Format

Send to

Choose Destination
Am J Physiol Lung Cell Mol Physiol. 2016 Dec 1;311(6):L1062-L1075. doi: 10.1152/ajplung.00327.2016. Epub 2016 Sep 30.

Neutrophils promote alveolar epithelial regeneration by enhancing type II pneumocyte proliferation in a model of acid-induced acute lung injury.

Author information

1
Division of Pulmonary, Allergy, and Critical Care Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.
2
Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
3
Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
4
Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
5
Department of Viral Immunology, Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Kunming, China.
6
Department of Pathology and Laboratory Medicine, Cell Pathology Division, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
7
Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati, Cincinnati, Ohio.
8
Hofstra Northwell School of Medicine, Hempstead, New York.
9
The Penn Center for Pulmonary Biology, Perelman School of Medicine, Philadelphia, Pennsylvania.
10
Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; and.
11
Penn Institute of Regenerative Medicine, Perelman School of Medicine, Philadelphia, Pennsylvania.
12
Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; worthen@email.chop.edu.

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.

KEYWORDS:

acute respiratory distress syndrome; granulocyte-colony stimulating factor; neutrophils; pneumocyte; regeneration

PMID:
27694472
PMCID:
PMC5206401
DOI:
10.1152/ajplung.00327.2016
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Atypon Icon for PubMed Central
Loading ...
Support Center