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Serine protease inhibitors in the upper and lower airways

Hollander, Camilla LU (2006) In Lund University Faculty of Medicine Doctoral Dissertation Series 2006:112.
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... (More)
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. (Less)
Abstract (Swedish)
Popular Abstract in Swedish

Kliniska och experimentella studier har visat att proteaser och deras inhibitorer deltar i mycket hög grad i luftvägarnas fysiologi och sjukdomsutveckling. Inflammatoriska celler, såsom neutrofiler, monocyter/makrofager, epitel- och mastceller, friger olika proteaser. Det är allmänt känt att ökad produktion eller aktivitet av proteaser eller inaktivering och minskad produktion av proteas-hämmare kan leda till proteas/proteas-hämmar obalans och nedbrytning av vävnad. Proteas-hämmare utgörs av dem som produceras lokalt av slem¬hinnan, som till exempel sekretorisk leukocyt proteas inhibitor (SLPI), och de som huvud¬sakligen produceras i levern och når luftvägarna via passiv diffusion, som till... (More)
Popular Abstract in Swedish

Kliniska och experimentella studier har visat att proteaser och deras inhibitorer deltar i mycket hög grad i luftvägarnas fysiologi och sjukdomsutveckling. Inflammatoriska celler, såsom neutrofiler, monocyter/makrofager, epitel- och mastceller, friger olika proteaser. Det är allmänt känt att ökad produktion eller aktivitet av proteaser eller inaktivering och minskad produktion av proteas-hämmare kan leda till proteas/proteas-hämmar obalans och nedbrytning av vävnad. Proteas-hämmare utgörs av dem som produceras lokalt av slem¬hinnan, som till exempel sekretorisk leukocyt proteas inhibitor (SLPI), och de som huvud¬sakligen produceras i levern och når luftvägarna via passiv diffusion, som till exempel ?1 antitrypsin (AAT). SLPI utgör en viktig komponent i försvaret mot neutrofilt elastas och är därför ett komplemet till AAT. Ärftig, allvarlig AAT-brist är en känd genetisk faktor för utvecklingen av kronisk obstruktiv lungsjukdom (KOL). Det finns ingen känd genetisk brist av SLPI.



För att pröva en hypotes om kompensatorisk ökning av nivåer i SLPI positivt skulle kunna förbättra proteas/proteas-hämmar balansen hos AAT-bristande individer, analyserade vi plasmanivåer av SLPI hos friska försökspersoner med och utan allvarlig AAT-brist. Resultaten visade att SLPI i plasma ej skillde mellan de studerade grupperna, vilket ledde oss till slutsatsen att SLPI ej kompenserar för brist av plasma AAT. Som stöd för detta tankesätt fann vi att SLPI koncentrationer i bronksköljvätska från astma och KOL patienter var anmärkningsvärt högre än i plasma. Vi fann också att SLPI i plasma var högre hos KOL-patienter oberoende av genetisk variant av AAT-brist. Det är av betydelse att analysera SLPI i rätt biologiskt matrial.



Utöver sina funktioner som proteas-hämmare har både SLPI och AAT visat sig inneha anti-inflammatoriska egenskaper. Att förstå mekanismerna involverade i protein-uttrycket av AAT och SLPI, deras frisättning och konsumtion kan ge viktiga kunskaper i regleringen av proteas/proteas-hämmare och andra händelser i den inflammatoriska reaktionen. Resultaten från våra studier avslöjade att SLPI-uttryck och -utsöndring av epitelceller är beroende av samverkan mellan epitel och mastceller. I nästa försöksmodell stimulerades friska försökspersoner med endotoxiner (LPS) i näsan. Vi fann ökningar av SLPI nivåer i nässköljningsvätska.



Vi fortsatte våra försök med att studera hur monocyter och neutrofiler svarar på endotoxin-stimulering med och utan SLPI och AAT. Resultaten visade att AAT hämmade LPS-inducerad pro-inflammatorisk monocyt och neutrofil respons. Observationer visade också att AAT inhiberade chemokiner (IL-8) frisättning hos LPS-stimulerade individer. SLPIs effekter var mycket mer komplexa. SLPI hämmade LPS-stimulerad IL-8 frisättning från monocyter, men hade ingen effekt på neutrofiler. Faktum var att SLPI själv stimulerade neutrofilers, men inte monocyters, migration och adhesion. Dessa fynd styrker hypotesen att SLPIs biologiska effekter är beroende av celltyp. Sammanfattningsvis styrker våra studier kunnskapen om att SLPI och AAT utövar andra effekter än enbart deras förmåga att vara proteas-hämmare. (Less)
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author
supervisor
opponent
  • Professor Stockley, Robert, Queen Elisabeth Hospital, Birmingham
organization
publishing date
type
Thesis
publication status
published
subject
keywords
auditive system and speech, Neutrophils, audiology, Otorhinolaryngology, Medicin (människa och djur), AAT, Medicine (human and vertebrates), SLPI, cytokines/chemokines, anti-proteases, audiologi, hörsel- och talorganen, Airway inflammation, Otorinolaryngologi
in
Lund University Faculty of Medicine Doctoral Dissertation Series
volume
2006:112
pages
169 pages
publisher
Department of Clinical Sciences, Lund University
defense location
The Aula of the Medical Department Entrance 35, Department of Medicine Malmö University Hospital
defense date
2006-10-27 13:00:00
ISSN
1652-8220
ISBN
91-85559-36-9
language
English
LU publication?
yes
id
46653117-409d-4bfa-ac40-c03c352c4142 (old id 547310)
date added to LUP
2016-04-01 16:48:51
date last changed
2019-05-22 06:00:00
@phdthesis{46653117-409d-4bfa-ac40-c03c352c4142,
  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.},
  author       = {Hollander, Camilla},
  isbn         = {91-85559-36-9},
  issn         = {1652-8220},
  language     = {eng},
  publisher    = {Department of Clinical Sciences, Lund University},
  school       = {Lund University},
  series       = {Lund University Faculty of Medicine Doctoral Dissertation Series },
  title        = {Serine protease inhibitors in the upper and lower airways},
  url          = {https://lup.lub.lu.se/search/ws/files/4788332/547312.pdf},
  volume       = {2006:112},
  year         = {2006},
}