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Published ahead of print on August 14, 2008, doi:10.1164/rccm.200803-386OC

Am. J. Respir. Crit. Care Med., Volume 178, Number 9, November 2008, 939-947

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Submitted on March 7, 2008
Accepted on August 14, 2008

Serum Inter-{alpha}-trypsin Inhibitor and Matrix Hyaluronan Promote Angiogenesis in Fibrotic Lung Injury

Stavros Garantziotis1*, Enrique Zudaire2, Carol S Trempus1, John W Hollingsworth3, Dianhua Jiang3, Lisa H Lancaster4, Elizabeth Richardson1, Lisheng Zhuo5, Frank Cuttitta2, Kevin K Brown6, Paul W Noble3, Koji Kimata5, and David A Schwartz7

1 National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA, 2 Angiogenesis Core Facility, National Cancer Institute, Gaithersburg, MD, USA, 3 Duke University Medical Center, Durham, NC, USA, 4 Vanderbilt University Medical Center, Nashville, TN, USA, 5 Institute for Molecular Science of Medicine, Aichi Medical University, Aichi, Japan, 6 National Jewish Medical and Research Center, Denver, CO, USA, 7 National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA; National Heart Lung and Blood Institute, Bethesda, MD, USA

* To whom correspondence should be addressed. E-mail: garantziotis{at}niehs.nih.gov.

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 and may contribute to the angiogenic response to tissue injury. Hypothesis: IaI promotes hyaluronan-mediated angiogenesis in tissue injury. Methods: Examination of angiogenesis in IaI-sufficient and deficient mice in the bleomycin model of pulmonary fibrosis and in angiogenesis assays in vivo and in vitro. Examination of IaI and hyaluronan in patients with IPF. Results: IaI significantly enhanced the angiogenic response to short-fragment hyaluronan in vivo and in vitro. IaI deficiency led to decreased angiogenesis in the matrigel model, and decreased lung angiogenesis after bleomycin exposure in mice. IaI is found in fibroblastic foci in IPF, where it co-localizes with hyaluronan. The co-localization is particularly strong in vascular areas around fibroblastic foci. Serum levels of IaI and hyaluronan were significantly elevated in IPF patients compared to controls. High serum IaI and hyaluronan levels were associated with decreased lung diffusing capacity, but not forced vital capacity. Conclusions: Our findings indicate that serum IaI interacts with hyaluronan, and promotes angiogenesis in lung injury. IaI appears to contribute to the vascular response to lung injury and may lead to aberrant angiogenesis. Clinical Trials Registry Information: ID# NCT00016627 registered at www.clinicaltrials.gov
Key words: inter-{alpha}-trypsin inhibitor, hyaluronan, angiogenesis, pulmonary fibrosis




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