Serum inter-alpha-trypsin inhibitor and matrix hyaluronan promote angiogenesis in fibrotic lung injury.
BACKGROUND
The etiology and pathogenesis of angiogenesis in idiopathic pulmonary fibrosis (IPF) is poorly understood. Inter-alpha-trypsin inhibitor (IaI) is a serum protein that can bind to hyaluronan (HA) and may contribute to the angiogenic response to tissue injury.


OBJECTIVE
To determine whether IaI promotes HA-mediated angiogenesis in tissue injury.


METHODS
An examination was undertaken of angiogenesis in IaI-sufficient and -deficient mice in the bleomycin model of pulmonary fibrosis and in angiogenesis assays in vivo and in vitro. IaI and HA in patients with IPF were examined.


RESULTS
IaI significantly enhances the angiogenic response to short-fragment HA in vivo and in vitro. lal deficiency Ieads to decreased angiogenesis in the matrigel model, and decreases lung angiogenesis after bleomycin exposure in mice. IaI is found in fibroblastic foci in IPF, where it colocalizes with HA. The colocalization is particularly strong in vascular areas around fibroblastic foci. Serum levels of IaI and HA are significantly elevated in patients with IPF compared with control subjects. High serum IaI and HA levels are associated with decreased lung diffusing capacity, but not FVC.


CONCLUSIONS
Our findings indicate that serum IaI interacts with HA, and promotes angiogenesis in lung injury. IaI appears to contribute to the vascular response to lung injury and may lead to aberrant angiogenesis. Clinical trial registered with www.clinicaltrials.gov (NCT00016627).
Garantziotis
Stavros
S
Clinical Research Unit, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA. garantziotis@niehs.nih.gov
Zudaire
Enrique
E
Trempus
Carol S
CS
Hollingsworth
John W
JW
Jiang
Dianhua
D
Lancaster
Lisa H
LH
Richardson
Elizabeth
E
Zhuo
Lisheng
L
Cuttitta
Frank
F
Brown
Kevin K
KK
Noble
Paul W
PW
Kimata
Koji
K
Schwartz
David A
DA
D000510:Alpha-Globulins / Q000378:metabolism*; D043925:Angiogenesis Inducing Agents / Q000097:blood*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D001761:Bleomycin / Q000008:administration & dosage; D018929:Cell Culture Techniques; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D006820:Hyaluronic Acid / Q000097:blood*; D008168:Lung / Q000098:blood supply; D055370:Lung Injury / Q000097:blood* / Q000139:chemically induced / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000097:blood*; D011658:Pulmonary Fibrosis / Q000097:blood* / Q000503:physiopathology; D012720:Severity of Illness Index; D014797:Vital Capacity
D000510:Alpha-Globulins; D043925:Angiogenesis Inducing Agents; D000903:Antibiotics, Antineoplastic; D001761:Bleomycin; C011877:inter-alpha-inhibitor; D006820:Hyaluronic Acid