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

Clinical Research Unit, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
American Journal of Respiratory and Critical Care Medicine (Impact Factor: 13). 09/2008; 178(9):939-47. DOI: 10.1164/rccm.200803-386OC
Source: PubMed


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.
To determine whether IaI promotes HA-mediated angiogenesis in tissue injury.
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.
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.
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 (NCT00016627).


Available from: Stavros Garantziotis
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    • "In bleomycin-challenged mice, IαI and HA normally appear to co-localize within inflamed lungs whereas in mice lacking IαI, increased levels of HA and cellular inflammation were noted. Together this suggests that HA–HC complexes may contribute to the resolution of lung injury (61, 192). Previous studies have shown HA–HC complexes are higher affinity for CD44 (74), and it is plausible that these HA-binding proteins work together to mediate tissue homeostasis within the lung. "
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