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,¶,
* Department of Physiology and Biophysics,
Department of Pathology,
Department of Medicine, and
Gregory Fleming James Cystic Fibrosis Center, University of Alabama at Birmingham, AL 35294; and
¶ Division of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
Lung transplantation is a therapeutic modality frequently used in end-stage lung disease. Unfortunately, lung transplant recipients have poor clinical outcomes, often due to the development of bronchiolitis obliterans syndrome (BOS). This process is often characterized by the pathologic findings of obliterative bronchiolitis: neutrophil influx and extracellular matrix remodeling leading to luminal obstruction and airway inflammation. The molecular mechanisms underlying BOS are poorly understood and disease-specific biomarkers are lacking. We report that in addition to increased levels of IL-8, the level of the neutrophil chemoattractant proline-glycine-proline (PGP) is elevated in BOS patient bronchoalveolar lavage (BAL) fluid. The enzymes responsible for generating PGP, matrix metalloproteases 8 and -9 and prolyl endopeptidase, are also elevated in these samples. Together, IL-8 and PGP account for most of the neutrophil chemoattractant capacity seen in BOS BAL fluid. Using specific neutralizing Abs to both IL-8 and PGP, we demonstrate that PGP is a prominent neutrophil chemoattractant found in BAL fluid from individuals at the time of diagnosis of BOS. These findings highlight the influence of a matrix-derived neutrophil chemoattractant in posttransplantation BOS and provide opportunities for the development of unique diagnostics and therapeutics to potentially improve disease outcomes.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 A.G. is funded through the UAB Clinical Investigative Fellowship Award (MO1RR00032) and the Cystic Fibrosis Foundation (GAGGAR07A0). J.E.B. is funded through the Cystic Fibrosis Foundation (Grant R464-CR02) and the National Institutes of Health (Grants HL07783 and HL090999). U.V.D. is funded through the National Institutes of Health (Grant T32A107493). Purchase of the API-4000 mass spectrometer was provided by a grant to Dr. Steven Barnes from the UAB Health Services Foundation. The operation of the Shared Facility was provided by a NCI Core Support grant to the UAB Comprehensive Cancer Center (P30 CA13148).
2 The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Institutes of Health.
3 M.T.H. and F.S.G. have contributed equally to this work.
4 Address correspondence and reprint requests to Dr. J Edwin Blalock and Dr. Amit Gaggar Gregory Fleming James Cystic Fibrosis Center, University of Birmingham, 1918 University Boulevard, MCLM 898, Birmingham, AL 35294-0005. E-mail addresses: blalock{at}uab.edu and agaggar{at}uab.edu
5 Abbreviations used in this paper: BOS, bronchiolitis obliterans syndrome; BAL, bronchoalveolar lavage; FEV1, forced expiratory volume 1 s; FVC, forced vital capacity; MMP, matrix metalloprotease; N-
-PGP, N-terminal acetylated PGP; PE, prolyl endopeptidase; PGP, proline-glycine-proline; MPO, myeloperoxidase; PMN, polymorphonuclear leukocyte; CF, cystic fibrosis; ECM, extracellular matrix; COPD, chronic obstructive pulmonary disease; IPF, interstitial pulmonary fibrosis.
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