Acute viral respiratory infections may induce clinically relevant biological and physiological changes within the lower airway in susceptible individuals [1]. Although such infections are a potent trigger of asthma symptoms, there is as yet no consensus as to whether they can initiate asthma de novo [2]. Eighty per cent of asthma exacerbations in school-aged children and half of all adult asthma exacerbations have been associated with viral upper respiratory infections, mostly due to human rhinovirus (HRV) [3,4]. Studies on experimentally induced HRV infections suggest that the rhinovirus may induce a greater effect on lower airway inflammation and function in subjects with established asthma or allergy [5][6][7][8]. Separate observations indicate that atopic individuals may be more susceptible to the development of HRV infections [9]. The mechanisms of these events, however, have not been systematically investigated.The epithelial cells (EC) are the primary target of HRV infection in human airways. EC express on their surface the intercellular adhesion molecule (ICAM)-1, which is the site of attachment for 90% of the approximately 100 HRV serotypes [10][11][12]. ICAM-1 interacts physiologically with leukocyte function-associated antigen (LFA)-1, expressed on leukocytes, and thus plays a vital role in the recruitment and migration of immune effector cells to sites of local inflammation. Recent reports suggest that HRV may interfere with this ICAM-1/LFA-1 binding on leukocytes and thus disrupt immune responses that are dependent on this interaction. These effects could lead to a disorder of local airway immunity with increased risk of productive viral replication [13]. Furthermore, HRV per se influences the expression of ICAM-1 on EC. Studies by the present authors [14] and others [15,16] have shown that HRV significantly upregulate EC ICAM-1 expression, an effect that would facilitate viral cell attachment and entry.HRV infection induces the local production of cytokines, known to mediate the acute-phase reactions of airway inflammation [15,17,18]. These cytokines [19][20][21][22][23] can increase the expression of ICAM-1, although the level of induced expression depends on the specific mediator and the cell type [14,[24][25][26]. Recently, it has been shown that tumour necrosis factor (TNF)-α, interleukin (IL)-1β and IL-8 maintain their induced increase in cell ICAM-1 expression during HRV infection; in contrast, interferon (IFN)-γ increases ICAM-1 expression in uninfected cells but produces a persistent downregulation of ICAM-1 in These data suggest that the effects of Th2-associated cytokines on intercellular adhesion molecule-1 expression and recovery of infectious virus are dominant over the effects of the Th1-associated cytokines such as interferon-γ. Since the airway mucosa in atopic asthma is predominantly infiltrated by Th2 lymphocytes, these results could explain both the increased susceptibility to human rhinovirus infection in asthmatic patients and the associated exacerbation of asthma symptoms. Eur...

SUMMARYHuman rhinoviruses (HRV) are a major cause of upper respiratory tract infections in man, and can exacerbate existing pulmonary disease. The major group of HRV attach to ICAM-1, which is expressed on nasal and bronchial epithelial cells. To study the influence of biological mediators on ICAM-1 expression, and consequently HRV attachment and infection, we compared the effects of various cytokines, alone and in combination, on ICAM-1 expression by an uninfected and HRV-infected bronchial epithelial cell line H292. Cytokines known to be released soon after viral infection, such as tumour necrosis factor-alpha (TNF-a), IL-1b and the chemokine IL-8 increase ICAM-1 expression on uninfected cells. Epithelial cells infected with live HRV-14 displayed marked up-regulation of ICAM-1 compared with baseline. TNF-a further enhanced the HRV-induced increase in ICAM-1 expression on epithelial cells, peaking at day 4 after infection, whilst IL-8 exhibited a steady increase in ICAM-1 expression over 14 days. In contrast, IFN-g, a known Th1 antiviral lymphokine, whilst increasing the level of ICAM-1 on uninfected cells, induced a significant persistent down-regulation of ICAM-1 expression on HRV-infected epithelial cells. With combinations of TNF-a and IFN-g, ICAM-1 expression on HRV-infected cells was reduced to basal levels. The effects of IFN-g were paralleled by a reduction in viral titres. Our in vitro model has provided useful insights into the early pathogenic events of HRV infection at the level of the host cell-virus interaction. Our data confirm that biological mediators play a crucial role in the pathogenesis as well as the course of HRV infection which is modulated by the types, and time kinetics of inflammatory cytokines in the immediate microenvironment.

SUMMARYSince clinical experimental studies indicate that upper respiratory tract viral infections may exacerbate acute asthma symptoms in atopic/asthmatic individuals, we have investigated the expression and modulation of ICAM-1 on human nasal epithelial cells (HNEC) from normal and atopic subjects. ICAM-1 is the attachment molecule for the majority of serotypes of human rhinovirus (HRV), including HRV-14, and is also critical for the migration and activation of immune effector cells. Basal ICAM-1 expression was significantly higher in HNEC obtained by brushings from atopic compared with non-atopic subjects (P 0´031), and was also significantly increased on atopic HNEC harvested in season compared with out of season (P , 0´05). Atopic HNEC showed further up-regulation in ICAM-1 expression when cultured with clinically relevant allergen (P 0´032). ICAM-1 levels on normal HNEC were also increased by infection with HRV-14 (P , 0´05). Basal expression of ICAM-1 on atopic nasal polyp epithelial cells (EC) was significantly higher than on both normal and atopic nasal HNEC. This elevated nasal polyp ICAM-1 level was not increased further by allergen, although HRV infection resulted in a small significant increase. Recovered viral titres from HRV-infected nasal polyp EC were 1´5-fold higher than from infected normal nasal HNEC. The data are consistent with the hypothesis that allergen, by enhancing expression of the HRV attachment target on host cells, facilitates viral infection in atopic subjects; simultaneously HRV-induced increases in ICAM-1 levels would favour migration and activation of immune effector cells to the airway, resulting in enhanced atopic inflammation.

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The structure of an intermediate, in drosopterin biosynthesis, as 6-acetylpyrimidodiazepine has been confirmed by high-resolution mass spectra, 13C NMR, chemical ionization mass spectra, and chemical properties. A trivial name of 6-acetylhomopterin is suggested and should replace the term "quench spot" used heretofore. The structure of drosopterin includes, in part, a pyrimidodiazepine, a compound that consists of a fused six- and seven-membered heterocyclic ring system. Earlier studies demonstrated that 6-acetylhomopterin strongly stimulated the enzymatic synthesis of drosopterin and related eye pigments by preparations from Drosophila. The occurrence in nature is quite limited for diazepines; drosopterin and homopterin are the first examples in eukaryotes.