TY - JOUR
T1 - Stress-induced eosinophil activation contributes to postoperative morbidity and mortality after lung resection
AU - Mei, Zhongcheng
AU - Khalil, May A.
AU - Guo, Yizhan
AU - Li, Dongge
AU - Banerjee, Anirban
AU - Taheri, Mojtaba
AU - Kratzmeier, Christina M.
AU - Chen, Kelly
AU - Lau, Christine L.
AU - Luzina, Irina G.
AU - Atamas, Sergei P.
AU - Kandasamy, Sivaveera
AU - Kreisel, Daniel
AU - Gelman, Andrew E.
AU - Jacobsen, Elizabeth A.
AU - Krupnick, Alexander Sasha
N1 - Publisher Copyright:
Copyright © 2024 The Authors, some rights reserved
PY - 2024/8/21
Y1 - 2024/8/21
N2 - Respiratory failure occurs more frequently after thoracic surgery than abdominal surgery. Although the etiology for this complication is frequently attributed to underlying lung disease present in patients undergoing thoracic surgery, this notion is often unfounded because many patients with normal preoperative pulmonary function often require prolonged oxygen supplementation even after minimal resection of lung tissue. Using a murine model of pulmonary resection and peripheral blood samples from patients undergoing resection of the lung or abdominal organs, we demonstrated that lung surgery initiates a proinflammatory loop that results in damage to the remaining lung tissue, noncardiogenic pulmonary edema, hypoxia, and even death. Specifically, we demonstrated that resection of murine lung tissue increased concentrations of the homeostatic cytokine interleukin-7, which led to local and systemic activation of type 2 innate lymphoid cells. This process activated lung-resident eosinophils and facilitated stress-induced eosinophil maturation in the bone marrow in a granulocyte-macrophage colony-stimulating factor–dependent manner, resulting in systemic eosinophilia in both mice and humans. Up-regulation of inducible nitric oxide synthase in lung-resident eosinophils led to tissue nitrosylation, pulmonary edema, hypoxia, and, at times, death. Disrupting this activation cascade at any stage ameliorated deleterious outcomes and improved survival after lung resection in the mouse model. Our data suggest that repurposing US Food and Drug Administration–approved eosinophil-targeting strategies may potentially offer a therapeutic intervention to improve outcomes for patients who require lung resection for benign or malignant etiology.
AB - Respiratory failure occurs more frequently after thoracic surgery than abdominal surgery. Although the etiology for this complication is frequently attributed to underlying lung disease present in patients undergoing thoracic surgery, this notion is often unfounded because many patients with normal preoperative pulmonary function often require prolonged oxygen supplementation even after minimal resection of lung tissue. Using a murine model of pulmonary resection and peripheral blood samples from patients undergoing resection of the lung or abdominal organs, we demonstrated that lung surgery initiates a proinflammatory loop that results in damage to the remaining lung tissue, noncardiogenic pulmonary edema, hypoxia, and even death. Specifically, we demonstrated that resection of murine lung tissue increased concentrations of the homeostatic cytokine interleukin-7, which led to local and systemic activation of type 2 innate lymphoid cells. This process activated lung-resident eosinophils and facilitated stress-induced eosinophil maturation in the bone marrow in a granulocyte-macrophage colony-stimulating factor–dependent manner, resulting in systemic eosinophilia in both mice and humans. Up-regulation of inducible nitric oxide synthase in lung-resident eosinophils led to tissue nitrosylation, pulmonary edema, hypoxia, and, at times, death. Disrupting this activation cascade at any stage ameliorated deleterious outcomes and improved survival after lung resection in the mouse model. Our data suggest that repurposing US Food and Drug Administration–approved eosinophil-targeting strategies may potentially offer a therapeutic intervention to improve outcomes for patients who require lung resection for benign or malignant etiology.
UR - http://www.scopus.com/inward/record.url?scp=85201998112&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.adl4222
DO - 10.1126/scitranslmed.adl4222
M3 - Article
C2 - 39167663
AN - SCOPUS:85201998112
SN - 1946-6234
VL - 16
JO - Science translational medicine
JF - Science translational medicine
IS - 761
M1 - eadl4222
ER -