Inter-alpha-trypsin inhibitor promotes bronchial epithelial repair after injury through vitronectin binding.
Pulmonary epithelial injury is central to the pathogenesis of many lung diseases, such as asthma, pulmonary fibrosis, and the acute respiratory distress syndrome. Regulated epithelial repair is crucial for lung homeostasis and prevents scar formation and inflammation that accompany dysregulated healing. The extracellular matrix (ECM) plays an important role in epithelial repair after injury. Vitronectin is a major ECM component that promotes epithelial repair. However, the factors that modify cell-vitronectin interactions after injury and help promote epithelial repair are not well studied. Inter-alpha-trypsin inhibitor (IaI) is an abundant serum protein. IaI heavy chains contain von Willebrand A domains that can bind the arginine-glycine-aspartate domain of vitronectin. We therefore hypothesized that IaI can bind vitronectin and promote vitronectin-induced epithelial repair after injury. We show that IaI binds vitronectin at the arginine-glycine-aspartate site, thereby promoting epithelial adhesion and migration in vitro. Furthermore, we show that IaI-deficient mice have a dysregulated response to epithelial injury in vivo, consisting of decreased proliferation and epithelial metaplasia. We conclude that IaI interacts not only with hyaluronan, as previously reported, but also other ECM components like vitronectin and is an important regulator of cellular repair after injury.
Adair
Jennifer E
JE
From the National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Stober
Vandy
V
From the National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Sobhany
Mack
M
From the National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Zhuo
Lisheng
L
Institute for Molecular Science of Medicine, Aichi Medical University, Aichi 480-1195, Japan.
Roberts
John D
JD
From the National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Negishi
Masahiko
M
From the National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Kimata
Koji
K
Institute for Molecular Science of Medicine, Aichi Medical University, Aichi 480-1195, Japan.
Garantziotis
Stavros
S
From the National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709. Electronic address: garantziotis@niehs.nih.gov.
D000510:Alpha-Globulins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D001980:Bronchi / Q000293:injuries* / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D004847:Epithelial Cells / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009842:Oligopeptides / Q000737:chemistry; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019096:Vitronectin / Q000737:chemistry / Q000378:metabolism*; D014945:Wound Healing / Q000502:physiology
D000510:Alpha-Globulins; D009842:Oligopeptides; D012333:RNA, Messenger; D019096:Vitronectin; C011877:inter-alpha-inhibitor; C047981:arginyl-glycyl-aspartic acid