Viral induction of a chronic asthma phenotype and genetic segregation from the acute response

Abstract

Paramyxoviral infections cause most of the acute lower respiratory tract illness in infants and young children and predispose to the development of chronic wheezing, but the relationship between these short-and long-term viral effects are uncertain. Here we show that a single paramyxoviral infection of mice (C57BL6/J strain) not only produces acute bronchiolitis, but also triggers a chronic response with airway hyperreactivity and goblet cell hyperplasia lasting at least a year after complete viral clearance. During the acute response to virus, same-strain ICAM-1-null mice are protected from airway inflammation and hyperreactivity despite similar viral infection rates, but the chronic response proceeds despite ICAM-1 deficiency. Neither response is influenced by IFN-γ deficiency, but the chronic response is at least partially prevented by glucocorticoid treatment. In contrast to viral infection, allergen challenge caused only short-term expression of asthma phenotypes. Thus, paramyxoviruses cause both acute airway inflammation/hyperreactivity and chronic airway remodeling/hyperreactivity phenotypes (the latter by a hit-and-run strategy, since viral effects persist after clearance). These two phenotypes can be segregated by their dependence on the ICAM-1 gene and so depend on distinct controls that appear critical for the development of lifelong airway diseases such as asthma. Conflict of interest:No conflict of interest has been declared. Nonstandard abbreviations used: Sendai virus (SeV); 50% egg infectious dose (EID50); periodic acid-Schiff (PAS); enhanced pause (Penh); ovalbumin (Ova).newly described yet invariant feature of asthma: an intrinsic abnormality in cellular programming of the airway epithelium toward an anti-viral Th1 response (26). In particular, airway epithelial cells are specially programmed with anti-viral networks, and the behavior of these cells in asthma resembles a persistent antiviral response (27)(28)(29)(30)(31). It is also not certain how the Th2 hypothesis reconciles its insights into the allergic response -a short-term response -with the development of a lifelong disease.In that context, a relationship between viral infection and the development of chronic inflammatory disease has been proposed for diverse clinical syndromes, but the mechanistic basis for this relationship is still uncertain. Relevant to asthma, paramyxoviral infections are the leading cause of lower respiratory tract illness in infants and young children (32,33), and children with clinically significant viral bronchiolitis appear to be marked for the subsequent development of a chronic wheezing illness that is independent of allergy (34). Presumably paramyxoviral infection triggers an abnormal host response, since paramyxoviruses (and other respiratory RNA viruses) are not thought to persist in airway tissue as an ongoing stimulus of chronic respiratory disease (35). In either case (i.e., with or without viral persistence), the role of specific host factors in the development of acute or chronic wheezing or lifelo...

Neutrophil elastase induces mucus cell metaplasia in mouse lung

“…Neutrophilic inflammation is a common inflammatory response associated with the development of goblet cell metaplasia after LPS exposure in mouse lung (65), endotoxin exposure to rat nasal epithelium (47), ozone-exposed rat nasal epithelium (8), combined endotoxin and ozone exposure to rat nasal epithelium (57), or cigarette smoke exposure to mouse lung (33). Importantly, inhibition of neutrophilic inflammation by glucocorticoid treatment (22,58), or anti-neutrophil antiserum (8,47,57), reduces goblet cell metaplasia. Similar to these other models, we suggest that NE-induced inflammation plays an important role in the development of goblet cell metaplasia.…”

“…Endotoxin induces goblet cell metaplasia in mouse airways (65) and in rat nose (47) and potentiates ozone-induced goblet cell metaplasia (57) in rat nasal epithelium. Infection with paramyxovirus in mice induces a chronic goblet cell metaplasia (58); this response is partially mitigated by glucocorticoid treatment. Environmental toxins can also stimulate secretory cell remodeling, usually associated with an inflammatory response.…”

Respiratory syncytial virus–induced airway hyperresponsiveness is independent of IL-13 compared with that induced by allergen

“…Mucus production has not been associated with development of AHR in allergeninduced models 33 or in a model in which cytomegalovirus infection is combined with allergen. 34 Walter et al 35 reported on the differences in genetic control of AHR and goblet cell hyperplasia in Sendai virus-infected mice. Furthermore, we have previously shown that mucus hyperproduction per se is not essential to development of AHR after allergen sensitization and challenge.…”

“…19 It has generally been thought that IL-13 is primarily produced by T H 2 cells, but many cell types, including mast cells, 15 macrophages, 35 CD8, and T H 1 cells, 17,18 prominent cells in RSV pathology, can produce IL-13. Although IL-13 can aggravate eosinophilic inflammation in allergen-induced models, [10][11][12][13][14] it also might exhibit important anti-inflammatory properties.…”

Effects of viral respiratory infections on lung development and childhood asthma

“…Relevant to both the immune and pulmonary responses to infection, the stage of development might be a key determinant to the severity of the infection and the eventual pulmonary outcomes. For example, evidence in animal models indicates that infections in early life could cause reprogramming of epithelial cells 28,29 and modify the generation of antiviral T cells 30 to alter immune responses in the airway mucosa. In addition, LRIs during an active period of lung and immune development could adversely affect these processes to cause airway remodeling or to interfere with the generation of new alveoli.…”