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Role of serine proteases in the regulation of interleukin-877 during the development of bronchopulmonary dysplasia in preterm ventilated infants

Chakraborty, Mallinath, McGreal, Eamon, Williams, Andrew, Davies, Philip, Powell, Wendy, Abdulla, Salima, Voitenok, Nikolai N., Hogwood, John, Gray, Elaine, Spiller, Brad, Chambers, Rachel C. and Kotecha, Sailesh 2014. Role of serine proteases in the regulation of interleukin-877 during the development of bronchopulmonary dysplasia in preterm ventilated infants. PLoS ONE 9 (12) , e114524. 10.1371/journal.pone.0114524

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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-877) is a less potent chemoattractant than other shorter isoforms. Although interleukin-877 is abundant in the preterm circulation, its regulation in the preterm lung is unknown. Objectives: To study expression and processing of pulmonary interleukin-877 in preterm infants who did and did not develop bronchopulmonary dysplasia. Methods: Total interleukin-8 and interleukin-877 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-877 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-877 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-877 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-877 by neutrophil serine proteases and thrombin. Processing of interleukin-8 provides an attractive therapeutic target to prevent development of bronchopulmonary dysplasia.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Publisher: Public Library of Science
ISSN: 1932-6203
Date of Acceptance: 11 November 2014
Last Modified: 21 May 2019 16:29
URI: http://orca.cf.ac.uk/id/eprint/79106

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