Neutrophils promote alveolar epithelial regeneration by enhancing type II pneumocyte proliferation in a model of acid-induced acute lung injury.
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.
Division of Pulmonary, Allergy, and Critical Care Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.|Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
Andrew J
0000-0002-9808-071X
AJ
Paris
Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.|Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
Yuhong
Y
Liu
Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.|Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
Junjie
J
Mei
Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.|Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
Ning
N
Dai
Department of Viral Immunology, Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Kunming, China.
Lei
L
Guo
Department of Pathology and Laboratory Medicine, Cell Pathology Division, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Lynn A
LA
Spruce
Division of Pulmonary, Allergy, and Critical Care Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.|Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.|Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati, Cincinnati, Ohio.
Kristin M
KM
Hudock
Division of Pulmonary, Allergy, and Critical Care Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.|Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
Jacob S
JS
Brenner
Division of Pulmonary, Allergy, and Critical Care Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.|Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
William J
WJ
Zacharias
Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.|Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
Hankun D
HD
Mei
Hofstra Northwell School of Medicine, Hempstead, New York.
April R
AR
Slamowitz
Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
Kartik
K
Bhamidipati
Division of Pulmonary, Allergy, and Critical Care Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.|Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.|The Penn Center for Pulmonary Biology, Perelman School of Medicine, Philadelphia, Pennsylvania.
Michael F
MF
Beers
Department of Pathology and Laboratory Medicine, Cell Pathology Division, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Steven H
SH
Seeholzer
Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.|The Penn Center for Pulmonary Biology, Perelman School of Medicine, Philadelphia, Pennsylvania.|Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; and.|Penn Institute of Regenerative Medicine, Perelman School of Medicine, Philadelphia, Pennsylvania.
Edward E
EE
Morrisey
Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; worthen@email.chop.edu.|Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.|The Penn Center for Pulmonary Biology, Perelman School of Medicine, Philadelphia, Pennsylvania.
G Scott
GS
Worthen
D000143:Acids; D055371:Acute Lung Injury / Q000139:chemically induced / Q000473:pathology*; D056809:Alveolar Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004848:Epithelium / Q000187:drug effects / Q000473:pathology*; D016179:Granulocyte Colony-Stimulating Factor / Q000172:deficiency / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D040901:Proteomics; D012038:Regeneration / Q000187:drug effects; D012128:Respiratory Distress Syndrome / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D014945:Wound Healing / Q000187:drug effects
D000143:Acids; D000906:Antibodies; D016179:Granulocyte Colony-Stimulating Factor
acute respiratory distress syndrome; granulocyte-colony stimulating factor; neutrophils; pneumocyte; regeneration
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