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Hageman Factor and Acute Gouty Arthritis.

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CURRENT COMMENT
Hageman Factor and Acute Gouty Arthritis
By R. W. KELLERMEYER
I
1900 Freudweiler offered data to support a primary role of urate crystals in
the acute inflammatory process of gout as
proposed by Garr0d.l At the same time,
several prominent investigators supported a
theory stating that the deposition of urate
crystals at the site of inflammation in gout
was secondary to a primary necrotic process.l The primary necrotic process purported to result in tissue breakdown products, which in turn were thought to be
responsible for the accumulation of urate
crystals, leukocytes, and other components
of the exudate. This hypothesis prevailed
until the primary role of urate crystals in
acute gouty arthritis was firmly established
by Seegmiller, Howell, and Malawista?
and Faires and McCarty in 1962.3Although
this recent work stresses the primary importance of the urate crystals in acute gouty
arthritis, it does not define the mechanism
which initiates the idammatory process
other than to state that the crystals probably serve as an irritant.
Inflammation is “a process which begins
following a sublethal injury to tissue and
ends in complete healing.”* The characteristic changes associated with an acute inflammatory process include pain, swelling,
increased warmth, redness and the accumulation of an exudate. These changes are
attributed to vasodilation, increased vascular permeability, and the emigration of leukocytes ( polymorphonuclear neutrophils )
to the site of “injury.” The development of
N
these changes is attributed to pharmacodynamic biochemical agents called inflammatory mediators. The physiologic mechanism
for the derivation of these inflammatory
mediators is not known.
Because the urate crystals associated with
acute gouty arthritis are sharp and needlelike, resembling slivers of glass, it is possible that synovial cells are damaged by
the sharp urate crystals causing mechanical
“sublethal injury to tissue.” Phagocytosis of
the urate crystals by synovial cells or tissue
macrophages might also injure these cells.
This injury could result in the release of
intracellular substances, e.g., lysosomal enzymes, into the synovial tissues and synovia1 fluid that would in turn lead to the
characteristic findings of inflammation. Although urate crystals might cause the release of inflammatory mediators by damaging the synovial lining cells, it is also
possible that urate crystals initiate chemical reactions in the synovial fluid resulting
in the development of inflammatory mediators. Since surfaces can cause catalysis, it
is possible that the surfaces of the urate
crystals induce the development of i d a m matory mediators in the synovial fluid.
Proposed Role for Hageman Factor (Factor XZZ) in Acute Gout
Hageman factor is an enzymic protein
present in plasma in an inactive form. Once
activated, Hageman factor can initiate at
least two series of chemical reactions in
-
From the Department of Medicine, Western Reserve University, Cleveland, Ohio 44106.
This work was supported b y research grants
AM 9560 and AM 07841 from the National Insti452
_
_
_
tutes of Arthritis and Metabolic Diseases.
R. W. KELLERMEYER,
M.D.: Assistant Professor
of Medicine, John G M a y R. Markle Scholar in
Academic Medicine.
ARTHRITISAND RHEUMATISM,
VOL.11, No. 3 (JUNE 1968)
~
453
HAGEMAN FACTOR AND ACUTE GOUTY ARTHRITIS
COMPLEMENT (C'l
INFLAMMATORY
MEDIATOR
PRECURSORS
+
PLASMINOGEN
I
FRAGMENT
]
PRO-PF
KALLIKREINOGEN
KININWEN
[ N:I ]
KALLIKREIN
I
A F~~~:!~IOASWLAR
PLASMIN
or C'3
ACTIVATED
PERMEABILITY
ENHANCING
FACTORS
CHEMOTACTIC
FACTORS
C'5.6.7.
+
[
C'3
\
ALTERATION OF ENOOTl4ELIAL SURFACE
PERMEABILITY
DIRECTS
LEUKOCYTE
MIGRATION
INTRA-ARTICULAR
ENHANCES
LEUKOCYTE
EMIGRATION
PAIN
ACCUMULATION
GRANULOCYTIC LEUKOCYTES
PLASMA P R O T E I N S
LACTATE
LYSOSOMAL DISRUPTION
nYmtoLYTic ENZYMES
PROTEOLYTU ENZYMES
CATIONIC
PROTEIN
DECREASED pn
ENHANCES CRYSTAL FORMATION
TISSUE OlSTRUCTlON
1
ENHANCES IEFLAMMATION
PHAGOCYTDSIS OF
URATE CRYSTP.LS
Fig. 1.-Schematic summary of a proposed inter-relationship of factors that may
play a role in the development of the inflammatory process in acute gout.
uitro. One reaction results in the activation
of the intrinsic clotting system,6 and the
other in the formation of factors that induce vasodilation,6 enhance vascular permeability,' stimulate smooth muscle contraction,* and induce pain8 Hageman
factor can be activated in uitro by glass,
ellagic acid, and numerous forms of particulate material. The comparison of needlelike sodium urate crystals to slivers of glass
suggested that Hageman factor might be
activated by urate crystal^.^ It was proposed
that the activation of Hageman factor in
synovial fluid by urate crystals initiates a
series of reactions that result in the formation of inflammatory mediators. These mediators then could induce the inflammatory
process associated with acute gout. This
proposal is supported by the followhg data:
( a ) Hageman factor is activated in vitro
by urate crystalsg; ( b ) Hageman factor is
present in normal synovial fluidlo; (c) permeability enhancing factors are formed in
normal human synovial fluid exposed to
urate crystals in uitroll; (d) the permeability enhancing factors are not activated
in normal human synovial fluid, if Hageman factor is inactivated by specific antibody1'; and (e) the presence of kinins in
synovial fluid exudates from individuals
with acute goutf2
The hypothesis that acute gout is initiated by Hageman factor might be applied
to other forms of arthritis associated with
intra-articular deposition of crystals, e.g.,
the negatively charged calcium pyrophosphate crystals associated with pseudogout
which are known to activate Hageman fac-
It is also of interest to note that chickens
do not have Hageman factor, nor do they
develop an acute inflammatory response following the intra-articular injection of nionosodium urate cry~ta1s.l~ Furthermore,
kaolin, a substance that activates Hageman
factor and induces a local inflammatory re-
454
R. W. KELLERMEYER
man factor does play a role in vivo in the
development of an acute inflammatory reaction, i.e., gout, it may not be active in the
induction of every inflammatory process.
The interrelationship of Hageman factor to
several of the inflammatory mediators is
Mediators of the Acute Inflammatory
summarized in the following paragraphs.
Process
Bradykinin is a polypeptide composed of
A number of factors have been identified nine amino acids and is capable of inand studied in experimental models as pos- creasing capillary permeability, stimulating
sible mediators of the acute inflammatory the contraction of smooth muscle, lowering
process. Investigators have tried to impli- blood pressure and causing pain, but it does
cate one of these factors as the agent re- not induce the accumulation of large numsponsible for all of the changes noted in bers of leukocytes when a “physiologic”
acute inflammation, i.e., vasodilation, in- concentration is injected as a single dose
creased vascular permeability, pain, and the into skin.lTAlthough not supported by any
accumulation of leukocytes. None of the fac- data at present, possibly a slow sustained
tors identified thus far appears to be a satis- release of this substance in vivo could
lead to significant leukocyte accumulation.
factory mediator of all these effects.
Several of these mediators, including Bradykinin was initially described by Rocha
kinins, PF/dil, and kallikrein, will readily e Silva as a vasodepressor substance reinduce vasodilation, increased vascular per- leased from the pseudo-globulin of blood by
meability, and pain, but will not induce the snake venom. There are several activators
accumulation of leukocytes unless present of bradykinin, but the only physiologic ones
in excessively large amounts. Factors that are granulocytic leukocytes and urate crysinduce the accumulation of leukocytes by t a l ~ . ~ * ~ *
“Kallikrein” is a term applied to a group
directing the movement of leukocytes
through the vascular endothelium to the of vasodepressor substances. Initially this
site of injury are called chemotactic agents. activity was described in human urine and
~.~~
an inactive
Recently two factors derived from serum p a n c r e a ~ . ~Subsequently,
complement components were found to precursor of this substance called kallikrehave chemotactic activity but lack the abil- inogen was identified in blood. Kallikrein
ity to induce increased vascular permea- has proteolytic activity that can catalyze
bility.14,15Leukocytes accumulating at the the formation of a kinin-like substance in
site of injury may release additional inflam- blood called kallidin, a decapeptide with
matory mediators in the form of lysosomal the same structure as bradykinin but with
hydrolytic enzymes that will enhance the an additional N-terminal lysine. Kallidin
may be rapidly converted to bradykinin by
inflammatory process.l8
It is likely that the acute inflammatory re- enzymatic cleavage of the N-terminal lysponse is a reflection of the concerted action sine. There are three other identifiable
of several mediators, including those that polypeptides with molecular structures and
induce vasodilation and increase vascular biologic activities similar to bradykinin, and
permeability, those that induce chemotaxis, these are summarily referred to as kinins.
and the lysosomal hydrolytic enzymes. It is 21.22
also likely that an acute inflammatory reKinins evolve slowly from plasma kept in
sponse can be induced by more than one a glass tube, but they do not evolve when
type or group of inflammatory mediators the plasma is prevented from coming in
depending on the etiologic agent. If Hage- contact with gla~s.2~
Hageman factor, as
sponse when injected intracutaneously in
humans, induces less intlammation in an
individual with Hageman factor deficiency
than in an individual without the
deficiency.
455
HAGEMAN FACXOR AND ACUTE GOUTY ARTHRITIS
noted above, is also activated by contact Hageman factor + activated Hageman
factor
with glass surfaces or other similarly negatively charged surfaces. Margolis recog- activated Hageman factor pro-PF + PF
nized this and demonstrated that kinins PF kallikreinogen + kallikrein
were not generated in plasma from patients kallikrein kininogen + kinin.
lacking Hageman factor whether the plasStill other plasma components have been
ma was exposed to glass or not. Moreover,
linked to the inflammatory process. C'1 esthe addition of purified partially activated
terase, the active form of the first compoHageman factor to plasma from a person
nent
of complement, will cause increased
with a congenital deficiency of Hageman
vascular
permeability when injected intrafactor promoted the formation of kinins8
cutaneously.26
This permeability enhancing
PF/ dil (permeability factor/ diluted sebe
inhibited by antihistamines,
activity
can
rum) is a factor that develops in guinea
suggesting
that
one of the mediators in this
pig or human plasma and induces increased
system
is
histamine.
The C'1 esterase-histavascular permeability in the skin of guinea
mine
system
can
be
activated by antigenpigs following intracutaneous inje~ti0n.l~
antibody
complexes,
but
this does not apSubsequently, it was demonstrated that
pear
to
be
dependent
on
Hageman factor.
PF/dil does not develop if the plasma is coltwo additional
Histamine
and
serotonin,
lected and prepared in silicone-coated containers. Again the role of glass suggested inflammatory mediators likely to have in
that Hageman factor might play a role. This uiuo importance in acute inflammatory
role was confirmed by demonstrating that processes, do induce vasodilation and inthe development of PF/dil is dependent on creased vascular permeability, yet neither
Hageman factor.24 PF/dil is derived from is a potent chemotactic agent. Further, the
an a-globulin precursor in plasma referred release of these substances has no known
to as pro-PF. The activated form is not a relationship to Hageman factor.
The role of PF/dil, kallikrein, and kinins
polypeptide but a larger molecule with
properties of a proteolytic enzyme. This in the initiation of an acute inflammatory
substance is found in inflammatory em- process was questioned because these subdates, but its role in the acute inflammatory stances were initially reported to produce
process is uncertain.l'
only short-lived venular damage in the
Both PF/dil and kallikrein are proteo- early phases of inflammation, and not to
lytic enzymes, both exist as precursor glob- produce the increased capillary permeabilulins in plasma, and both are activated ei- ity that has been proposed to produce the
ther directly or indirectly in plasma by major changes in acute inflammatory procHageman factor. Although there was coness. Recently, however, data have been residerable speculation that PF/ dil and kalliported to indicate that the major quantity
krein might be identical compounds, Becker
of edema in an experimentally induced inand Kagen have separated them by puri6cation pr0cedures.2~PF/ dil and kallikrein flammation is secondary to increased perhave electrophoretic mobilities of beta and meability of the venules, and that leakage
gamma globulins and sedimentation values from the capillaries is prominent only in
the delayed phase of altered vascular perof 5.7 and 11.3, respectively.
meability
and probably contributes little to
Margolis and others have suggested that
the
fluid
exudate.27
These data offer conHageman factor changes kallikreinogen to
siderable
support
for
the possible role of
kallikrein directly or through an effect on
PF/dil. This proposed interrelationship can permeability factors and kinins in the inflammatory process.
be outlined as follow^^^^^^:
+
+
+
456
Role of Inflammatory Mediators in Acute
Gouty Arthritis
Although it has been demonstrated that
urate crystals can induce both a kinin-like
activity and permeability enhancing factor
with properties similar to PF/dil and kallikrein in normal human synovial fluid,11028
it is unlikely that these agents are responsible for the entire inflammatory process. Injection of bradykinin into a canine joint
rapidly induces a transient episode of pain
associated with relatively small exudative
reaction and accumulation of leukocytes, far
less than that associated with the intra-articular injection of urate crystals.29The incomplete and transient nature of this inflammatory response was presented as
evidence against the role of kinins in acute
gouty arthritis. Yet this response to bradykinin may reflect only one portion of the
process leading to acute gout, or it may
reflect the rapid destruction of bradykinin,
since the half-life in plasma in only a few
seconds.
Furthermore, Phelps et al. were unable
to block the arthritis induced by urate crystals in dogs when carboxypeptidase-B was
given intra-arterially or injected into the
synovium with the crystals. Carboxypeptidase-B is a potent inhibitor of bradykinin and
other kinin polypeptides with C-terminal
arginine groups. These authors recognized
that it is possible that carboxypeptidase-B
does not inhibit the development of arthritis, because the site of kinin release and
action is not readily accessible to carboxypeptidase-B. Moreover, it is reasonable to
consider that the kinins functioning in acute
gouty arthritis are not susceptible to carboxypeptidase-B, since it has been suggested
that several plasma kinins exist with different suscepsbilities to enzymatic inactivation.21The experiments by Phelps, Prockop,
and McCarty suggest that bradykinin alone
does not produce an acute gouty arthritis,
yet these studies do not eliminate other
kinins as an active component in acute gout.
R. W. KELLERMEYER
There are no data to support a role for
histamine, C’1 esterase, or serotonin in the
development of acute gouty arthritis.
Role of Leukocytes in Acute Gout
The importance of leukocytes to crystalinduced inflammation can be demonstrated
experimentally. The acute arthritis induced
in dogs by urate crystals does not develop
when marked granulocytopenia is induced
in the animal by the cytotoxic drug vinblastine (Velbana) .31 There is always the
concern that potent cytotoxic agents affect
multiple biologic processes of the body and
may also interfere with the development of
the arthritis by deleting other essential
components, yet these data support an essential role of the leukocytes in the development of acute gouty arthritis.
Leukocytes accumulating within the synovia can intensify and prolong the intlammatory process ( a ) by releasing proteolytic
and hydrolytic enzymes from lysosomes
during phagocytosis or cellular disintegration, (b) by decreasing the synovial pH
caused by accumulation of lactic acid, and
(c) by activating additional kinin.
The hydrolytic enzymes released from lysosomes are capable of damaging living
cells and will produce an arthritis when
injected intra-articularly.l6 Janoff and
Zweifach have demonstrated that a cationic
protein isolated from the lysosomes of rabbit polymophonuclear leukocytes induces
leukocytic emigration from both capillaries
and venules and increases vascular permeability.3o This observation suggests that
the leukocytes migrating into the joint
space early in the inflammatory process
could lyse, release cationic protein and enhance the accumulation of additional leukocytes in a cyclic fashion.
Leukocytes accumulating at the site of
crystal deposition will produce lactic acid
as the major end product of their metab.olism, which in turn will bring about a
reduction in the pH of the synovial fluid.
The maximal pH change is approximately
457
HAGEMAN FACTOR AND ACUTE GOUTY AHTHRITIS
0.5
It is doubtful that t h i s degree
of acidity per se will cause tissue destruction, pain, or accentuation of the idammatory process. This change might enhance
the effectiveness of enzymatic reactions
which promote the infhnmatory process,
or it might lead to further crystallization of
urate.
Leukocytes can induce the activation of
kinins in plasma.18 It is, therefore, possible
that leukocytes could interact with protein
components in synovia or in the plasma
exudate to release additional kinins.
Chemotactic Factors in Gouty Arthritis
As noted previously, none of the kinins
or other permeability enhancing factors
have been found to be potent chemotactic
agents.” Perhaps the kinins act to bring
about increased vascular permeability and
thereby permit the migration of leukocytes
from the vessels into the joint. Leukocytes
may be attracted into the joint by still other
factors that develop within the synovial
fluid and serve as potent chemotactic
agents. At the present time, there are no
data to support the formation or presence
of chemotactic factors in synovial fluid.
Ward et al. demonstrated that the formation of either a complex of serum complement components, C’5, 6, and 7,14 or a
fragment of C’316 will serve as a potent
chemotactic agent. In an in vitro experimental model, bradykinin, kallidin, histamine, serotonin, and cationic protein described by Janoff and Zweifach30 do not
possess chemotactic ~r0perties.l~
Complement is present in synovial fluid, but there
has been no recognized mechanism for its
conversion to a chemotactic agent in acute
gout. Recently NafE and Byers have demonstrated that urate crystals will deplete
complement in human serum.33If this depletion represents an activation of complement, it is probable that mate crystals
could activate chemotactic factor derived
from complement similar to those described
by Ward. Preliminary evidence suggests
that a chemotactic factor does develop in
both rabbit and human serum exposed to
urate cry~ta1s.a~
Hageman factor may also play a role in
chemotaxis. The fragment of C’3 that is
reported by Ward to be a chemotactic
factor, can be cleaved from C’3 by plasmin.16 There is some evidence to suggest
that plasminogen can be converted to
~ ~ con~~~
plasmin by Hageman f a ~ t o rIf. this
version of pIasminogen to plasmin is catalyzed by Hageman factor, then it can be
proposed that urate crystals might promote
the development of a chemotactic factor
by activating Hageman factor, which in
turn resulted in the formation of plasmin
and the C‘3 fragment that is active as a
chemotactic agent. In a study done by Graham et al., in the rabbit ear chamber,
purged Hageman factor resulted in
vasodilation and the accumulation of leukocytes to a greater degree than bradykinin. These data suggest that Hageman
factor alone has chemotactic properties, or
that it induces the formation of a chemotactic agent.37Whether the reaction is a direct
or indirect result of the Hageman factor
could not be determined.
SUMMARY
It is proposed that arthritis induced by intra-articular crystals is initiated by the
activation of Hageman factor by the negatively charged crystals (Fig. 1).The activated
Hageman factor in turn initiates a series of reactions resulting in the development of
permeability enhancing activity, perhaps PF/dil, kallikrein, or kinins.
The kallikreins, kinjns, and PF/dil, can initiate the process by inducing vasodilation,
increased vascular permeability, and leukocyte emigration though the vessel wall.
It is possible that kinins do not direct.the movement of the leukocytes through the
tissues to the “site of injury” or the urate crystals and, therefore, fail to
large
accumulations of leukocytes. The urate crystals may activate still an0KOduce
er series
of
458
H. W. KELLEXMEYER
reactions in the synovi that results in the activation of chemotactic factors from
complement components. The chemotactic components could then direct the movement
of the leukocytes to the urate crystals resulting in a marked accumulation of leukocytes.
The release of lysosomal proteolytic and hydrolytic enzymes from the accumulation of
leukocytes may enhance and prolong the inflammatory process. Thus, acute gouty
arthritis can be viewed as the end result of several reaction sequences, each responsible
for a phase of the inflammatory process. These reactions and others discussed in the
body of this report are summarized in Fig. 1. The data supporting the hypothesis implicating Hageman factor in the initiating mechanism of inflammation is discussed.
Whether correct or incorrect, the proposal for the initiation of acute gouty arthritis
by the activation of Hageman factor-PF-kallikrein-kinin system and possibly chemotactic factors remains attractive and will serve as a working hypothesis to stimulate
further experimentation on the mechanism of idammation in gout and other forms
of arthritis and to extend our knowledge of the physiologic and pathologic role of
biologic inflammatory mediators. Further, the proposal and the experimentation
prompted by the proposal encourages a biochemical explanation for the initiation and
development of arthritis induced by crystals.
SUMMARIO
IN INTERLINGUA
Es postulate que arthritis inducite per crystallos intra-articular es initiate per le
activation de factor de Hageman. Iste activation esserea causate per le negativemente
cargate crystallos. Le activate factor de Hageman, de su parte, initiarea un sene de
reactiones resultante in le disveloppamento de un activitate que promove le permeabilitate, i.e., possibilemente, PF/dil, kallikreina, o kininas.
Le kallikreinas, kininas, e PF/dil pote initiar le processo per inducer vasodilatation,
augment0 del permeabilitate vascular, e migration de leucocytos a transverso le pariete
vascular. I1 es possibile que kininas non dirige le movimento del leucocytos a transverso le tissu verso le “sit0 del trauma” o le crystallos de urato e assi non produce
grande accumulationes de leucocytos. Le crystallos de urato effectua possibilemente le
activation de ancora un altere serie de reactiones in le synovio que resulta in le activation de factores chimotactic a b componentes complementari. Postea le componentes
chimotactic dirigerea le movimento del leucocytos verso le crystallos de urato con le
resultato de un marcate accumulation de leucocytos. Le liberation de lysosomal
enzymas proteolytic e hydrolytic ab le accumulation de leucocytos pote promover e
prolongar le processo idammatori. Assi acute arthritis guttose pote esser reguardate
como le resultato terminal de plure series de reactions, cata-un rsponsabile pro un
del phases del processo inflammatori. Le datos que supporta le hypothese de incrimination del factor de Hageman in le initiation del mechanism0 de inflammation es
commentate.
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HAGEMAN FACTOR AND ACUTE GOUTY AHTHHITIS
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