title: Role of serine proteases in the regulation of interleukin-877 during the development of bronchopulmonary dysplasia in preterm ventilated infants.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Department of Child Health, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: Mallinath
authors.initials: M
authors.lastname: Chakraborty
authors.affiliation: Department of Child Health, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: Eamon P
authors.initials: EP
authors.lastname: McGreal
authors.affiliation: Centre for Inflammation and Tissue Repair, Rayne Institute, University College London, London, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Williams
authors.affiliation: Department of Child Health, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: Philip L
authors.initials: PL
authors.lastname: Davies
authors.affiliation: Department of Child Health, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: Wendy
authors.initials: W
authors.lastname: Powell
authors.affiliation: Department of Child Health, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: Salima
authors.initials: S
authors.lastname: Abdulla
authors.affiliation: Fund for Molecular Haematology and Immunology, Moscow, Russia.
authors.forename: Nikolai N
authors.initials: NN
authors.lastname: Voitenok
authors.affiliation: Division of Haematology, National Institute for Biological Standards and Control, Potters Bar, Hertfordshire, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Hogwood
authors.affiliation: Division of Haematology, National Institute for Biological Standards and Control, Potters Bar, Hertfordshire, United Kingdom.
authors.forename: Elaine
authors.initials: E
authors.lastname: Gray
authors.affiliation: Department of Child Health, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: Brad
authors.initials: B
authors.lastname: Spiller
authors.affiliation: Centre for Inflammation and Tissue Repair, Rayne Institute, University College London, London, United Kingdom.
authors.forename: Rachel C
authors.initials: RC
authors.lastname: Chambers
authors.affiliation: Department of Child Health, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: Sailesh
authors.initials: S
authors.lastname: Kotecha
mesh_terms: D001997:Bronchopulmonary Dysplasia / Q000201:enzymology / Q000209:etiology / Q000378:metabolism*; D002478:Cells, Cultured; D002633:Chemotaxis; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007234:Infant, Premature; D016209:Interleukin-8 / Q000097:blood* / Q000378:metabolism*; D009504:Neutrophils / Q000502:physiology; D012121:Respiration, Artificial / Q000009:adverse effects*; D057057:Serine Proteases / Q000378:metabolism*
chemical_list: D016209:Interleukin-8; C083743:interleukin 8 (77); D057057:Serine Proteases