The regulation of pulmonary vascular permeability by PAF [Elektronische Ressource] : role of caveolae and acid sphingomyelinase / Yang Yang

Yyang

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• Gesundheit

Informations

• Publié par: rheinisch-westfalischen_technischen_hochschule_-rwth-_aachen
• Publié le: 01 janvier 2011
• Nombre de lectures: 9
• Langue: English
• Poids de l'ouvrage: 2 Mo

Extrait

The regulation of pulmonary vascular permeability by PAF
Role of caveolae and acid sphingomyelinase



Von der Fakultät für Mathematik, Informatik und Naturwissenschaften der RWTH
Aachen University zur Erlangung des akademischen Grades eines Doktors der
Naturwissenschaften genehmigte Dissertation

vorgelegt von

M. Eng. Yang Yang
aus QingHai, China

Berichter: Universitätsprofessor: Univ.-Prof. Dr. rer. nat. Stefan Uhlig
Universitätsprofessor: Univ.-Prof. Dipl. Ing. Dr. Werner Baumgartner

Tag der mündlichen Prüfung: 12. 01. 2011

Diese Dissertation ist auf den Internetseiten der Hochschulbibliothek online verfügbar
Dedication

This dissertation is dedicated to the very precious people that I have in my life. These
people have instilled in me an unquenchable thirst for knowledge, undying zest for
success, and an unparalleled determination. To my loving parents, Guohao Hao and
Zhaoan Yang, thanks for allowing your only son many opportunities to explore the
world as I matured in your care. I am thankful for the strength, courage and resilience
that I have inherited from you. And certainly Ivy Yu, without you beside me I am
certain all these would not have been possible. Thank you all greatly from the
deepest crevices of my being for inspiring, motivating, and supporting me.


















IAcknowledgements

Throughout my Ph.D. program, I have received a tremendous amount of assistance
and encouragement from my advisor and mentor. My deepest gratitude goes first and
foremost to Professor Stefan Uhlig, my supervisor, for his constant guidance and
encouragement. He has walked me through all the stages of my dissertation
research here at institute of pharmacology and toxicology, RWTH Aachen. Without
his consistent and illuminating instruction, this thesis could not have reached its
present form. I also would like to thank Professor Werner Baumgartner and Dr.
Christian Martin for being supervisors of my dissertation.
I would like to thank our partner group of Professor Wolfgang Kübler, Charité
Universitätsmedizin, Berlin, for the Real-time fluorescence imaging performances and
all the other excellent experiments and assistances. It is a pleasure and privilege to
work with you for the last three years. I want to thank our cooperating group of
Professor Werner Baumgartner for the size and number of caveolae measurement.
My gratitude is also given to our cooperating group of Professor Veit Flockerzi,
Universität des Saarlandes for the TRPC antibodies developments and group of
Professor Arenz Christoph, Humboldt Universität zu Berlin for the ASM inhibitors
developments. I also would like to thank group of Thomas Gudermann for providing
TRPC6 knockout mice and group of Dieter Adam for providing ASM knockout mice.
I have spent my last three years at institute of pharmacology and toxicology, RWTH
Aachen. To all my colleagues and friends within the institute, sprinkled in various
research groups, a special thanks to you for your attention and many help not only
my work, but also my life. Thank Dr. Ulrike Uhlig and Dr. Christian Martin for the
theoretical and experimental support. Thank Anke Kowallik and Nadine Ruske for
being excellent technicians. Thank Dr. Daniela Dreymüller, Lucy Kathleen Reiss,
Stephanie Siegl, Marco Schlepütz, Franz Martin Heß, Dennis Lex, Oliver Pack,
Chrisovalantis Papadopoulos and Ulf Soppa for being not just colleagues but friends
also. Last, but certainly not least, our kind and warm secretaries Mrs. Marion Peters
and Mrs. Vera Lothmann.
To our departed colleague Jie Gao, may she rest in peace.


IIPublications

1. Yang Y, Yin J, Baumgartner W, Samapati R, Solymosi EA, Reppien E, Kuebler
WM, and Uhlig S. Platelet-activating factor reduces endothelial nitric oxide
production: role of acid sphingomyelinase. Eur Respir J 36: 417-427, 2010.

2. Kuebler WM, Yang Y, Samapati R, and Uhlig S. Vascular barrier regulation by
PAF, ceramide, caveolae, and NO - an intricate signaling network with discrepant
effects in the pulmonary and systemic vasculature. Cell Physiol Biochem 26: 29-40,
2010.

3. Roth AG, Drescher D, Yang Y, Redmer S, Uhlig S, and Arenz C. Potent and
selective inhibition of acid sphingomyelinase by bisphosphonates. Angew Chem Int
Ed Engl 48: 7560-7563, 2009.

4. Rudi Samapati, Yang Yang, Jun Yin, Christoph Arenz, Alexander Dietrich,
Thomas Gudermann, Dieter Adam, Xyy Wu, Chrostoph Stoerger, Veit Flockerzi,
Stefan Uhlig and Wolfgang M. Kuebler. Regulation of lung vascular permeability by
ASM dependent activation of TRPC6 In lung endothelial cells. Manuscript in
preparation.

5. Yang Y and Uhlig S. The role of sphingolipids in respiratory disease. The journal of
Therapeutic Advances in Respiratory Disease. Manuscript in preparation.

Conferences presentions

1. Y. Yang, J. Jin, Rudi Samapati, C. Stoerger, V. Flockerzi, W.M. Kuebler and S
Uhlig. PAF-induced recruitment of caveolin-1 reduces endothelial NO levels-Role of
acid sphingomyelinase. 8th European respiratory society – lung science conference
2010, Estorul, Portugal.


2. R. Samapati, Y. Yang, S. Uhlig and W.M. Kuebler. PAF causes vascular barrier
failure by acid sphingomyelinase- and ceramide-dependent activation of endothelial
TRPC channels. Symposium of microcirculation and vascular biology, 2009, Bern,
Swiss land.

3. Y. Yang, J. Jin, Rudi Samapati, W.M. Kuebler and S Uhlig. PAF-induced
recruitment of caveolin-1 reduces endothelial NO levels. 5th International symposium
on respiratory diseases,ISRD 2008, Shanghai, China.




IIITable of contents
Dedication------------------------------------------------------------------------------------------------- I
Acknowlegements--------------------------------------------------------------------------------------- I
Publications--------------------------------------------------------------------------------------------- III
1 Introduction-------------------------------------------------------------------------------------------- 1
1.1 Concise lung morphology----------------------------------------------------------------------------------------------1
1.2 Acute respiratory distress syndrome (ARDS)---------------------------------------------------------------------4
1.3 The regulation of vascular permeability ----------------------------------------------------------------------------8
1.4 Platelet activating factor 18
1.5 Sphingolipids------------------------------------------------------------------------------------------------------------ 22
1.6 Lipid rafts and caveolae 31
1.7 The isolated perfused lung model --------------------------------------------------------------------------------- 39
2 The aim of the study -------------------------------------------------------------------------------41
3 Material and Methods------------------------------------------------------------------------------42
3.1 Materials ----------------------------------------------------------------------------------------------------------------- 42
3.2 Methods ------------------------------------------------------------------------------------------------------------------ 45
4 Results ------------------------------------------------------------------------------------------------52
4.1 PAF induced edema formation ------------------------------------------------------------------------------------- 52
4.2 PAF induced caveolin recruitment and endothelial nitric oxide synthase (eNOS) distribution ------ 53
4.2.1 Number and size of caveolae ------------------------------------------------------------------------------------ 53
4.3 PAF activates ASM to decrease endothelial NO production ------------------------------------------------ 61
2+4.4 PAF activates ASM to increase endothelial Ca levels ------------------------------------------------------ 66
4.5 Effects of steroids------------------------------------------------------------------------------------------------------ 73
5 Discussion --------------------------------------------------------------------------------------------77
5.1 Regulation of caveolin-1 by PAF ----------------------------------------------------------------------------------- 78
5.2 Endothelial permeability regulation by caveolin and NO in lungs ------------------------------------------ 80
5.3 Caveolae, calcium influx and permeability regulation--------------------------------------------------------- 82
5.4 Endothelial permeability regulation in the lungs and in extra-pulmonary organs----------------------- 88
5.5 Concluding remarks --------------------------------------------------------------------------------------------------- 93
6 Summary----------------------------------------------------------------------------------------------95
7 References -------------------------------------------------------------------------------------------96

IVAbbreviation

ACE: angiotensin con