Serine protease inhibitors in the upper and lower airways

Forskningsoutput: AvhandlingDoktorsavhandling (sammanläggning)

Bibtex

@phdthesis{46653117409d4bfaac40c03c352c4142,
title = "Serine protease inhibitors in the upper and lower airways",
abstract = "Proteases and their inhibitors are implicated in the physiology and pathology of the airways. Protease inhibitors include those produced locally, such as secretory leukocyte protease inhibitor (SLPI), and those produced mainly by the liver that can reach the airways via passive diffusion, such as alpha1-antitrypsin (AAT). SLPI is a significant component of the anti-neutrophil elastase shield in the respiratory tract and is therefore complementary to the AAT, a major inhibitor of neutrophil elastase and protease 3. Inherited, severe AAT deficiency is a recognised genetic risk factor for the development of chronic obstructive lung disease (COPD), whereas no gene polymorphism has been found for SLPI. There is, therefore, no indication of whether a deficit in SLPI could be responsible for the development of COPD in patients that otherwise have sufficient levels of AAT. To test the hypothesis that a compensatory increase in levels of SLPI might favourably improve the protease/protease-inhibitor balance in AAT deficient individuals, we analysed plasma levels of SLPI in healthy subjects with and without severe AAT deficiency. The finding that plasma SLPI did not differ between these groups led to the conclusion that SLPI does not compensate for the deficiency of plasma AAT. SLPI levels in bronchial lavage fluid from asthma and COPD patients are remarkably higher than in plasma, suggesting that plasma may not be the appropriate biological fluid in which to measure SLPI. In addition to anti-protease activities, both SLPI and AAT, exhibit other anti-inflammatory properties in vitro and in vivo. Therefore, an understanding of the mechanisms involved in AAT and SLPI protein expression, release and consumption provides important knowledge on the dynamics of the regulation of the protease/anti-protease and other systems in the inflammatory responses. Our studies revealed that SLPI expression and release by epithelial cells are dependent on the interaction of epithelial and mast cells and that endotoxin (LPS) increases SLPI levels in nasal lavage. Interestingly, while AAT was found to inhibit LPS-induced monocyte and neutrophil responses in vitro, and to suppress nasal interleukin-8 (IL-8) release in LPS-challenged individuals, in vivo, SLPI effects shown to be much more complex. In vitro, SLPI significantly inhibited LPS-stimulated IL-8 release from monocytes but had no effect in neutrophil models. Indeed, SLPI itself stimulated neutrophil, but not monocyte, chemotaxis and adhesion. These findings further expand our knowledge on the regulatory effects of SLPI and AAT during inflammatory reactions which may be potentially more biologically profound than their ability to inhibit proteases.",
keywords = "auditive system and speech, Neutrophils, audiology, Otorhinolaryngology, Medicin (m{\"a}nniska och djur), AAT, Medicine (human and vertebrates), SLPI, cytokines/chemokines, anti-proteases, audiologi, h{\"o}rsel- och talorganen, Airway inflammation, Otorinolaryngologi",
author = "Camilla Hollander",
note = "Defence details Date: 2006-10-27 Time: 13:00 Place: The Aula of the Medical Department Entrance 35, Department of Medicine Malm{\"o} University Hospital External reviewer(s) Name: Stockley, Robert Title: Professor Affiliation: Queen Elisabeth Hospital, Birmingham ---",
year = "2006",
language = "English",
isbn = "91-85559-36-9",
series = "Lund University Faculty of Medicine Doctoral Dissertation Series",
publisher = "Department of Clinical Sciences, Lund University",

}