Early interleukin 4-dependent response can induce airway hyperreactivity before development of airway inflammation in a mouse model of asthma

in experimental models of bronchial asthma with mice, airway inflammation a nd increase in airway hyperreactivity (AHR) are induced by a combination of systemic sensitization and airway challenge with allergens. In this report , we present another possibility: that systemic antigen-specific sensitizat ion alone can induce AHR before the development of inflammation in the airw ay. Male BALB/c mice were sensitized with ovalbumin (OVA) by a combination of intraperitoneal injection and aerosol inhalation, and various parameters for airway inflammation and hyperreactivity were sequentially analyzed. Br onchial response measured by a noninvasive method (enhanced pause) and the eosinophil count and interleukin (IL)-5 concentration in bronchoalveolar la vage fluid (BALF) gradually increased following the sensitization, and sign ificant increase was achieved after repeated OVA aerosol inhalation along w ith development of histologic changes of the airway. In contrast, AHR was a lready significantly increased by systemic sensitization alone, although ai rway inflammation hardly developed at that time point. BALF IL-4 concentrat ion and the expression of IL-4 mRNA in the lung reached maximal values afte r the systemic sensitization, then subsequently decreased. Treatment of mic e with anti-IL-4 neutralizing antibody during systemic sensitization signif icantly suppressed this early increase in AHR. In addition, IL-4 gene-targe ted mice did not reveal this early increase in AHR by systemic sensitizatio n. These results suggest that an immune response in the lung in an early st age of sensitization can induce airway hyperreactivity before development o f an eosinophilic airway inflammation in BALB/c mice and that IL-4 plays an essential role in this process. If this early increase in AHR does occur i n sensitized human infants, it could be another therapeutic target for earl y prevention of the future onset of asthma.