Neutrophil defensins enhance lung epithelial wound closure and mucin gene expression in vitro.
Human airways are frequently exposed to potentially harmful agents that cause tissue injury. Upon such injury, a repair process is initiated that comprises cell migration, proliferation, and differentiation. We have previously shown that human neutrophil defensins (human neutrophil peptides 1-3 [HNP1-3]) induce airway epithelial cell proliferation. Because of the role of cell proliferation in epithelial wound repair, we investigated the effect of HNP1-3 on airway epithelial wound closure and mucin gene expression in vitro. Using NCI-H292 airway epithelial cell cultures, we demonstrated that HNP1-3 cause a dose- and time-dependent increase of wound closure as well as increased cell migration. Furthermore, HNP1-3 caused a biphasic activation of the mitogen-activated protein kinase extracellular-regulated kinase 1 and 2 (ERK1/2). Both the effects of HNP1-3 on wound closure and ERK1/2 activation were blocked by specific inhibitors of the mitogen-activated protein kinase kinase MEK, whereas inhibitors of epidermal growth factor receptor tyrosine kinase, phosphatidylinositol 3-kinase, and Src did block defensin-enhanced wound closure but not ERK1/2 activation. Finally, HNP1-3 increased mRNA encoding the mucins MUC5B and MUC5AC, suggesting a role for defensins in mucous cell differentiation. These results indicate that neutrophil defensins increase epithelial wound repair in vitro, which involves migration and proliferation, and mucin production. Neutrophil defensin-enhanced wound repair appears to require epidermal growth factor receptor activation and downstream signaling pathways.
Aarbiou
Jamil
J
Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands. j.aarbiou@lumc.nl
Verhoosel
Renate M
RM
Van Wetering
Sandra
S
De Boer
Willem I
WI
Van Krieken
J Han J M
JH
Litvinov
Sergey V
SV
Rabe
Klaus F
KF
Hiemstra
Pieter S
PS
D000890:Anti-Infective Agents / Q000378:metabolism*; D002460:Cell Line; D002465:Cell Movement; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009077:Mucins / Q000235:genetics / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000166:cytology / Q000473:pathology*; D023084:alpha-Defensins / Q000378:metabolism*
D000890:Anti-Infective Agents; D009077:Mucins; D023084:alpha-Defensins; C406413:human neutrophil peptide 1; C406416:human neutrophil peptide 2; C406427:human neutrophil peptide 3; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases