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A2704 - IL-5 Signaling Protects Mice Against Mortality from Acute Lung Injury
Author Block: C. L. Hrusch1, K. A. M. Mills1, P. A. Krishack1, D. M. Decker1, K. M. Blaine1, A. I. Sperling2; 1Medicine, University of Chicago, Chicago, IL, United States, 2Medicine/PCCM, University of Chicago, Chicago, IL, United States.
Objectives: Acute respiratory distress syndrome (ARDS) affects almost 200,000 people in the US each year with a mortality rate of 20-40%. Importantly, no specific therapeutic exists for patients with ARDS, and supportive care is the only treatment. 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 mice with defective type-2 immune responses are more susceptible to death. Further, exogenous treatment of mice with the type-2 cytokine IL-5 reduces ALI-induced edema and mortality. We hypothesized that IL-5 signaling is necessary for survival from ALI and may function by activating eosinophils.
Methods: IL-5Rα-/- mice, PHIL mice, or wild-type (WT) littermate control mice were treated intratracheally with 1.0-2.0U/kg bleomycin to induce ALI. Lungs were harvested at 3, 5, or 7 days post-treatment for analysis. Pulmonary edema was measured using the weight-to-dry weight ratio of lung tissue, and cell infiltrates were analyzed by flow cytometry. Mouse weights and survival were recorded daily.
Results: 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). Regulatory T cells (Tregs) are known to limit inflammation in a number of mouse models of ALI, and we examined whether IL-5Rα-/- mice had sufficient Tregs. No defect was observed in Treg activation and expansion in the IL-5Rα-/- mice, suggesting a different pathway was responsible for the poor outcomes in these mice. In WT mice, IL-5Rα was constitutively expressed by lung eosinophils and neutrophils. However, bleomycin challenge upregulated the receptor on alveolar macrophages, dendritic cells, and monocytes, indicating that IL-5 may regulate multiple innate cell populations during inflammation.
Conclusions: Our study demonstrates that IL-5 is a critical mediator of protection against lung injury, as IL-5 signaling was critical for survival and 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.