection normally promote CD4+ Th1 and CD8+ Tc1 responses, resulting in antiviral effects through the activation of Natural Killer cells by IL-2 and IFN-y. However, in atopic patients wit high levels of IL-4, the T-lymphocyte responses to viral infection may be different compared with that of non-atopic subjects. Coyle et al showed that a CD8+ lymphocyte-rich transgenic mouse model sensitised to ovalbumin increased the production if IL-5 but deceased IFN-y. In addition, CD8+ lymphocytes lost their cytotoxicity and increased production of IL-5 when cultured with IL-4 in vitro. These is some evidence that a Th2-like response during rhinovirus injection occurs in atopic subjects. Gern et al also showed that CD8+ lymphocytes from atopic subjects produce a higher amount of IL- than those from normal subjects. In cases of RSV bronchiolitis in infants, there is an imbalance in the immune factors produced in a Th2-like response. Further investigations area needed to clafiry these hypotheses.

Neutrophils are increased in the airways during viral infections. Nasal aspirates of asthmatic subjects contain increased levels of IL-8, with chemotaxis of neutrophils and myeloperoxidase from neutrophils during virus induced asthma exacerbation. Increased IL-8 levels have been reported in nasal lavage, and levels correlating with airway hyperactivity have been observed during rhinovirus infections. IL-8 from bronchial epithelial cells is also increased in virus induced asthma exacerbation. However, the role of neutrophils in the asthmatic airway is not clearly understood.

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The recruitment of inflammatory cells into the airways depends largely on epithelial cells. Epithelial cells are the initial sites of virus entry and replication, and adhesion molecules implicated in cell recruitment in virus induced asthma. The expresion of ICAM-1, the major receptor or rhinoviruses in epothelial cells, is induced by rhinovirus infections both in vitro and in vivo. This results in the recruitment and activation of intraepitelial lymphocytes and eosinophils. RSV alsi increases ICAM-1 expression. RANTES and GM-CSF from epithelial cells may also play an important role in the recruitment and activation of eosinophils, while IL-8 recruits neutropphils. In addition to these, eotaxin and MCP-4 are involved in eosinophil chemotaxis and activation. Epithelial cells also produce IL-11, which induced airway hyperresposiveness.

Adenoviruses, influenza viruses and RSV are well known to involve the lower airway, however it is not yet clear whether rhinoviruses invade the lower airway. Recently it has been reported that rhinoviruses are able to replicate at 37 C in addition to 30 C, their optimum temperature for replication. Virus genomes were also revealed to invade respiratory epithelial cells. This suggests that rhinoviruses may be directly involved in the aggravation of the allergic inflammation associated with brochial asthma.

Aggravation of Airway Hyperresponsiveness
The most common characteristics of asthma is airway hyperresponsiveness. It is wel known that aitrway hyperresponsiveness is aggravated by viral infections, resulting in virus induced exacerbation of airway hyperresponsiveness are as follows.

Alteration of Autonomic Nerveous System Function

Increase of Vagally Mediated Bronchocontriction

During viral infections, the activity of the cholinergic nerve asytem which cause bronchoconstriction is preventable by premedication woth atropine. This suggests that viral infection induces and increases vagally mediated bronchoconstritian. This is mainly due to the dysfunction of M2 muscarinic receptors, caused by various mediators, espercially the major basic protein from eosinophils which infiltrates the area around the vagus nerve. M2 muscarinic receptors are responsible for the feedback inhibiton of cholinergic activity.

Decrease of β2-Adrenergic Function The β2-adrenergic nervous system is implicated in the relaxation of bronchial smooth muscle, the decrease in leukocyte inflammatory response, and the inhibiton of mediator release. Leukocytes from patients with virus induced asthma exacerbation exhibit diminished β2-adrenergic function, suggesting that respiratory viruses can lead to grater inflammatory activity.

Sensory C Fibres and Neouropeptides Additional contributors to airway hyperreactivity are sensory C fibres which locally release sustance-P and neurokinin A, which are impotant meditaors in neurogenic inflammation.