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More on vasodilatation joint swelling and nitric oxide.

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ARTHRITIS & RHEUMATISM
Vol. 39, No. 6, June 1996, pp 1071-1076
0 1996. American College of Rheumatology
1071
LETTERS
More on vasodilatation, joint swelling, and nitric
oxide
To the Editor:
Drs. Evans and Stefanovic-Racic (1) kindly comment
on our views (2) that (i) high synovial fluid (SF) hydrostatic
pressures (Psf) require locally raised mean capillary pressure
(P,.,) that (ii) may depend on arteriolar vasodilatation and
(iii) contribute to swelling. Vasodilatation was suspected (iv) to
be driven by cartilage metabolic demands, and possibly (v)
mediated by chondrocytic nitric oxide (NO). Their comments
call for clarification.
(i) Capillary pressure. Fluid flow across endothelia
depends on Starling pressures (3-5). Normal escape of fluid
into S F (direction +, resorption -) depends on a positive net
pressure (CP), the difference between a positive hydrostatic
pressure difference (Pcnp - PSp)and a net back-sucking (-)
colloid osmotic pressure difference (COP,,,, - COP,,) of
varying efficiency (100-0% = a reflection coefficient (r of 1-0).
The normally negative P,, “sucks“ [ -( -) = t] into SF. Thus,
Equation 1:
z p = (Pmp
~
Pr,) -
(COPl,,“,- COP,,)
In the near-normal example, simplified for didactic
reasons, T P is + 7 (unit cm H,O).
XP
=
[20 -
7
=
25
( -
5)] - 0.9 (35 - 15)
-
I8
If the effective COP difference drops to 0 (COP,,,, = COP,,, or
(r = 0 at m permeability), both the CP (by 18) and the flow into
SF increase. Due to limited joint compliance, the effusion
gradually raises the P,,, decreasing the CP. If the CP returns to
7, this decrease in the COP difference may raise the P,, to 13
cm H,O (-5 + 18). A negative COP difference (COP,,,, <
COP,,), a lower CP, and a higher PC:,,, permit a higher Psp A CP
of 0 does not induce swelling (equation 2). At negative CP, S F
is resorbed.
In 1940 Bauer et al (6) proposed that rheumatoid S F
“colloids’’ raise COP,,, as these “colloids” do (7), sucking fluid
into SF. They never considered hydrostatic P (equation I not
yet formulated). The failure to grasp that high P,, requires
elevated PcaP explains how the proposal (6,7), in otherwise
excellent studies, could be found misleading (8,9). This interlude does not weaken the conclusion that in a steady state
(normal or swelling), Pcap n u s t exceed (or equal) P,, +
(r(COP,,,, - COP,,), a sum of negative terms (equation I),
which opposes flow into S F (see Knox et al as referenced in 5).
In >50% of the traumatic joints in our study (2). the “opposing” sum exceeded Pcap averages, and the effusions would
already have been resorbed unless the Pcapwas elevated to give
a positive CP.
(ii) Arteriolar dilatation. PJnduced venous tamponade may decrease blood flow and raise Pcap.The former can be
compensated for by arteriolar dilatation, raising the Pcap to
levels “required” (item i) or higher (2). This (and item i)
agrees with Levick’s statement (3), that “A fall in precapillary
resistance and a possible rise in postcapillary resistance readily
explain . . . that intra-articular pressures frequently exceed
normal capillary pressure in acute rheumatoid effusions.”
(iii) SF volume. Transendothelial flow is a product of
CP (+ or -1 equation 1) and of endothelial hydraulic conductance (L,) (high in fenestrated capillaries and increased by
“pore” enlargement) and surface area (A) (ref. 3, cf. ref. 4).
Excess S F is removed by the lymphatics (Jv,,ymph). Thus, an
increase or decrease in S F volume (V,,) per unit of time
(dV,,/dt) is reflected (cf. ref. 3) by Equation 2:
A n increase (items i and ii) in [CP] increases the formation of
SF (3). The effect on SF accumulation (dVJdt+) is stronger if
permeability (Ll, t , (r J, ) and A are increased or if Jv~,ym,,,lis
decreased. In heavy exercise, muscle blood flow may increase
>20-fold, which is mainly due to an increase in arteriolar
conductance (correlates with the fourth power of the lumen
radius) (10). Fenestral flow “jets,“ increasing COP differences
( 5 ) . and increase of Jv,,ymp,,, etc., may well prevent short
exercises that result in a 7-fold blood flow increase (1) (considerably less for Pcap in equation 2) from inducing clinical
swelling.
(iv) Mechanism of arteriolar dilatation (item ii). We
suspected metabolic vasodilatation. Finding joint cartilage
avascular, Hunter (1 1) described synovial vessels: “From these
(large branches) again there arises a Crop of small short Twigs,
that shoot towards the outer Surface; and whether they serve
for nourishing oizfv [our italics] or if they pour out a dewy Fluid,
I shall not pretend to determine. However that be, I cannot
help observing, that the Distribution of the Blood-vessels to the
articulating Cartilages . . . seems calculated for obviating great
Inconveniences.” This fits our “capillaries of cartilage in the
synovium” (see ref. 6 in ref. 2).
Cartilage gets energy from glycolysis. It is true that
Bywaters found O? uqtake to be very small (“if there is any at
all”) in slices (ret. 8 in ref. 1) soon considered to represent
“senile equine cartilage” (12): it was higher in younger cattle.
In 1940, this Philadelphia group (12) found that low glucose
further enhances 0, uptake, a Crabtree effect that was confirmed later (ref. 9 in ref. 2). If lactate release (-3.54
pmoles/l2 hours + 295 nmoles/hour) and 0, uptake (-3
nnioles/minute + 180 nmoles/hour) rates in 10’ control chondrocytes (ref. 9 in ref. 1) are converted (+) to the same unit,
ATP stoichiometry does not support the belief that oxidation is
unimportant (1). If metabolic (-low glucose) “acidotic hypoxia” (Crabtree) explains the links between SF lactate and 0,
better than “hypoxic acidosis’’ (Pasteur), the lack of effect of
cyanide on glycolysis (ref. 9 in ref. 1) cannot support Evans and
Stefanovic-Racic’s belief. They note (ref. 9 in ref. 1) that a low
energy supply decreases cartilage synthesis of macromolecules,
the breakdown of which is possibly enhanced in acidosis. What
they fail to appreciate is that both are opposed by vasodilatation (item ii) and the Crabtree switch. Correlations between SF
acidotic hypoxia and elevated P,, (-Vsf) which may lead to
reactive hyperemia still fit (2) metabolic vasodilatation (ref. 10
and Renkin in ref. 4).
LETTERS
1072
(v) NO. Chondrocytic NO could (1) b e vasodilatatory.
NO seemed to fit the role better (2) than “old” mediator
metabolites (ref. 10 and Renkin in ref. 4) “diluted” en route to
synovial arterioles.
Views i-iii are false if I have simplified physiologists’
(3-5) messages incorrectly. It has not been disproved (1) that
the vasodilatation (item ii) could be metabolic (item iv), but
any other type of arteriolar dilatation may be responsible.
Proposal v is false if there was no increase in NO synthesis in
those traumatic joints (1) in which P,, exceeded 10-20 cm H,O
(item i).
Johan Ahlqvist, M D
Sibbvik
Vastarzfiard, Finland
1. Evans CH, Stefanovic-Racic M: Reply (letter). Arthritis Rheum
38:1530-1531, 1995
2. Ahlqvist J, Osterlund K: Possible role of inducible nitric oxide
synthase in articular chondrocytes in the pathogenesis of arthritic
swelling (letter). Arthritis Rheum 38:1529-1530, 1995
3. Levick JR: Synovial fluid dynamics: the regulation of volume and
pressure. In, Studies in Joint Disease. Edited by A Maroudas, EJ
Holborow. London, Pitman Books, 1983
4. Renkin EM, Michel CC, editors: Microcirculation. In, Handbook
of Physiology. Vol. IV. Cardiovascular System. Bethesda, MD,
American Physiological Society, 1984
5. Levick JR: An analysis of the interaction between interstitial
plasma protein, interstitial flow. and fenestral filtration and its
application to synovium. Microvasc Res 47:90-125, 1994
6. Bauer W, Ropes MW, Waine H: The physiology of articular
structures. Physiol Rev 20:272-312, 1940
7. Makinen (Miikisara) P: Synovial fluid in rheumatoid arthritis. Ann
Med Exp Biol Fenn 36 (suppl 7):l-70, 1958
8. Lipson RL, Baldes El, Anderson JA, Polley HF: Osmotic pressure
gradients and joint effusions. Arthritis Rheum 8:29-37, 1965
9. Palmer DG, Myers DB: Some observations of joint effusions.
Arthritis Rheum 11:745-755, 1968
10. Guyton AC: Textbook of Medical Physiology. Philadelphia, WB
Saunders, 1981
11. Hunter W: On the structure and diseases of articular cartilages.
Philos Trans R SOC42514-521, 1743
12. Rosenthal 0. Bowie MA, Wagoner G: Studies in the metabolism
of articular cartilage. J Cell Comp Physiol 17:221-233, 1941
Fibroblast adhesion to articular cartilage
To the Editor:
We read with interest the recent article by McCurdy et
al (l),in which they show enhancement of rheumatoid synovial
fibroblast adhesion to articular cartilage exposed to neutrophil
proteases. In our recent work (2), exposure of cartilage to
neutrophil proteases did not result in increased adhesion of
fibroblasts unless: 1) the fibroblasts were previously treated
with collagenase to free the membrane-bound collagen receptors from collagen synthesized by these cells, thus allowing
adhesion to the cartilage surface collagen; or 2) the damaged
cartilage surface was replenished with fibronectin, which in the
case of McCurdy et al, it was provided by the fetal calf serum
used for incubation with the cartilage prior to the adhesion
assay. It is also unclear in their work if the results reported
represent cell adhesion to the artifactually produced cut surface of the cartilage pieces or to the true articular surface.
We would also like to point out that our previous work
on the effects of neutrophil proteases unmasking collagen
epitopes at the cartilage surface (3) was misquoted by
McCurdy et al. We used EDTA, and not EGTA, in an
unsuccessful attempt to inhibit the attack by neutrophil granules. The failure to show a role for metalloproteinases in
damage to the articular surface was supported by the negative
results obtained with cartilage explants stimulated in vitro with
cytokines. In those experiments, in spite of evidence of matrix
depletion presumably due to metalloproteinase secretion by
activated chondrocytes, there was no increase in collagen
antibody binding to the surface.
Hugo E. Jasin, M D
University of Arkansas for Medical Sciences
Little Rock, A R
1. McCurdy L, Chatham WW, Blackburn WD Jr: Rheumatoid synovial fibroblast adhesion to human articular cartilage: enhancement
by neutrophil proteases. Arthritis Rheum 38:1694-1700, 1995
2. Noyori K, Jasin HE: Inhibition of human fibroblast adhesion by
cartilage surface proteoglycans. Arthritis Rheum 37:1656-1663,
1994
3. Jasin HE, Taurog JD: Mechanisms of disruption of the articular
cartilage surface in inflammation: neutrophil elastase increases
availability of collagen I1 epitopes for binding with antibodies on the
surface of articular cartilage. J Clin Invest 87:1531-1536, 1991
To the Editor:
We appreciate Dr. Jasin’s interest in our recent article
and recognize his previous work in the area of fibroblast
adhesion. As Dr. Jasin has demonstrated, using human skin
fibroblasts and bovine cartilage, pretreatment with collagenase
and addition of fibronectin is necessary for enhanced fibroblast
adhesion to cartilage (1). In our system, using human synovial
fibroblasts and human cartilage, we did not need to pretreat
the cells with collagenase (2). As Dr. Jasin suggested, fibronectin may have played a role it our results, but was not explored
in our study.
Regarding adhesion to “native” versus cut articular
surface, we were very careful in our studies to use thin discs
(1-2 mm thickness) of cartilage, which were studied with the
cut surface down. Therefore, we do not think that adhesion to
the cut surface was responsible for our results.
Dr. Jasin’s observation that the addition of cytokines to
cartilage explants did not result in articular surface damage
would seem to be more relevant to chondrocyte-mediated
tissue resorption. Our studies involve the effects of neutrophils,
which as we have previously demonstrated, do degrade surface
cartilage by a mechanism that, in part, is mediated by
collagenase (3).
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oxide, joint, nitric, morel, swelling, vasodilatation
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