Asthma was the most common comorbidity in hospitalized patients during the 2009 influenza pandemic. structural physiological and immunological changes induced by influenza in the context of asthma. and were higher in healthy donor cells following viral infection (Figure 1c). Taken together these data suggest that epithelial cells from the asthmatic donor are equally susceptible to pH1N1 infection but are resistant to virus-induced damage possibly through reduced production of inflammatory cytokines such as IL-1α. These findings provided a rationale for more in-depth studies in mice. Stage in allergic asthma pathogenesis alters influenza morbidity Two murine models were created by infecting mice during different stages of allergic asthma pathogenesis (Figure 2A): a fungal asthma model where mice were infected with pH1N1 during peak acute inflammation (AA+Flu; Figure 2Aa) and a fungal asthma model where mice were Edoxaban infected with pH1N1 during chronic remodeling (CA+Flu; Figure 2Ab). Histological images are representative of the state of the large airways in Edoxaban the allergen-challenged mice at the time of virus infection (Figure 2A). Weight loss was used as an indicator of influenza morbidity. Naive mice did not lose weight in either model while flu-only controls gradually lost weight until day 8 with peak weight loss of 12-15% before recovery (Figure 2B). AA+Flu mice maintained weight throughout the model while CA+Flu Edoxaban mice lost Nfia weight after infection mimicking their flu-only counterparts (Figure 2B). Viral load in lungs peaked at day 3 and remained high through day 7 in flu-only controls correlating with peak weight loss (Figure 2B). Viral titers in the Edoxaban AA+Flu group were decreased at this time point indicating accelerated viral clearance; this was not observed in the CA+Flu model (Figure 2B). These data indicate that the allergic state of the airways at the time of influenza virus infection affects viral pathogenesis marked by body weight loss and viral replication. Figure 2 The developmental stage of allergic asthma impacts influenza morbidity. Schema of comorbidity models (A): (a) AA+Flu and (b) CA+Flu. Images represent the level of airway remodeling in AA and CA lungs at the time of infection. Weight loss … As viral Edoxaban infection causes symptomology that may mimic asthma episodes 13 and respiratory viruses such as rhinovirus and respiratory syncytial virus have been shown to induce asthma we measured the resistance in the conducting airways (Rn) and changes in tissue parameters tissue damping (G) and tissue elastance (H) in the models. Mice in the flu-only control groups of both models responded to methacholine challenge with values and trends equivalent to the AA+Flu groups (data not shown). However responses in the CA+Flu groups were lower than in the AA+Flu group (Figure 2C). Thus the allergic state of the airways at the time of virus introduction alters the physiological response of the lungs to virus infection. We investigated airway immune profiles next because inflammatory cells and their products can cause pathophysiological changes. Cell recruitment patterns differed between acute and chronic models after influenza Lung inflammation occurs in asthma and respiratory infections albeit with different types of immune cells taking precedence. There were threefold more cells in the airways at day Edoxaban 0 in AA compared with that of the CA model and naive controls (Figure 3). A reduction in cell infiltration occurred over time after virus in the AA+Flu model but not in the CA+Flu model (Figure 3). Peak airway inflammation of flu-only controls occurred at day 7 (Figure 3) coinciding with sustained viral replication in these mice (Figure 2). Figure 3 Inflammatory cell recruitment into the airways after pH1N1 infection. There were more cells recruited into the AA+Flu airways particularly eosinophils and flu-specific CD8+ T cells (a). The influx of cells was reduced in the CA+Flu … Influenza virus is known to induce neutrophil and T-cell recruitment and this was seen in both ‘flu-only’ control groups (Figure 3). Eosinophils which were prominent in AA airways continued.