Title: Neutrophils promote alveolar epithelial regeneration by enhancing type II pneumocyte proliferation in a model of acid-induced acute lung injury.
Authors: Paris, Andrew J; Liu, Yuhong; Mei, Junjie; Dai, Ning; Guo, Lei; Spruce, Lynn A; Hudock, Kristin M; Brenner, Jacob S; Zacharias, William J; Mei, Hankun D; Slamowitz, April R; Bhamidipati, Kartik; Beers, Michael F; Seeholzer, Steven H; Morrisey, Edward E; Worthen, G Scott
Published In Am J Physiol Lung Cell Mol Physiol, (2016 12 01)
Abstract: Alveolar epithelial regeneration is essential for resolution of the acute respiratory distress syndrome (ARDS). Although neutrophils have traditionally been considered mediators of epithelial damage, recent studies suggest they promote type II pneumocyte (AT2) proliferation, which is essential for regenerating alveolar epithelium. These studies did not, however, evaluate this relationship in an in vivo model of alveolar epithelial repair following injury. To determine whether neutrophils influence alveolar epithelial repair in vivo, we developed a unilateral acid injury model that creates a severe yet survivable injury with features similar to ARDS. Mice that received injections of the neutrophil-depleting Ly6G antibody had impaired AT2 proliferation 24 and 72 h after acid instillation, which was associated with decreased reepithelialization and increased alveolar protein concentration 72 h after injury. As neutrophil depletion itself may alter the cytokine response, we questioned the contribution of neutrophils to alveolar epithelial repair in neutropenic granulocyte-colony stimulating factor (G-CSF)-/- mice. We found that the loss of G-CSF recapitulated the neutrophil response of Ly6G-treated mice and was associated with defective alveolar epithelial repair, similar to neutrophil-depleted mice, and was reversed by administration of exogenous G-CSF. To approach the mechanisms, we employed an unbiased protein analysis of bronchoalveolar lavage fluid from neutrophil-depleted and neutrophil-replete mice 12 h after inducing lung injury. Pathway analysis identified significant differences in multiple signaling pathways that may explain the differences in epithelial repair. These data emphasize an important link between the innate immune response and tissue repair in which neutrophils promote alveolar epithelial regeneration.
PubMed ID: 27694472
MeSH Terms: Acids; Acute Lung Injury/chemically induced; Acute Lung Injury/pathology*; Alveolar Epithelial Cells/drug effects; Alveolar Epithelial Cells/metabolism; Alveolar Epithelial Cells/pathology*; Animals; Antibodies/pharmacology; Bronchoalveolar Lavage Fluid; Cell Proliferation/drug effects; Disease Models, Animal; Epithelium/drug effects; Epithelium/pathology*; Granulocyte Colony-Stimulating Factor/deficiency; Granulocyte Colony-Stimulating Factor/metabolism; Mice, Inbred C57BL; Neutrophils/drug effects; Neutrophils/metabolism; Neutrophils/pathology*; Proteomics; Regeneration*/drug effects; Respiratory Distress Syndrome, Adult/pathology; Signal Transduction/drug effects; Up-Regulation/drug effects; Wound Healing/drug effects