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Serum Inter–-Trypsin Inhibitor and Matrix Hyaluronan Promote Angiogenesis in Fibrotic Lung Injury

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

Correspondence and requests for reprints should be addressed to Stavros Garantziotis, M.D., Staff Clinician Medical Director, Clinical Research Unit, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709. E-mail: garantziotis{at}niehs.nih.gov

Rationale: The etiology and pathogenesis of angiogenesis in idiopathic pulmonary fibrosis (IPF) is poorly understood. Inter--trypsin inhibitor (IaI) is a serum protein that can bind to hyaluronan (HA) and may contribute to the angiogenic response to tissue injury.

Objectives: 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.

Measurements and Main 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).

Key Words: inter–-trypsin inhibitor • hyaluronan • angiogenesis • pulmonary fibrosis

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Pulmonary fibrosis leads to respiratory failure and death. The pathogenesis of pulmonary fibrosis is still unclear, but angiogenesis is believed to be a significant component. Extracellular matrix plays an important role in angiogenesis. What This Study Adds to the Field Serum inter–-trypsin inhibitor (IaI) and matrix hyaluronan are necessary for the angiogenic response to lung injury. IaI serum levels are inversely associated with gas exchange in fibrosis patients, indicating that IaI may be linked to aberrant angiogenesis.