title: Hypoxia down-regulates expression of secretory leukocyte protease inhibitor in bronchial epithelial cells via TGF-β1.
abstract: BACKGROUND
  Secretory leukocyte protease inhibitor (SLPI) is a protein with anti-protease and antimicrobial properties that is constitutively secreted from the airway epithelium. The importance of maintaining a balance between proteases and anti-proteases, and robust innate defence mechanisms in the airways, is exemplified by inflammatory lung conditions such as chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF). Both conditions present with a high protease burden in the airways which leads to tissue destruction. These patients also have an impaired innate immune system in the lungs with bacterial colonization and frequent airway infections. Moreover, both diseases are associated with airway hypoxia due to inflammation and mucus plugs. The aim of the present study was to investigate the role of hypoxia on SLPI production from the airway epithelium.
  
  
  METHODS
  Primary human bronchial epithelial cells were grown in sub-immersed cultures or as differentiated epithelium in air liquid interface cultures. Cells were incubated at 21% O2 (normoxia) or 1% O2 (hypoxia), and the release of SLPI was analysed with ELISA. RT-PCR was used to study the expression of SLPI and transforming growth factor β1 (TGF-β1).
  
  
  RESULTS
  Hypoxia decreased the constitutive production of SLPI by bronchial epithelial cells. The multifunctional cytokine TGF-β1, which is known to affect SLPI expression, showed increased expression in hypoxic bronchial epithelial cells. When bronchial epithelial cells were exposed to exogenous TGF-β1 during normoxia, the SLPI production was down-regulated. Addition of TGF-β1-neutralizing antibodies partially restored SLPI production during hypoxia, showing that TGF-β1 is an important regulator of SLPI during hypoxic conditions.
  
  
  CONCLUSIONS
  The mechanism described here adds to our knowledge of the pathogenesis of severe pulmonary diseases associated with hypoxia, e.g. COPD and CF. The hypoxic down-regulation of SLPI may help explain the protease/anti-protease imbalance associated with these conditions and vulnerability to airway infections. Furthermore, it provides an interesting target for the treatment and prevention of exacerbation in these patients.
authors: Lisa I
authors: LI
authors: Påhlman
authors: Annika
authors: A
authors: Jögi
authors: Magnus
authors: M
authors: Gram
authors: Michiko
authors: M
authors: Mori
authors: Arne
authors: A
authors: Egesten
mesh_terms: D001980:Bronchi / Q000166:cytology / Q000378:metabolism; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D000860:Hypoxia / Q000235:genetics* / Q000378:metabolism; D019272:Leukocyte Elastase / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053481:Secretory Leukocyte Peptidase Inhibitor / Q000235:genetics* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D012333:RNA, Messenger; C506814:SLPI protein, human; D053481:Secretory Leukocyte Peptidase Inhibitor; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D019272:Leukocyte Elastase