Purpose of the Study.

To determine if bronchial epithelial cells (BECs) from asthma patients have abnormal innate responses to rhinovirus infection.

Study Population.

BECs from 14 subjects with moderate persistent asthma treated with inhaled corticosteroids (ICSs), 10 subjects with mild intermittent asthma who were never treated with ICSs, and 10 healthy controls.

Methods.

BECs were cultured from bronchial brushings obtained by bronchoscopy. BECs were studied prerhinovirus-16 infection, postinfection, and post–inactivated rhinovirus-16 exposure. Cytokines and chemokines were measured. Viable cell numbers, numbers of apoptotic cells, and cell lysate caspase activity were used to measure apoptotic activity. Apoptotic activity inhibition using the caspase-3 inhibitor, ZMD-fmk, was used to verify the presence of apoptosis. Rhinovirus-infection induction of interferon-β (IFN-β) was measured. Influence of IFN-β on apoptosis induction was evaluated by prerhinovirus and postrhinovirus infection treatment of BECs with exogenous IFN-β. The effect of IFN-β was also measured on virus titer preinfection and postinfection.

Results.

Rhinovirus-16 infection induced ICAM-1 (intercellular adhesion molecule-1), IL-6 (interleukin-6), and RANTES (regulated upon activation, normal T cells expressed and secreted) expression equally in BECs from asthmatic and healthy subjects. Viral RNA expression, lactate dehydrogenase activity, and virus titers all significantly increased in asthmatic versus healthy subjects’ BECs. The percentage of viable cells was 63% in asthmatic versus 80% in healthy subjects’ BECs, whereas apoptosis increased 1.4-fold in asthmatic and 2.2-fold in control subjects’ BECs (P = .02). Caspase activity increased significantly more in the control versus asthmatic subjects’ BECs postinfection. Induction of apoptosis in the healthy controls was inhibited by treatment of BECs with ZVD-fmk, and in a similar experiment, viral titers increased in the control BECs posttreatment and closely approximated the titers seen in infected asthmatic subjects’ BECs. Induction of IFN-β messenger RNA and IFN-β production were both significantly greater in the control versus the asthmatic subjects’ BECs. The effect of IFN-β on induction of apoptosis was evaluated: although apoptosis increased with posttreatment, there was significantly greater (P = .02) induction of apoptosis with pretreatment. Likewise, viral titers in the supernatant of infected asthmatic subjects’ BECs were inhibited by postinfection treatment with IFN-β but were most inhibited by pretreatment with IFN-β. Responses were similar between ICS-treated and ICS-naive asthmatic subjects.

Conclusions.

Examination of early innate immune responses revealed profound impairment of virus-induced IFN-β messenger RNA expression and IFN-β production from BECs of subjects with asthma. A novel use for type 1 interferons in the treatment or prevention of virus-induced asthma exacerbations is proposed.

Reviewer Comments.

How a rhinovirus infection induces an asthma exacerbation remains largely speculative. Differences between the innate immune response to rhinovirus infection of asthmatic and healthy subjects are demonstrated by using this novel approach. Very interesting is the lack of difference seen in ICS-naive and ICS-treated asthmatic subjects, which may explain why controversy remains regarding the role of ICSs in prevention of viral-induced asthma exacerbations. These data suggest that impairment in IFN-β production may be important in the induction of immune responses resulting in an asthma exacerbation. The authors’ proposal that type 1 interferon use may treat or prevent viral-induced asthma exacerbations is intriguing.

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