TY - JOUR T1 - Eosinophil-derived IL-13 Promotes Emphysema JF - European Respiratory Journal JO - Eur Respir J DO - 10.1183/13993003.01291-2018 SP - 1801291 AU - Alfred D. Doyle AU - Manali Mukherjee AU - William E. LeSuer AU - Tyler B. Bittner AU - Saif M. Pasha AU - Justin J. Frere AU - Joseph L. Neely AU - Jake A. Kloeber AU - Kelly P. Shim AU - Sergei I. Ochkur AU - Terence Ho AU - Sarah Svenningsen AU - Benjamin L. Wright AU - Matthew A. Rank AU - James J. Lee AU - Parameswaran Nair AU - Elizabeth A. Jacobsen Y1 - 2019/01/01 UR - http://erj.ersjournals.com/content/early/2019/01/23/13993003.01291-2018.abstract N2 - The inflammatory responses in chronic airway diseases leading to emphysema are not fully defined. We hypothesised that lung eosinophilia contributes to airspace enlargement in a mouse model, and emphysema in patients with COPD.A transgenic mouse model of chronic type 2 pulmonary inflammation (I5/hE2) was used to examine eosinophil-dependent mechanisms leading to airspace enlargement. Human sputum samples were collected for translational studies examining eosinophilia and MMP-12 levels in patients with chronic airways disease.Airspace enlargement was identified in I5/hE2 mice and was dependent on eosinophils. Examination of I5/hE2 bronchoalveolar lavage identified elevated MMP-12, a mediator of emphysema. We showed, in vitro, that eosinophil-derived IL-13 promoted alveolar macrophage MMP-12 production. Airspace enlargement in I5/hE2 mice was dependent on MMP-12 and eosinophil-derived IL-4/13. Consistent with this, MMP-12 was elevated in patients with sputum eosinophilia and CT-evidence of emphysema, and also negatively correlated with FEV1.A mouse model of chronic type 2 pulmonary inflammation exhibited airspace enlargement dependent on MMP-12 and eosinophil-derived IL-4/13. In chronic airways disease patients, lung eosinophilia was associated with elevated MMP-12 levels, which was a predictor of emphysema. These findings suggest an underappreciated mechanism by which eosinophils contribute to the pathologies associated with asthma and COPD.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. Mukherjee has nothing to disclose.Conflict of interest: Mr. LeSuer has nothing to disclose.Conflict of interest: Mr. Bittner has nothing to disclose.Conflict of interest: Saif Pasha has nothing to disclose.Conflict of interest: Mr. Frere has nothing to disclose.Conflict of interest: Joseph Neely has nothing to disclose.Conflict of interest: Jake Kloeber has nothing to disclose.Conflict of interest: Kelly Shim has nothing to disclose.Conflict of interest: Dr. Ochkur has nothing to disclose.Conflict of interest: Dr. Ho has nothing to disclose.Conflict of interest: Dr. Svenningsen has nothing to disclose.Conflict of interest: Dr. Wright reports other from Donald R. Levin Family Foundation, during the conduct of the study.Conflict of interest: Dr. Rank has nothing to disclose.Conflict of interest: Dr. Nair reports grants and personal fees from AstraZeneca, grants from Boehringer Ingelheim, grants and personal fees from Novartis, grants and personal fees from Sanofi, grants and personal fees from Teva, grants and personal fees from GSK, personal fees from Theravance, personal fees from Knopp, outside the submitted work.Conflict of interest: Dr. Jacobsen has nothing to disclose of conflict. Donald Levine donor money was given to Mayo Clinic as a gift to support research in eosinophils in allergy.Conflict of interest: Dr. James J. Lee is deceased (3/26/2017) and therefore nothing to disclose. This is filled by corresponding author Dr. Elizabeth Jacobsen.Conflict of interest: Dr. Doyle reports grants from NIH, other from Donald R. Levin Family Foundation, other from Mayo Clinic Sidney Luckman Family Predoctoral Fellowship, during the conduct of the study. ER -