Acute Respiratory Distress Syndrome (ARDS) is characterized by non-cardiogenic pulmonary edema leading to severe hypoxemia requiring mechanical ventilation. ARDS occurs as a result of acute lung injury (ALI) to pulmonary epithelium and/or endothelium. Using two different murine model of ALI, we found that the type 2- associated cytokine, IL-5, reduces lung edema and protects mice from mortality1. However, the mechanisms by which this cytokine attenuates ALI is not known, and elucidating these mechanisms is a primary goal of my new independent research group. IL-5 has classically been associated with detrimental eosinophilic responses in asthma and atopic disease. However, we found a novel beneficial role for IL-5 in the airways. Surprisingly, treatment with exogenous IL-5 in the airways was sufficient to reduce lung edema and rescue mice from death induced by bleomycin (BLM) challenge. Our preliminary data demonstrates an essential role for endogenous IL- 5 in survival from ALI, as IL-5 receptor-deficient (IL-5R?-/-) mice have increased edema and death after BLM challenge. No increase in mortality was observed in eosinophil-deficient mice compared to their wild-type littermates, suggesting that IL-5 may act in an eosinophil-independent manner. We confirmed the importance of IL-5 signaling in a second model of ALI induced by LPS and found that IL-5R?-/- mice had increased lung permeability and neutrophils compared to IL-5R?+/+ mice. These findings suggest that IL-5 is a critical cytokine for preserving barrier function in the lungs and protecting from ALI-induced mortality. To understand why barrier function is reduced in IL-5R?-/- mice, we examined structural cells in the lungs after injury and found a defect in epithelial proliferation. Further, we made the surprising discovery that the epithelium itself expressed IL-5R?. Expression of the IL-5R? was increased after BLM challenge and highest on dividing Ki67+ epithelial cells. IL- 5R? mRNA and protein was also expressed in primary human airway epithelial cells (AECs). AEC IL-5R? is functional since IL-5 treatment of differentiated epithelium in air-liquid interface cultures led to phosphorylation of Erk and Akt. The overall hypothesis of the proposed studies is that IL-5 acts on lung epithelium to reduce the edema and mortality associated with ALI. The effect of IL-5R? ligation on epithelial cells is completely unknown, and may be a novel pathway by which IL-5 protects against lung injury. These studies will provide essential understanding of the role of IL-5 in lung homeostasis and pathology and may change the paradigm that IL-5 acts solely on lung eosinophils. To test this hypothesis, we will perform the following two Aims.
Aim 1 : Determine the mechanism by which epithelial cells respond to IL-5 to promote survival from ALI in vivo.
Aim 2 : Determine the pathways activated by IL-5 in human airway epithelial cells in vitro. Our studies will demonstrate new, heretofore undescribed beneficial immune responses that occur during ALI and lung edema. IL-5 blocking antibodies are increasingly being used to treat eosinophilic diseases such as asthma, thus it is critical to understand the biological role of IL-5 on all cell types in lung disease.
Acute respiratory distress syndrome is the result of acute lung injury leading to severe pulmonary edema and hypoxia. We have preliminary data that specific types of immune responses can act on lung epithelium to reduce edema and support recovery. The goal of this study is to determine how these immune responses are protective.
