IL-5 signaling protects mice against mortality from acute lung injury

Acute respiratory distress syndrome (ARDS) affects almost 200,000 people in the US each year with a mortality rate of 20–40%. ARDS occurs as a result of acute lung injury (ALI)-induced damage to pulmonary epithelium and/or endothelium. In a bleomycin model of ALI, we previously have shown that ICOS−/− mice, which have defective type-2 immune responses, are more susceptible to death. However, exogenous treatment of these mice with IL-5 reduces lung edema and mortality. We hypothesized that IL-5 signaling is necessary for survival from ALI and examined how mice deficient in IL-5Rα respond during ALI. IL-5Rα−/− mice had significantly increased lung edema at day 5 post-bleomycin challenge compared to WT mice (P=0.014), and had 100% mortality by day 15 (P=0.0002). IL-5Rα−/− mice had severely reduced numbers of lung eosinophils before and after challenge compared to WT mice, suggesting that eosinophils may provide protection from ALI. However, we found no difference in survival between eosinophil-deficient PHIL mice and WT mice (P=0.36). In WT mice, IL-5Rα was constitutively expressed by lung eosinophils and neutrophils. However, bleomycin challenge upregulated the receptor on myeloid cells and epithelial cells, indicating that IL-5 may regulate multiple cell populations during inflammation. Our study demonstrates that IL-5 is a critical mediator of protection against lung injury by maintaining barrier function in the lung. Surprisingly, eosinophils may not be required for the protective effect, and our data suggests that many lung cell types are capable of responding to IL-5 in the context of ALI. Thus, IL-5 may be a novel therapeutic strategy to protect against lung injury following pulmonary infection, sepsis, or trauma.