Role of Serine Proteases in the Regulation of Interleukin-877 during the Development of Bronchopulmonary Dysplasia in Preterm Ventilated Infants

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Abstract

Rationale

The chemokine interleukin-8 is implicated in the development of bronchopulmonary dysplasia in preterm infants. The 77-amino acid isoform of interleukin-8 (interleukin-8 ₇₇) is a less potent chemoattractant than other shorter isoforms. Although interleukin-8 ₇₇ is abundant in the preterm circulation, its regulation in the preterm lung is unknown.

Objectives

To study expression and processing of pulmonary interleukin-8 ₇₇ in preterm infants who did and did not develop bronchopulmonary dysplasia.

Methods

Total interleukin-8 and interleukin-8 ₇₇ were measured in bronchoalveolar lavage fluid from preterm infants by immunoassay. Neutrophil serine proteases were used to assess processing. Neutrophil chemotaxis assays and degranulation of neutrophil matrix metalloproteinase-9 were used to assess interleukin-8 function.

Main Results

Peak total interleukin-8 and interleukin-8 ₇₇ concentrations were increased in infants who developed bronchopulmonary dysplasia compared to those who did not. Shorter forms of interleukin-8 predominated in the preterm lung (96.3% No-bronchopulmonary dysplasia vs 97.1% bronchopulmonary dysplasia, p>0.05). Preterm bronchoalveolar lavage fluid significantly converted exogenously added interleukin-8 ₇₇ to shorter isoforms (p<0.001). Conversion was greater in bronchopulmonary dysplasia infants (p<0.05). This conversion was inhibited by α-1 antitrypsin and antithrombin III (p<0.01). Purified neutrophil serine proteases efficiently converted interleukin-8 ₇₇ to shorter isoforms in a time- and dose-dependent fashion; shorter interleukin-8 isoforms were primarily responsible for neutrophil chemotaxis (p<0.001). Conversion by proteinase-3 resulted in significantly increased interleukin-8 activity in vitro (p<0.01).

Conclusions

Shorter, potent, isoforms interleukin-8 predominate in the preterm lung, and are increased in infants developing bronchopulmonary dysplasia, due to conversion of interleukin-8 ₇₇ by neutrophil serine proteases and thrombin. Processing of interleukin-8 provides an attractive therapeutic target to prevent development of bronchopulmonary dysplasia.

Related collections

Most cited references 45

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Neutrophil gelatinase B potentiates interleukin-8 tenfold by aminoterminal processing, whereas it degrades CTAP-III, PF-4, and GRO-alpha and leaves RANTES and MCP-2 intact.

Wim Wuyts, Karolien P B Van den Bergh, Jacqueline van der Spuy … (2000)

Chemokines are mediators in inflammatory and autoimmune disorders. Aminoterminal truncation of chemokines results in altered specific activities and receptor recognition patterns. Truncated forms of the CXC chemokine interleukin (IL)-8 are more active than full-length IL-8 (1-77), provided the Glu-Leu-Arg (ELR) motif remains intact. Here, a positive feedback loop is demonstrated between gelatinase B, a major secreted matrix metalloproteinase (MMP-9) from neutrophils, and IL-8, the prototype chemokine active on neutrophils. Natural human neutrophil progelatinase B was purified to homogeneity and activated by stromelysin-1. Gelatinase B truncated IL-8(1-77) into IL-8(7-77), resulting in a 10- to 27-fold higher potency in neutrophil activation, as measured by the increase in intracellular Ca(++) concentration, secretion of gelatinase B, and neutrophil chemotaxis. This potentiation correlated with enhanced binding to neutrophils and increased signaling through CXC chemokine receptor-1 (CXCR1), but it was significantly less pronounced on a CXCR2-expressing cell line. Three other CXC chemokines-connective tissue-activating peptide-III (CTAP-III), platelet factor-4 (PF-4), and GRO-alpha-were degraded by gelatinase B. In contrast, the CC chemokines RANTES and monocyte chemotactic protein-2 (MCP-2) were not digested by this enzyme. The observation of differing effects of neutrophil gelatinase B on the proteolysis of IL-8 versus other CXC chemokines and on CXC receptor usage by processed IL-8 yielded insights into the relative activities of chemokines. This led to a better understanding of regulator (IL-8) and effector molecules (gelatinase B) of neutrophils and of mechanisms underlying leukocytosis, shock syndromes, and stem cell mobilization by IL-8. (Blood. 2000;96:2673-2681)

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α-1 Antitrypsin regulates human neutrophil chemotaxis induced by soluble immune complexes and IL-8.

Oliver McElvaney, A Bergin, C Condron … (2010)

Hereditary deficiency of the protein α-1 antitrypsin (AAT) causes a chronic lung disease in humans that is characterized by excessive mobilization of neutrophils into the lung. However, the reason for the increased neutrophil burden has not been fully elucidated. In this study we have demonstrated using human neutrophils that serum AAT coordinates both CXCR1- and soluble immune complex (sIC) receptor-mediated chemotaxis by divergent pathways. We demonstrated that glycosylated AAT can bind to IL-8 (a ligand for CXCR1) and that AAT-IL-8 complex formation prevented IL-8 interaction with CXCR1. Second, AAT modulated neutrophil chemotaxis in response to sIC by controlling membrane expression of the glycosylphosphatidylinositol-anchored (GPI-anchored) Fc receptor FcγRIIIb. This process was mediated through inhibition of ADAM-17 enzymatic activity. Neutrophils isolated from clinically stable AAT-deficient patients were characterized by low membrane expression of FcγRIIIb and increased chemotaxis in response to IL-8 and sIC. Treatment of AAT-deficient individuals with AAT augmentation therapy resulted in increased AAT binding to IL-8, increased AAT binding to the neutrophil membrane, decreased FcγRIIIb release from the neutrophil membrane, and normalization of chemotaxis. These results provide new insight into the mechanism underlying the effect of AAT augmentation therapy in the pulmonary disease associated with AAT deficiency.

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Pathology of new bronchopulmonary dysplasia.

Jacqueline J. Coalson (2003)

Technological advances, improved ventilatory strategies and better nursing techniques, coupled with the use of prenatal steroids and postnatal surfactant, have resulted in the survival of smaller and more immature infants. Preterm infants likely to develop bronchopulmonary dysplasia (BPD) are born during the canalicular phase of lung development at 24-26 weeks, a time when alveolar and distal vascular development commences. The histopathologic lesions of severe airway injury and alternating sites of overinflation and fibrosis in 'old' BPD have been replaced in 'new' BPD with the pathologic changes of large, simplified alveolar structures, a dysmorphic capillary configuration and variable interstitial cellularity and/or fibroproliferation. Airway and vascular lesions, when present, tend to occur in infants who over time develop more severe disease. The alveolar and capillary hypoplasia of new BPD will require the development of specific therapies, but avoiding volutrauma, oxidant injury and inflammation/infection will improve lung morphology.

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Author and article information

Contributors

Oliver Eickelberg: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2014

Publication date (Electronic): 4 December 2014

Volume: 9

Issue: 12

Electronic Location Identifier: e114524

Affiliations

[1 ]Department of Child Health, School of Medicine, Cardiff University, Cardiff, United Kingdom

[2 ]Centre for Inflammation and Tissue Repair, Rayne Institute, University College London, London, United Kingdom

[3 ]Fund for Molecular Haematology and Immunology, Moscow, Russia

[4 ]Division of Haematology, National Institute for Biological Standards and Control, Potters Bar, Hertfordshire, United Kingdom

Helmholtz Zentrum München/Ludwig-Maximilians-University Munich, Germany

Author notes

* E-mail: kotechas@ 123456cardiff.ac.uk

Competing Interests: This study was funded in part by Arriva Pharmaceuticals. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Conceived and designed the experiments: MC EPM SK. Performed the experiments: MC EPM AW PLD WP SA JH EG BS RCC. Analyzed the data: MC EPM AW PLD WP SA JH EG BS RCC. Contributed reagents/materials/analysis tools: NNV. Wrote the paper: MC EPM SK.

¶ These authors are joint first authors on this work.

Article

Publisher ID: PONE-D-14-11424

DOI: 10.1371/journal.pone.0114524

PMC ID: 4256433

PubMed ID: 25474412

SO-VID: 459365fd-a230-4f5a-9d95-699b08b3dc0b

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 14 March 2014

Date accepted : 11 November 2014

Page count

Pages: 22

Funding

This work was supported by Sparks, The Children's Medical Research Charity ( http://www.sparks.org.uk/) and by Arriva Pharmaceuticals. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Data Availability The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files.

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