Acute viral infections increase airway responsiveness and increase vagally mediated reflex bronchoconstriction by decreasing the function and/or expression of inhibitory M2 muscarinic receptors on the parasympathetic nerves. In vitro studies suggest that interferon-gamma (IFNgamma) may be involved in this effect. Induction of interferon gene expression is a response of the cell to double stranded RNA (dsRNA) produced during replication of RNA viruses. Intraperitoneal (i.p.) injection of dsRNA causes airway hyperresponsiveness and loss of airway M2 muscarinic receptors. Our hypothesis is that interferon, expressed in response to double stranded RNA, is inhibiting M2 receptor gene expression in the lungs. The following specific aims are proposed:
Specific aim number 1: To confirm the effects of i.p. dsRNA, and determine the role of IFN-gamma in these responses by pretreating animals with IFN-specific monoclonal antibodies. Circulating interferon will also be measured.
Specific aim number 2: To determined the role of macrophages, and of CD4+ and CD8+ T-lymphocytes, in the response to dsRNA. Macrophages will be depleted using liposome-encapsulated clodronate, and CD4+ and CD8+ T- lymphocytes will be depleted using specific monoclonal antibodies, before dsRNA treatment, and the effects of these treatment on the subsequent response ro dsRNA will be determined.
Specific aim number 3: To examine the effect of IFNbeta and dsRNA on M2 receptor gene expression and function in cultures of airway parasympathetic neurons.
| Bowerfind, William M L; Fryer, Allison D; Jacoby, David B (2002) Double-stranded RNA causes airway hyperreactivity and neuronal M2 muscarinic receptor dysfunction. J Appl Physiol 92:1417-22 |
