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Research Article Free access | 10.1172/JCI118612

Constitutive activation of 5-lipoxygenase in the lungs of patients with idiopathic pulmonary fibrosis.

J Wilborn, M Bailie, M Coffey, M Burdick, R Strieter, and M Peters-Golden

Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, Ann Arbor, 48109, USA.

Find articles by Wilborn, J. in: PubMed | Google Scholar

Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, Ann Arbor, 48109, USA.

Find articles by Bailie, M. in: PubMed | Google Scholar

Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, Ann Arbor, 48109, USA.

Find articles by Coffey, M. in: PubMed | Google Scholar

Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, Ann Arbor, 48109, USA.

Find articles by Burdick, M. in: PubMed | Google Scholar

Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, Ann Arbor, 48109, USA.

Find articles by Strieter, R. in: PubMed | Google Scholar

Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, Ann Arbor, 48109, USA.

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Published April 15, 1996 - More info

Published in Volume 97, Issue 8 on April 15, 1996
J Clin Invest. 1996;97(8):1827–1836. https://doi.org/10.1172/JCI118612.
© 1996 The American Society for Clinical Investigation
Published April 15, 1996 - Version history
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Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive disorder characterized by inflammation, fibroblast proliferation, and accumulation of extracellular matrix proteins. Leukotrienes (LTs) are pro-inflammatory and pro-fibrogenic mediators derived from the 5-lipoxygenase (5-LO) pathway of arachidonic acid metabolism. They are thought to play a role in a number of disease processes, but have received relatively little attention in investigations into the pathogenesis of IPF. In this study, we measured the levels of immunoreactive LTs B(4) and C(4) in homogenates of lung tissue obtained from patients with newly diagnosed, untreated IPF, as compared to levels measured in homogenates of uninvolved nonfibrotic lung tissue from patients undergoing resectional surgery for bronchogenic carcinoma. Compared to homogenates on nonfibrotic control lung, homogenates from IPF patients contained 15-fold more LTB(4) and 5-fold more LTC(4). IPF homogenate levels of LTB(4) were significantly correlated with histologic indices of both inflammation (r=0.861) and fibrosis (r=0.926). Activation of 5-LO is known from in vitro studies to be associated with localization of the enzyme at the nuclear membrane. Immunohistochemical staining for 5-LO protein in alveolar macrophages (AMs) demonstrated that such an "activated" localization pattern was significantly more frequent in IPF lung (19.2+/-3.3% of cells) than in control lung (9.3+/-0.9%); this localization pattern was rarely seen (3.2%) in sections from a truly normal transplant donor lung. Consistent with these data, AMs obtained from IPF patients by bronchoalveolar lavage, purified by adherence, and cultured in the absence of a stimulus for 16 h elaborated significantly greater amounts of LTB(4) and LTC(4) than did control AMs obtained from normal volunteers. These data indicate that the 5-LO pathway is constitutively activated in the lungs of patients with IPF, and the AM represents at least one cellular source of LT overproduction in this disorder. We speculate that LTs participate in the pathogenesis of IPF, and their overproduction in this disorder may be amenable to specific pharmacotherapy.

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