Investigating the role of the secretory leukocyte protease inhibitor (SLPI) in lung adenocarcinoma

  • Caoifa Dougan

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

Secretory leukocyte protease inhibitor (SLPI) is an 11.7kDa serine protease inhibitor, which possesses anti-protease, anti-inflammatory, and anti-microbial properties. However, SLPI is reported to acquire pathogenic features in diseases such as cancer. Indeed, SLPI has been identified to be significantly increased in lung cancer patient plasma, with further increased SLPI levels observed with metastatic disease. In this thesis it was hypothesised that SLPI is aiding tumourigenesis by influencing the Hallmarks of Cancer. Significantly reduced xenograft tumour burden was identified in SLPr/_ mice with significantly decreased functional blood vessel number compared to tumours from WT mice. Further investigation revealed the addition of recombinant human SLPI (rSLPI) to human umbilical vein endothelial cells (HUVEC) significantly increased enclosed structure number, with substantially reduced p- VEGF R2 levels in tumours from SLPI7' mice. Increased SLPI levels have been identified in chronic obstructive pulmonary disease (COPD) patient BAL fluid where it is thought to be beneficial due to its functional properties. Therefore, the PENaC-Tg model of chronic inflammatory lung disease was utilised to evaluate the effect of host SLPI loss in this COPD- like model. Results demonstrated significantly increased inflammatory cell counts in (3ENaC- Tg SLPI7' mouse BAL fluid compared to PENaC-Tg mice. No substantial difference was observed in airspace enlargement and destruction between PENaC-Tg mice and pENaC-Tg SLPI7' mice. Increased expression of syndecan-4 in PENaC-Tg SLPImice was identified compared to WT, SLPI', and PENaC-Tg mice. Therefore, it was postulated that there may be potentially elevated NE activity in the PENaC-Tg SLPI7 mice, which increases shedding of syndecan-4 and therefore heightened inflammation. In conclusion, SLPI promotes 3LL lung adenocarcinoma tumourigenesis by increasing neo-vascularisation but reduces lung inflammation in a COPD-like murine model.
Date of AwardJul 2019
Original languageEnglish
Awarding Institution
  • Queen's University Belfast
SupervisorCliff Taggart (Supervisor), Sinead Weldon (Supervisor) & Donna Small (Supervisor)

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