PROTEASES
Potential Role in Health and Disease
Edited by
Walter H. Hörl
and
August Heidland
University of Würzburg
Würzburg, Federal Republic of Germany
PLENUM PRESS • NEW YORK AND LONDON
Library of Congress Cataloging in Publication Data
International Symposium on Proteases: Potential Role in Health and Disease (1982:
Würzburg, Germany)
Proteases, potential role in health and disease.
(Advances in experimental medicine and biology; v. 167)
"Proceedings of the International Symposium on Proteases: Potential Role in Health
and Disease, held October 17-20, 1982, in Würzburg, Federal Republic of Germany"—
Verso t.p.
Includes bibliographical references and index.
1. Proteolytic enzymes —Congresses. 2. Proteolytic enzyme inhibitors —Congresses.
I. Hörl, Walter H. II. Heidland, August. III. Series. [DNLM: 1. Protease inhibitors Congresses. 2. Peptide hydrolases-Congresses. Wl AD559 v. 167 / QU 136 I615p
1982]
QP609.P78I57 1982
599 / .019256
83-19186
ISBN 0-306-41488-0
Proceedings of the International Symposium on Proteases: Potential Role in Health
and Disease, held October 17-20, 1982, in Würzburg, Federal Republic of Germany
© 1984 Plenum Press, New York
A Division of Plenum Publishing Corporation
233 Spring Street, New York, N.Y. 10013
All rights reserved
No part of this book may be reproduced, stored in a retrieval system, or transmitted
in any form or by any means, electronic, mechanical, photocopying, microfilming,
recording, or otherwise, without written permission from the Publisher
Printed in the United States of America
CONTENTS
PHYSIOLOGY ÄND PATHOPHYSIOLOGY OF PROTEASES
AND THEIR INHIBITORS
P h y s i o l o g y and Pathophysiology
o f Human G r a n u l o c y t e s
K. Havemann a n d M. Gramse
of Neutral Proteinases
1
Regulation of Protease A c t i v i t y
M. S t e i n b u c h
21
Human K i n i n o g e n s a n d T h e i r F u n c t i o n i n t h e K a l l i k r e i n K i n i n Systems
W. Müller-Esterl a n d H. F r i t z
P o s s i b l e Involvement o f K i n i n s i n Muscle Energy
Metabolism
G. D i e t z e , E . M a e r k e r , C. L o d r i , R. S c h i f m a n ,
M. W i c k l m a y r , R. G e i g e r , E . F i n k , I . B o e t t g e r ,
H. F r i t z , a n d H. Mehnert
S t r u c t u r e and F u n c t i o n o f N a t u r a l I n h i b i t o r s a s
Antagonists of Proteinase A c t i v i t i e s
H. T s c h e s c h e
Oxidation of Alpha-1-Proteinase I n h i b i t o r :
S i g n i f i c a n c e f o r Pathobiology
J . T r a v i s , K. B e a t t y , a n d N. Matheson
I n Vivo S i g n i f i c a n c e of K i n e t i c Constants o f
Macromolecular P r o t e i n a s e I n h i b i t o r s
J . G. B i e t h
On
t h e M u l t i p l i c i t y o f C e l l u l a r E l a s t a s e s and t h e i r
I n e f f i c i e n t C o n t r o l by N a t u r a l I n h i b i t o r s
W. Hornebeck, D. B r e c h e m i e r , M. P. J a c o b ,
C. F r a n c e s , a n d L . R o b e r t
ix
41
63
73
89
97
I l l
x
CONTENTS
Proteases - Proteases Inhibitors:
C e l l u l a r Information System
H. H e i n e
a Local
121
PROTEASES AND HORMONES
Regulatory P r o t e o l y s i s during C o r t i c o s t e r o i d
Hormone A c t i o n
M. K. A g a r w a l
P r o t e a s e s i n Hormone P r o d u c t i o n
W. A. Hsueh
and Metabolism
P r e c u r s o r P r o c e s s i n g and Metabolism o f
P a r a t h y r o i d Hormone: R e g u l a t i o n
by C a l c i u m
J . A. F i s c h e r
P r o c e s s i n g and D e g r a d a t i o n o f M e t - E n k e p h a l i n
by P e p t i d a s e A s s o c i a t e d w i t h R a t B r a i n
C o r t i c a l Synaptosomes
W. Demmer a n d K. B r a n d
129
141
153
165
PROTEASES I N KIDNEY AND I N T E S T I N A L TRACT
C h a r a c t e r i z a t i o n and C l i n i c a l S i g n i f i c a n c e o f
Membrane Bound P r o t e a s e s f r o m Human
Kidney Cortex
J . E . S c h e r b e r i c h , C. G a u h l , G. H e i n e r t ,
W. Mondorf, a n d W. Schoeppe
Advances i n P r o t e a s e R e s e a r c h u s i n g
Synthetic Substrates
R. G o s s r a u , Z. L o j d a , R. E . S m i t h , a n d
P. S i n h a
179
Recent
K i n e t i c C h a r a c t e r i z a t i o n o f B r u s h B o r d e r Membrane
Proteases i n R e l a t i o n s h i p t o Mucosal
A r c h i t e c t u r e by S e c t i o n B i o c h e m i s t r y
S. G u t s c h m i d t , R. Hoper, a n d R. G o s s r a u
F l u o r e s c e n c e D e t e c t i o n o f P r o t e a s e s w i t h AFC,
AMC and MNA P e p t i d e s u s i n g I s o e l e c t r i c
Focusing
P. S i n h a , R. G o s s r a u , R. E . S m i t h , a n d
Z. L o j d a
191
209
219
CONTENTS
xi
PROTEASES AND BLOOD SYSTEM
Pathophysiology o f t h e I n t e r a c t i o n between
Complement a n d Non-Complement
Proteases
U. E . Nydegger a n d S. S u t e r
I n t e r a c t i o n s between t h e
Complement P a t h w a y
of t h e C o a g u l a t i o n
M. D. K a z a t c h k i n e a n d
The
Alternative
and P r o t e a s e s
System
M.-H. J o u v i n
Calcium-Dependent N e u t r a l P r o t e a s e o f
Human B l o o d P l a t e l e t s : a C o m p a r i s o n
o f i t s E f f e c t s on t h e R e c e p t o r s f o r
von W i l l e b r a n d F a c t o r a n d f o r t h e
F c - F r a g m e n t D e r i v e d from I g G
M. 0. S p y c h e r , U. E . N y d e g g e r , a n d
E. F. L u e s c h e r
A l p h a - 2 - P l a s m i n I n h i b i t o r I n a c t i v a t i o n by
Human G r a n u l o c y t e E l a s t a s e
M. Gramse, K. Havemann, a n d R. E g b r i n g
H e p a r i n and P l a s m a P r o t e i n a s e I n h i b i t o r s :
I n f l u e n c e o f H e p a r i n on t h e I n h i b i t i o n
o f Thrombin b y a 2 a c r o g l o b u l i n
P. Lambin, F . Pochon, a n d M. S t e i n b u c h
M
The
The
Involvement
Systems i
nephritis
K. A n d r a s s y ,
o f P l a s m a t i c and F i b r i n o l y t i c
n I d i o p a t h i c Glomerulo(GN)
E . R i t z , a n d R. W a l d h e r r
E f f e c t o f A p r o t i n i n on P l a t e l e t F u n c t i o n ,
Blood C o a g u l a t i o n and Blood
Lactate
Level i n T o t a l Hip Replacement - a
Double B l i n d C l i n i c a l T r i a l
S. Haas, R. K e t t e r l , A. S t e m b e r g e r ,
P. Wendt, H.-M. F r i t s c h e , H. K i e n z l e ,
F . L e c h n e r , a n d G. Blume1
-
22 7
235
241
253
263
2 73
287
PROTEASES AND LUNG
Interaction of Granulocyte Proteases with
I n h i b i t o r s i n Pulmonary D i s e a s e s
K. O h l s s o n , U. F r y k s m a r k , M. O h l s s o n ,
and H. T e g n e r
299
xii
CONTENTS
L e u k o p r o t e i n a s e s and P u l m o n a r y Emphysema:
C a t h e p s i n G and Other ChymotrypsinL i k e P r o t e i n a s e s Enhance t h e E l a s t o l y t i c A c t i v i t y o f E l a s t a s e on Lung
Elastin
Ch. B o u d i e r , Ph. L a u r e n t , a n d J . G. B i e t h
A d u l t R e s p i r a t o r y D i s t r e s s Syndrome (ARDS):
E x p e r i m e n t a l Models w i t h E l a s t a s e a n d
Thrombin I n f u s i o n i n P i g s
H. B u r c h a r d i , T. S t o k k e , I . H e n s e l , H. Köstering,
G. R a h l f , G. S c h l a g , H. H e i n e , a n d
W. H. Hörl
313
319
PROTEASES AND A R T H R I T I S
I n t e r a c t i o n s of Granulocyte Proteases with
I n h i b i t o r s i n Rheumatoid A r t h r i t i s
L . E k e r o t a n d K. O h l s s o n
Q u a n t i t a t i o n o f Human L e u k o c y t e E l a s t a s e ,
C a t h e p s i n G,Ot - 2 - M a c r o g l o b u l i n a n d
a-1-Proteinase I n h i b i t o r i n Osteoa r t h r o s i s a n d Rheumatoid A r t h r i t i s
Synovial Fluids
G. D. V i r c a , R. K. M a l l y a , M. B. P e p y s ,
and H. P. S c h n e b l i
P l a s m a L e v e l s o f I n h i b i t o r Bound L e u k o c y t i c
E l a s t a s e i n Rheumatoid A r t h r i t i s
Patients
H. P. S c h n e b l i , P. C h r i s t e n , M. Jochum,
R. K. M a l l y a , and M. B. P e p y s
a ^ M - P a s e b i c A s s a y : a S o l i d P h a s e Immunosorbent Assay t o C h a r a c t e r i z e A l p t ^ M a c r o g l o b u l i n - P r o t e i n a s e Complexes
and t h e P r o t e i n a s e B i n d i n g - C a p a c i t y
of Alpha^-Macroglobulin
W. B o r t h
Role o f Alpha -Macroglobulin:
Proteinase
Complexes i n P a t h o g e n e s i s o f I n f l a m m a t i o n :
'F' a^M b u t n o t 'S' a M I n d u c e s S y n o v i t i s
i n R a b b i t s a f t e r Repeated I n t r a - A r t i c u l a r
Administration
W. B o r t h a n d M. S u s a n i
335
345
355
36 3
2
2
3 71
CONTENTS
xiii
HYPERCATABOLISM
E n z y m e - L i n k e d Immunoassay f o r Human G r a n u l o c y t e
E l a s t a s e i n Complex w i t h a - P r o t e i n a s e
Inhibitor
S. Neumann, N. H e n n r i c h , G. G u n z e r , and
H. Lang
P r o t e i n a s e s and t h e i r I n h i b i t o r s i n S e p t i c e m i a
B a s i c C o n c e p t s and C l i n i c a l I m p l i c a t i o n ^
M. Joehum, K.-H.
D u s w a l d , S. Neumann,
J . W i t t e , and H. F r i t z
Proteolytic A c t i v i t y i n Patients with Hypercatabolic
Renal F a i l u r e
W. H. Hörl, R. M. Schäfer, K. S c h e i d h a u e r ,
M. Jochum, and A. H e i d l a n d
3 79
391
405
R e l e a s e of Granulocyte N e u t r a l P r o t e i n a s e s i n
P a t i e n t s w i t h A c u t e and C h r o n i c R e n a l
Failure
A. H e i d l a n d , W. H. Hörl, N. H e l l e r , H. H e i n e ,
S. Neumann, and E . H e i d b r e d e r
417
Changes i n Components o f t h e P l a s m a K a l l i k r e i n K i n i n and F i b r i n o l y t i c S y s t e m s I n d u c e d
by a S t a n d a r d i z e d S u r g i c a l Trauma
A. O. Aasen, J . S t a d a a s , T. E . Ruud, and
P. K i e r u l f
433
E n d o t o x i n s and C o a g u l a t i o n P a r a m e t e r s i n P a t i e n t s
w i t h T r a u m a t i c H a e m o r r h a g i c - and B a c t e r i o t o x i c Shock
A. S t e m b e r g e r , F . S t r a s s e r , G. Blümel,
B. v. H u n d e l s h a u s e n , S. J e l e n , 0. S c h m i d t ,
and G. Tempel
S t u d i e s on P a t h o l o g i c a l P l a s m a P r o t e o l y s i s i n
S e v e r e l y B u r n e d P a t i e n t s u s i n g Chromogenic
Peptide S u b s t r a t e Assays: A P r e l i m i n a r y
Report
T. E . Ruud, P. K i e r u l f , H. C. G o d a l , S. Aune,
and A. 0. A a s e n
Changes i n Components o f t h e P l a s m a P r o t e a s e
S y s t e m s R e l a t e d t o C o u r s e and Outcome
of S u r g i c a l S e p s i s
N. S m i t h - E r i c h s e n , A. 0. A a s e n , and
E . Amundsen
439
449
455
xiv
CONTENTS
PANCREATITIS
R o l e o f P r o t e a s e s i n t h e Development
Acute P a n c r e a t i t i s
M. Wanke
of
463
On t h e P o t e n t i a l R o l e o f T r y p s i n and T r y p s i n
I n h i b i t o r s i n Acute P a n c r e a t i t i s
A. L a s s o n and K. O h l s s o n
47 7
S t u d i e s on t h e K a l l i k r e i n - K i n i n S y s t e m i n
P l a s m a and P e r i t o n e a l F l u i d d u r i n g
Experimental P a n c r e a t i t i s
T. E . Ruud, A. 0. A a s e n , P. K i e r u l f ,
J . S t a d a a s , and S. Aune
489
The I n f l u e n c e o f t h e K a l l i k r e i n - K i n i n S y s t e m
i n t h e Development o f t h e P a n c r e a t i c
Shock
H. Kortmann, E . F i n k , and G. Bonner
PROTEASES AND
495
MUSCLE FUNCTION
P r o t e o l y t i c Enzymes and E n h a n c e d M u s c l e
P r o t e i n Breakdown
B. Dahlmann, L . Kuehn, and H. R e i n a u e r
2
Ca - A c t i v a t e d P r o t e i n a s e s , P r o t e i n D e g r a d a t i o n
and M u s c u l a r D y s t r o p h y
J . Kay
505
519
M u s c l e C a t h e p s i n D A c t i v i t y , and RNA, DNA and
P r o t e i n C o n t e n t i n M a i n t e n a n c e Hemodialysis Patients
G. F . G u a r n i e r i , G. T o i g o , R. S i t u l i n ,
L . F a c c i n i , R. R u s t i a , and F . D a r d i
533
E n h a n c e d M u s c l e P r o t e i n D e g r a d a t i o n and Amino
A c i d R e l e a s e from t h e Hemicorpus o f
A c u t e l y Uremic R a t s
R. M. F l u g e l - L i n k , I . B. S a l u s k y ,
M. R. J o n e s , and J . D. K o p p l e
545
Enhanced Muscle P r o t e i n C a t a b o l i s m i n Uremia
H. R. H a r t e r , T. A. D a v i s , and I . E . K a r l
557
CONTENTS
xv
C a t a b o l i c S t r e s s on I n t r a c e l l u l a r
Pool
P. Fürst
Amino
Rhabdomyolysis: a C l i n i c a l E n t i t y
Study o f Role o f P r o t e a s e s
S. G. M a s s r y
f o r the
INDEX
Acid
571
581
5 87
PROTEOLYTIC ACTIVITY IN PATIENTS WITH
HYPERCATABOLIC RENAL FAILURE
W a l t e r H. H ö r l * Roland M. Schäfer , Klemens S c h e i d h a u e r ,
Marianne Jochum^, and August H e i d l a n d
1
1
1
1
d e p a r t m e n t o f M e d i c i n e , U n i v e r s i t y o f Würzburg,
S u r g i c a l C l i n i c , Department o f C l i n i c a l Chemistry
and B i o c h e m i s t r y , U n i v e r s i t y o f Munich, FRG
2
INTRODUCTION
Despite s e v e r a l advances i n d i a l y s i s and medical t h e r a p y , t h e
m o r t a l i t y r a t e f o r p a t i e n t s w i t h acute r e n a l f a i l u r e (ARF) remains
d i s t r e s s i n g l y h i g h . When ARF i s a s s o c i a t e d w i t h major s u r g e r y o r
trauma, t h e m o r t a l i t y r a t e i s about 50 t o 70 %. Such p a t i e n t s a r e
o f t e n h y p e r c a t a b o l i c as a r e s u l t o f s e p s i s , hemorrhage, o r opend r a i n i n g wounds. They may be wasted o r malnourished from u n d e r l y i n g
i l l n e s s e s . Losses o f g l u c o s e , amino a c i d s and p r o t e i n s d u r i n g hemod i a l y s i s or peritoneal d i a l y s i s c o n t r i b u t e t o wasting.
T o t a l p a r e n t e r a l n u t r i t i o n w i t h amino a c i d s and h y p e r t o n i c
glucose has been r e p o r t e d t o : s t a b i l i z e o r reduce serum l e v e l s o f
urea n i t r o g e n , potassium and phosphorous improve wound h e a l i n g ; enhance s u r v i v a l from ARF and p o s s i b l y i n c r e a s e t h e r a t e o f r e c o v e r y
o f renal f u n c t i o n . However, n i t r o g e n balance remains n e g a t i v e i n
a l l p a t i e n t s s u g g e s t i n g t h a t decreased p r o t e i n s y n t h e s i s i s n o t
the s o l e cause o f l o s s o f body n i t r o g e n . Several s t u d i e s have shown
that proteinases p a r t i c i p a t e i n p r o t e i n catabolism o f patients w i t h
h y p e r c a t a b o l i c ARF3-6. T h i s r e p o r t summarizes data c o n c e r n i n g t h e
p o t e n t i a l r o l e o f proteases i n enhanced p r o t e i n breakdown i n
p a t i e n t s w i t h acute and c h r o n i c r e n a l f a i l u r e ,
1
2
MATERIAL AND METHODS
P r o t e o l y t i c a c t i v i t y i n plasma, d i a l y s a t e and u r i n e f r a c t i o n s
was measured, as p r e v i o u s l y d e s c r i b e d , u s i n g as s u b s t r a t e s Phosp h o r y l a s e k i n a s e (from r a b b i t s k e l e t a l m u s c l e ) , azocasein o r a
p a r t i c u l a r f r a c t i o n o f hepatocytes3-7, P o l y a c r y l a m i d e gel e l e c t r o 405
406
W. H. H Ö R L E T A L
p h o r e s i s i n the presence o f sodium d o d e c y l s u l f a t e was c a r r i e d o u t
a c c o r d i n g t o Weber and Osborn . The i n h i b i t o r y a c t i v i t y o f a l p h a i protease i n h i b i t o r ( a l p h a ^ - a n t i t r y p s i n ) was determined w i t h a comm e r c i a l t e s t system ( B o e h r i n g e r , Mannheim, FRG). Plasma c o n c e n t r a t i o n s o f a l p h a 2 - m a c r o g l o b u l i n (o^M) and a l p h a s - p r o t e a s e i n h i b i t o r
('oqPI) were e v a l u a t e d by a r a d i a l i m m u n o d i f f u s i o n t e c h n i q u e w i t h
s t a n d a r d i z e d i m m u n o d i f f u s i o n p l a t e s (Behringwerke, Marburg, FRG).
Q u a n t i t a t i v e e s t i m a t i o n o f t h e plasma l e v e l s o f t h e e l a s t a s e - a l p h a i protease i n h i b i t o r ( E - ^ P I ) complex was c a r r i e d o u t w i t h a h i g h l y
s e n s i t i v e enzyme-linked immunoassay . We r e p o r t here the r e s u l t s
o b t a i n e d i n : 12 h e a l t h y s u b j e c t s aged from 22 - 39 y e a r s (seven
males, f i v e f e m a l e s ) , 12 c h r o n i c a l l y uremic p a t i e n t s aged from 22 66 years undergoing r e g u l a r d i a l y s i s t h e r a p y (RDT) f o r 41.3 + 11.6
month ( n i n e males, t h r e e f e m a l e s ) and 10 p a t i e n t s w i t h p o s t t r a u m a t i c
ARF aged from 19 - 45 y e a r s . Every 4 t h day venous blood was c o l l e c t ed immediately b e f o r e and a f t e r d i a l y s i s . Furthermore, d i a l y s a t e
and u r i n e f r a c t i o n s were c o l l e c t e d weekly on i c e i n the presence o f
0.01 % a z i d e .
8
9
RESULTS
U l t r a f i l t r a t e d plasma f r a c t i o n s , o b t a i n e d from h e a l t h y subj e c t s and RDT p a t i e n t s and prepared by u l t r a f i l t r a t i o n w i t h an Amicon XM 50 f i l t e r , had no e f f e c t on d e g r a d a t i o n o f Phosphorylase k i nase. However, t h e u l t r a f i l t r a t e d plasma f r a c t i o n s , o b t a i n e d from
p a t i e n t s w i t h p o s t t r a u m a t i c ARF, were p r o t e o l y t i c . F i g u r e 1 shows
the d i g e s t i o n o f t h e t h r e e s u b u n i t s o f Phosphorylase k i n a s e a f t e r
i n c u b a t i o n w i t h u l t r a f i l t r a t e d plasma f o r 1 min as w e l l as 10 and
24 hours. One minute a f t e r i n c u b a t i o n , t h e t y p i c a l s u b u n i t s t r u c t u r e o f t h i s enzyme w i t h t h e t h r e e p o l y p e p t i d e c h a i n s : alpha (MW
135,000), beta (MW 120,000) and gamma (MW 42,000) was observed. Ten
hours l a t e r , t h e alpha s u b u n i t was p a r t i a l l y degraded, whereas t h e
gamma s u b u n i t was c o m p l e t e l y d i g e s t e d . A f t e r 24 hours t h e whole enzyme was d e s t r o y e d . Phosphorylase kinase was a l s o d i g e s t e d by p l a s ma u l t r a f i U r a t e s o f t h e o t h e r n i n e p a t i e n t s w i t h p o s t t r a u m a t i c ARF
w i t h i n 5 - 3 6 hour i n c u b a t i o n p e r i o d a t 37 °C.
Free p r o t e o l y t i c a c t i v i t y i n t h e plasma may be a consequence
o f t h e low a l p h a 2 - m a c r o g l o b u l i n v a l u e s , whereas t h e c o n c e n t r a t i o n s
o f a l p h a i - p r o t e a s e i n h i b i t o r ( a l p h a i - a n t i t r y p s i n ) were markedly e n hanced. F i g u r e 2 shows the t r y p s i n b i n d i n g c a p a c i t y o f plasma taken
from p a t i e n t s w i t h p o s t t r a u m a t i c ARF and from RDT p a t i e n t s . The
l e v e l s o f p r o t e o l y t i c a c t i v i t y ( a f t e r the a d d i t i o n o f i n c r e a s i n g
amounts o f t r y p s i n ) a r e s i g n i f i c a n t l y h i g h e r i n p a t i e n t s w i t h p o s t t r a u m a t i c ARF compared w i t h RDT p a t i e n t s i n d i c a t i n g a lower t r y p s i n
b i n d i n g c a p a c i t y o f t h e plasma i n both groups o f p a t i e n t s compared
with healthy subjects.
407
PROTEOLYTIC ACTIVITY IN PATIENTS
F i g . 1 : E f f e c t o f an ultrafilträte o f plasma from p a t i e n t H.H. on
Phosphorylase k i n a s e . 0.1 ml u l t r a f i l t r a t e ( 2 . 1 mg/ml), o b t a i n e d by
u l t r a f i l t r a t i o n o f plasma t h r o u g h an Ami con XM 50 f i l t e r , was added
t o 0.1 ml Phosphorylase kinase (1.5 mg/ml). Samples ( 1 m i n , 10 and
24 h r a f t e r i n c u b a t i o n ) were s u b j e c t e d t o P o l y a c r y l a m i d e (5 % ) g e l
e l e c t r o p h o r e s i s i n t h e presence o f sodium d o d e c y l s u l f a t e .
8
The e f f e c t o f h e m o d i a l y s i s t h e r a p y on plasma p r o t e i n a s e a c t i v i t y , l e u k o c y t e c o u n t s , plasma e l a s t a s e - a l p h a i - p r o t e a s e i n h i b i t o r
(E- i P I ) complex as w e l l as \Pl a c t i v i t y and plasma c o n c e n t r a t i o n
i s shown i n t a b l e 1 . The p r o t e o l y t i c a c t i v i t y o f t h e plasma f r a c t i o n s was measured using azocasein as a s u b s t r a t e . Before hemodial y s i s we found a s i g n i f i c a n t i n c r e a s e i n RDT p a t i e n t s (+ 244 %; p <
0.01) compared w i t h plasma samples o f h e a l t h y s u b j e c t s (0.052 +
0.004 U/mg p r o t e i n ) . The h i g h e s t plasma p r o t e o l y t i c a c t i v i t y was observed i n p a t i e n t s w i t h p o s t t r a u m a t i c ARF (0.255 + 0.044 U/mg).
During h e m o d i a l y s i s t h e r a p y , however, t h e r e was a permanent decrease
of plasma p r o t e i n a s e a c t i v i t y (0.127 + 0.019 v s . 0.037 + 0.007 U/mg;
-71 %; p 0.001). Leukocyte counts decreased 10 min ( 2 1 . 1 %; n.s.)
and 30 min ( 4 1 . 1 %; p < 0 , 0 0 1 ) a f t e r i n i t i a t i o n o f h e m o d i a l y s i s
t h e r a p y . We observed a maximal i n c r e a s e o f t h e plasma E- a j P I complexes a f t e r t h r e e hours (+ 409 %; p < 0 , 0 0 1 ) . I n c o n t r a s t , plasma
oi]PI a c t i v i t y and 'ajPI c o n c e n t r a t i o n were unchanged d u r i n g hemodial y s i s therapy.
408
W. H. H Ö R L E T A L .
A p a r a l l e l d i g e s t i o n o f t h e s u b u n i t s a l p h a , beta and gamma o f
Phosphorylase kinase was observed a f t e r i n c u b a t i o n o f u r i n e f r a c t i o n s
o f p a t i e n t s w i t h p o s t t r a u m a t i c ARF f o r 12 hours. However, when
approx. 100-times c o n c e n t r a t e d d i a l y s a t e s (pore s i z e 10,000 d a l t o n )
were i n c u b a t e d w i t h Phosphorylase kinase t h e alpha p o l y p e p t i d e c h a i n
o f t h e enzyme was c o m p l e t e l y degraded w i t h i n 1 hour. A f t e r 4 h r o f
i n c u b a t i o n t h e gamma s u b u n i t was a l s o t o t a l l y d e s t r o y e d , w h i l s t
approx. 2/3 o f t h e beta c h a i n was d i g e s t e d .
-
400Acute
renal
Regular
failure
dialysis
treatment
300200-
105
165
Trypsin
225
285
( u g / 0 . 1 ml plasma)
F i g . 2: P r o t e o l y t i c i n h i b i t o r y c a p a c i t y i n t h e plasma o f RDT
p a t i e n t s and p a t i e n t s w i t h p o s t t r a u m a t i c ARF expressed i n p e r c e n t
o f h e a l t h y s u b j e c t s . 0.1 ml o f plasma from e x p e r i m e n t a l s u b j e c t s
were incubated f o r 60 min a t 37 °C w i t h i n c r e a s i n g amounts o f
bovine t r y p s i n . P r o t e o l y t i c a c t i v i t y was measured u s i n g azoc a s e i n as a s u b s t r a t e ? . Means + SEM from f i v e experiments.
Table 1
E f f e c t o f h e m o d i a l y s i s t h e r a p y on plasma p r o t e i n a s e a c t i v i t y , l e u k o c y t e c o u n t s , plasma e l a s t a s e a l p h a ^ - p r o t e i n a s e i n h i b i t o r (E- o ^ P I ) complex as w e l l as o^PI a c t i v i t y and plasma c o n c e n t r a t i o n
0
Proteinase a c t i v i t y
(U/mg p r o t e i n )
0.127
+ 0.019
Leukocytes
(cells/mm )
10
0.103
+ 0.014
30
0.095
+ 0.014
+
7,133
582
+
5,625
696
+
4,200
251
+
188
20
+
196
25
+
326
56
+
1.98
0.11
1.89
+0.11
+
2.07
0.10
+
254
14
257
± 1 3
3
E-iaiPI
(ng/ml)
60
120
0.087
+ 0.013
c
a
+
6,658
441
+
373
32
+
2.06
0.09
180 minutes
0.059.
+ 0.010°
c
+
5,950
607
+
602
84
+
2.01
0.09
0.037
+ 0.007°
+
c
7,192
824
+
769
128
+
2.08
0.11
+
1
aiPI
(U/ml)
aiPI
(mg/dl)
Mean values,+ SEM from 12 exoeriments
(Sp<0.05; >p<0.01; p < 0 . 0 0 1 )
t
t
268
+ 1
3
258
+ 1
2
+
260
1 1
b e f o r e and d u r i n g h e m o d i a l y s i s t h e r a p y
a
271
3
c
W. H. H Ö R L E T A L
410
DISCUSSION
The o b j e c t o f our s t u d y was t o i n v e s t i g a t e t h e r o l e o f p r o teases on t h e h y p e r c a t a b o l i c s t a t e a s s o c i a t e d w i t h ARF,
F i g u r e 1 shows t h e p r o t e o l y t i c d i g e s t i o n o f Phosphorylase k i nase by u l t r a f i l t r a t e d plasma from a h y p e r c a t a b o l i c p a t i e n t w i t h
p o s t t r a u m a t i c ARF, Comparable data were o b t a i n e d w i t h plasma u l t r a f i l t r a t e s from a l l p a t i e n t s w i t h p o s t t r a u m a t i c ARF,
Plasma u l t r a f i l t r a t e s from normal s u b j e c t s and p a t i e n t s w i t h
ARF a f t e r drug overdosage ( b a r b i t u r a t e , f l u r a z e p a m , c a r b r o m a l ,
d i f f e r e n t analgesics, aminoglycosides or c y t o s t a t i c s ) d i d not
a f f e c t t h e s u b u n i t s t r u c t u r e o f Phosphorylase kinase w i t h i n 24
hours i n c u b a t i o n . F u r t h e r m o r e , plasma u l t r a f i l träte o f p a t i e n t s
w i t h p o s t t r a u m a t i c ARF a l s o d i g e s t s hepatocyte membrane f r a c t i o n s ,
whereas c o n t r o l ultrafilträte o n l y demonstrates v e r y f a i p t p r o t e o l y t i c d e g r a d a t i o n w i t h i n 24 hours o f i n c u b a t i o n a t 37 ° C .
4
6
Normally, d i g e s t i o n o f p r o t e i n i n t h e plasma i s e f f e c t i v e l y
l i m i t e d by i n h i b i t o r s o f p r o t e a s e s . A l p h a i - a n t i t r y p s i n ( a l p h a s protease i n h i b i t o r ) and a l p h a 2 - m a c r o g l o b u t i n accounted f o r more
than 90 % o f t h e t o t a l protease i n h i b i t i n g c a p a c i t y o f p l a s m a . I t
has been shown t h a t plasma a l p h a i - a n t i t r y p s i n l e v e l i n c r e a s e s i n
p a t i e n t s w i t h ARF p a r t i c u l a r l y a f t e r m u l t i p l e t r a u m a t i c i n j u r i e s .
In c o n t r a s t t o a l p h a i - a n t i t r y p s i n , t h e values o f plasma alpha2-macr o g l o b u l i n were markedly d e c r e a s e d . Free p r o t e o l y t i c a c t i v i t y i n
the plasma may be a consequence o f t h e r e l a t i v e low alpha2-macrog l o b u l i n v a l u e s . However, these i n h i b i t o r s were measured by immunol o g i c a l techniques and t h e i r c o n c e n t r a t i o n shows no r e l a t i o n s h i p t o
the b i o l o g i c a l a c t i v i t y o f these i n h i b i t o r s . T r y p s i n b i n d i n g capac i t y was s i g n i f i c a n t l y lower i n RDT p a t i e n t s and d r a m a t i c a l l y r e duced i n p a t i e n t s w i t h p o s t t r a u m a t i c ARF compared t o h e a l t h y controls.
1 0
4
We have p r e v i o u s l y shown t h a t p r o t e o l y t i c a c t i v i t y o f t h e adm i n i s t e r e d plasma p r o t e i n s o l u t i o n s a r e lower than p r o t e o l y t i c act i v i t y o f plasma f r a c t i o n s o f h e a l t h y c o n t r o l s . Thus we can conc l u d e t h a t no p r o t e o l y t i c a c t i v i t y was i n f u s e d i n t o our p a t i e n t s
w i t h ARF. However, a l p h a 2 ~ m a c r o g l o b u l i n was n o t d e t e c t i b l e i n t h e
a v a i l a b l e plasma p r o t e i n s o l u t i o n s i n c o n t r a s t t o r e l a t i v e low conc e n t r a t i o n s o f a l p h a i - a n t i t r y p s i n . Free p r o t e o l y t i c a c t i v i t y i n
t h e plasma o f a p a t i e n t w i t h p o s t t r a u m a t i c ARF was observed due t o
p r o t e a s e - a n t i p r o t e a s e imbalance. A f t e r an i n i t i a l d e t e r m i n a t i o n o f
80 mg/dl t h e a l p h a 2 - m a c r o g l o b u l i n values were t o o low t o be d e t e c t ed. A d d i t i o n o f p u r i f i e d alpha2-niacroglobul i n t o t h e u l t r a f i l t r a t e s
r e s u l t e d i n complete i n h i b i t i o n o f Phosphorylase kinase d i g e s t i o n
i n v i t r o . According t o our s t u d i e s we f a v o u r t h e a p p l i c a t i o n o f
a l p h a 2 - m a c r o g l o b u l i n o r f r e s h f r o z e n plasma t o h y p e r c a t a b o l i c
4
4
5
PROTEOLYTIC ACTIVITY IN PATIENTS
p a t i e n t s . B a l l d i n e t a l , have demonstrated t h a t t h e a v a i l a b i l i t y o f
a l p h a - m a c r o a l o b u l i n i s o f v i t a l importance f o r p r o t e c t i o n a g a i n s t
proteinases . Elastase
and t r y p s i n ^ a r e bound by alpha-macroglob u l i n . Increased c a t a b o l i s m o f a l p h a - m a c r o g l o b u l i n s a f t e r i n t r a venous i n f u s i o n o f t r y p s i n - a l p h a i - a n t i t r y p s i n complexes has been observed i n dogs. More than h a l f o f t h e t r y p s i n molecules were taken
up by a l p h a - m a c r o g l o b u l i n s d u r i n g t h e f i r s t hour. Subsequent t o sat u r a t i o n o f a l p h a - m a c r o g l o b u l i n s dogs became s h o c k e d .
1 1
1 2
1
11
P r o t e o l y t i c d e g r a d a t i o n o f t h e s u b u n i t s a l p h a , beta and gamma
of p u r i f i e d Phosphorylase kinase was o b t a i n e d by u r i n e f r a c t i o n s o f
p a t i e n t s w i t h p o s t t r a u m a t i c ARF^, whereas u r i n e f r a c t i o n s o f p a t i e n t s
w i t h n e p h r o t i c syndrome l e d t o a p r e v a l e n d d i g e s t i o n o f the alpha
polypeptide c h a i n .
1 4
When d i a l y s a t e s o f RDT p a t i e n t s were c o n c e n t r a t e d approx. 100t i m e s we a l s o observed r a p i d d i g e s t i o n o f Phosphorylase k i n a s e .
From these experiments we may assume t h a t p r o t e i n a s e may a l s o be
i n v o l v e d i n t h e p r o t e i n c a t a b o l i s m o f RDT p a t i e n t s . Furthermore,
i t may be p o s s i b l e t o remove i n p a r t p r o t e o l y t i c enzymes d u r i n g
d i a l y s i s treatment.
4
Hemodialysis t h e r a p y has been r e p o r t e d t o be a c a t a b o l i c event.
I t has been shown t h a t glucose i n the d i a l y s a t e i S as w e l l as c o n t i nuous amino a c i d i n f u s i o n ^ are i n e f f e c t i v e t o p r e v e n t t h i s c a t a b o l i c s t a t e . The pathogenesis o f h e m o d i a l y s i s induced p r o t e i n c a t a b o l i s m remains u n c l e a r . One p o s s i b i l i t y c o u l d be t h e r e l e a s e o f
granulocyte proteinases a f t e r s t a r t i n g hemodialysis therapy.
Craddock e t a l . have demonstrated h e m o d i a l y s i s - i n d u c e d l e u k o p e n i a
and pulmonary v a s c u l a r l e u k o s t a s i s r e s u l t i n g from complement a c t i v a t i o n by d i a l y z e r c e l l o p h a n e membranes ?.
1
1
N e u t r o p h i l g r a n u l o c y t e s c o n t a i n a broad v a r i e t y o f agents t h a t
a r e i n v o l v e d i n the defence and d i g e s t i o n o f i n v a d i n g m i c r o o r g a n i s m s ^ . These i n c l u d e e l a s t a s e ^ , c a t h e p s i n G, p r o t e i n a s e - 3 ,
c a t h e p s i n B, c a t h e p s i n D and c o l l a g e n a s e ' " . Lysosomal p r o t e i n ases are n o t r e s t r i c t e d t o the i n t r a c e l l u l a r compartment. They are
r e a d i l y released e x t r a c e l l u l a r l y d u r i n g c e l l death, phagocytosis,
exposure t o a n t i g e n a n t i b o d y complexes, complement components and
t o x i c substances such as e n d o t o x i n s ^ , 2 7 . Under p a t h o l o g i c a l cond i t i o n s massive p r o t e a s e r e l e a s e may occur. T h i s r e s u l t s i n t i s s u e
i n j u r y 2 8 , 2 9 and d e g r a d a t i o n o f plasma p r o t e i n s , i f t h e a c t i v i t i e s
of t h e c o n t r o l l i n g p r o t e i n a s e i n h i b i t o r s i n plasma and t i s s u e s are
insufficient.
1
1
1 9
2 0
R e c e n t l y , Aasen e t a l . ^ 0 observed i n an e x p e r i m e n t a l study
( l e t h a l e n d o t o x i n shock i n c a n i n e s ) a c l e a r r e l a t i o n o f t h e i n i t i a l
drop o f l e u k o c y t e s ( p r o b a b l y combined w i t h d e g r a n u l a t i o n o f these
c e l l s ) t o t h e appearance o f t h e l e u k o c y t e e l a s t a s e - ^ a j - p r o t e i n a s e i n -
412
W. H. H Ö R L E T A L .
h i b i t o r complex i n plasma. S h o r t l y t h e r e a f t e r , the well-known d i s turbances o f t h e blood systems arose i n d i c a t i n g t h a t consumption
o f t h e i r components might be due, a t l e a s t i n p a r t , t o the a c t i o n
of liberated leukocytic proteinases.
Granulocyte e l a s t a s e may be r e l e a s e d d u r i n g h e m o d i a l y s i s
t r e a t m e n t p r o b a b l y due t o t h e c o n t a c t o f blood c e l l s w i t h t h e blood
l i n e s and t h e d i a l y z e r membrane (cuprophane) system. This c o n t a c t
may r e s u l t i n a " f r u s t r a t e d p h a g o c y t o s i s " and a subsequent p r o t e i nase r e l e a s e . However, leukopenia d u r i n g h e m o d i a l y s i s t h e r a p y does
not p a r a l l e l t h e i n c r e a s e o f E - a j P I . Pulmonary v a s c u l a r l e u k o s t a s i s
r e s u l t i n g from complement a c t i v a t i o n by d i a l y z e r c e l l o p h a n e membranes may be i n v o l v e d i n t h i s process*?. Plasma 04PI a c t i v i t y and
a i P I c o n c e n t r a t i o n were unchanged d u r i n g h e m o d i a l y s i s t h e r a p y
(Table 1 ) .
Alphas-protease i n h i b i t o r i s a d o m i n a t i n g protease i n h i b i t o r
i n plasma. I t forms complexes w i t h v i r t u a l l y a l l s e r i n e p r o t e i n a s e s
31,32
d
bacterial proteinases. A v a r i e t y of oxidants i n c l u d i n g myeloperoxidase produced by n e u t r o p h i l s as w e l l as c i g a r e t t e
smoke are capable o f i n a c t i v a t i n g a l p h a j - p r o t e a s e i n h i b i t o r " .
a n
s
o
m
e
3 3
3 5
With decreased a l p h a i - a n t i p r o t e i n a s e c o n c e n t r a t i o n i n h i b i t i o n
o f b a c t e r i a l and l e u k o c y t e p r o t e i n a s e s i n t h e b r o n c h i a l s e c r e t i o n
may be i n s u f f i c i e n t o r absent r e s u l t i n g i n a l v e o l a r damage and
emphysema ^. I n i d i o p a t h i c pulmonary f i b r o s i s p r o g r e s s i o n o f t h e
disease i s assumed due t o a p r o t e i n a s e / a n t i p r o t e i n a s e imbalance.
A c t i v e c o l l a g e n a s e has been observed i n t h e lavage f l u i d o f t h e
lower r e s p i r a t o r y t r a c t 7
3
3
#
Our r e s u l t s o f f e r t h e p o s s i b i l i t y t h a t t h e h e m o d i a l y s i s - i n duced r e l e a s e o f e l a s t a s e may enhance t h e r i s k f o r development o f
d e s t r u c t i v e l u n g disease i n l o n g - t e r m RDT p a t i e n t s .
P r o t e o l y t i c a c t i v i t y o f t h e plasma f r a c t i o n s u s i n g azocasein
as a s u b s t r a t e was h i g h e r i n RDT p a t i e n t s (+ 244 %; p < 0 . 0 1 ) compared w i t h h e a l t h y c o n t r o l s (0.052 + 0.004 U/mg p r o t e i n ) . However,
p r o t e i n a s e a c t i v i t y decreased permanently d u r i n g h e m o d i a l y s i s
t h e r a p y i n d i c a t i n g an a c t i v a t i o n o f t h e plasma i n h i b i t o r y c a p a c i t y .
I n agreement w i t h t h i s h y p o t h e s i s we observed a f u r t h e r decrease
o f plasma p r o t e i n a s e a c t i v i t y d u r i n g h e m o d i a l y s i s t h e r a p y a f t e r t h e
a d d i t i o n o f pork pancrease e l a s t a s e t o t h e plasma samples o b t a i n e d
38
SUMMARY
1) P r o t e o l y t i c enzymes e x i s t i n u l t r a f i l t r a t e d plasma, conc e n t r a t e d d i a l y s a t e s and u r i n e f r a c t i o n s o f p a t i e n t s w i t h p o s t t r a u m a t i c r e n a l f a i l u r e . D i f f e r e n c e s i n d i g e s t i o n p a t t e r n o f phosphory-
PROTEOLYTIC ACTIVITY IN PATIENTS
läse kinase suggest t h e e x i s t a n c e o f d i f f e r e n t proteases
w i t h hypercatabolic renal f a i l u r e .
413
in patients
2) T r y p s i n b i n d i n g c a p a c i t y i s reduced i n RDT p a t i e n t s and
markedly lower i n p a t i e n t s w i t h p o s t t r a u m a t i c ARF.
3) P r o t e i n c a t a b o l i s m i s i n h i b i t e d i n v i t r o by alpha2-macrog l o b u l i n . From our i n v i t r o s t u d i e s we f a v o u r t h e a p p l i c a t i o n o f
f r e s h f r o z e n plasma i n s t e a d o f t h e a v a i l a b l e plasma p r o t e i n sol u t i o n s t o hypercatabolic patients.
4) Hemodialysis may enhance p r o t e i n a s e i n h i b i t o r y c a p a c i t y o f
t h e plasma.
5) Hemodialysis t h e r a p y induces t h e i n c r e a s e o f plasma E - X i
P I . The continuous r e l e a s e o f g r a n u l o c y t e e l a s t a s e d u r i n g hemodial y s i s t h e r a p y may enhance t h e r i s k f o r the development o f d e s t r u c t i v e lung disease.
ACKNOWLEDGEMENT
This work was supported by t h e Deutsche Forschungsgemeins c h a f t , Ho 781/3-2 and Sonderforschungsbereich
5 1 , München. The
e x c e l l e n t t e c h n i c a l a s s i s t a n c e o f Mrs. M. Röder and Mrs. U. Hof
as w e l l as t h e s e c r e t a r i a l h e l p o f Miss M. E i r i n g i s g r e a t l y
appreciated.
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