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Inflammation in lung injury: the key mediators
S50 Evaluation of secretory leucoprotease inhibitor (SLPI) as an anti-inflammatory therapy for donor lung inflammation
  1. H R Walden1,
  2. D M Karamanou1,
  3. C R Fox1,
  4. A J Rostron1,
  5. J A Kirby1,
  6. A J Simpson2,
  7. J H Dark1,
  8. A J Fisher1
  1. 1University of Newcastle, Newcastle-upon-Tyne, UK
  2. 2University of Edinburgh, Edinburgh, UK

Abstract

Introduction Donor lung inflammation, reflected by high concentrations of interleukin-8 in bronchoalveolar lavage (BAL) and an imbalance between pro-inflammatory IL-6 and anti inflammatory IL-10 in tissue, correlates with poor graft function and reduced survival after human lung transplantation. Secretory leucoprotease inhibitor (SLPI) is an anti-protease abundant in the lung. SLPI inhibits neutrophil elastase and down regulates inflammatory cytokine transcription via the NFκB pathway. We investigated the effect of SLPI on inflammatory mediators, in a rat model of brain death induced lung injury.

Methods Brain death (BD) was induced in anesthetised ventilated male Wistar rats (n=16) by rapid inflation of an intracranial balloon, the balloon was not inflated in non-BD sham animals. Rats received intra-tracheal human recombinant SLPI (400 ng/g) (n=8) or saline (control n=8, sham n=9) at 1 h. The experiment was terminated at 5 h. Serum samples were taken at 0, 1, 3 and 5 h, and BAL from one lung was taken for cytokine analysis. The second lung was used for wet/dry ratio and Q-PCR analysis.

Results CXCL1, TNF-α, IFN-γ and IL-6 were significantly higher in BAL and serum of control than sham rats, demonstrating that BD induced lung inflammation in this model. There was no change in lung wet-dry ratio between SLPI treated and control groups. Surprisingly, CXCL1 levels were higher in the BAL of SLPI treated rats than controls (p=0.05), however no significant difference was detected for any other cytokine. There was a non-significant trend towards a higher number of CD45+ leucocytes in BAL in SLPI treated rats compared to controls. CXCL1 mRNA was also increased 1.5-fold in the SLPI treated group compared to controls (p<0.05).

Conclusions In this study, SLPI does not appear to have an anti-inflammatory effect in the rat lung, and may exacerbate inflammation as seen by an increased concentration of the chemokine CXCL1. This surprising effect may be due to the short time course of this experiment where the initial effect of SLPI may be pro-inflammatory. Given the small window of opportunity available to treat donor lungs we believe that SLPI is an inappropriate intervention for use in lung transplantation.

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