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Inflammation.

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INFLAMMATION
264
knee stability by recording anterioposterior tibial force
versus displacement and varus-valgus moment versus
angulation during manipulation of the knee (M73).
Joint stiffness and laxity were also measured with knee
muscles relaxed and tensed. A new knee goniometer
was described which was designed to quantify the total
relative motion of the lower leg relative to the upper leg
(T80).
Sagittal instability of the knee joint indicates injury to the cruciate ligaments, and also implies damage
to the medial collateral ligament and joint capsule. An
interesting radiologic method was developed which appears to separate most patients with tom anterior cruciate ligaments from individuals with normal ligaments
(L82). Evidence was developed indicating that in the
human knee, the menisci bear a substantial portion of
the total joint load throughout flexion and extension
(S192). Varus stress applied to moving rabbit knee
joints led to degenerative changes confined to the medial tibial and femoral articular surfaces (015). Duration of stress appeared to be more important than the
actual magnitude of stress in determining severity of
cartilage damage. A technique for the study of contact
between visco-elastic bodies was developed and applied
to the patellofemoral joint (S142).
Radiographic study of the wrist in flexion and
extension defined the contribution of the radiocarpal
and midcarpal joints, and analyzed the angular relationships of the radiocarpal components (S35). Kinematic investigation of the normal metacarpophalangeal
joint demonstrated that functionally it is equivalent to a
universal joint with 2" of freedom and negligible axial
rotation (Y17).
Biomechanical characteristics of the metacarpophalangeal joint were the subject of several investigations (B117, P7). The synergistic patterns of muscle mo-
ments and energy flows during normal gait were
analyzed, making it clear that forces of gravitation,
muscle action, and knee joint acceleration act synergistically during both acceleration and deceleration
(W162). Patterns of generation, absorption, and transfer
of mechanical energy at joints during walking were described, and the unwary were cautioned concerning extrapolating from simple biomechanical experiments
which may generate information not likely to apply to
natural movements. Gait evaluation includes kinematic
(displacement) and kinetic (force) parameters which
may be useful in evaluating pathologic processes or the
effects of treatment.
In a study of the effects of walking velocity and
age on hip kinematics and kinetics, it was shown that
many of these parameters have a significant dependence
on subject age and walking velocity (C228). While hip
flexion-extension, stride length, hip resultant force, hip
resultant moment, and hip contact force all increase
with increasing velocity, only the hip resultant force was
unaffected by the age of the subject. Clearly, then, the
use of such parameters for clinical purposes requires appropriate correction for subject size, age, and walking
velocity.
The compliance of the human ankle joint was
examined, and the dependence of the measured compliance on the mean joint angle was found primarily to
be related to the passive properties of the joint and limb
tissues (A25,G175). In a kinematic study, the shoulder
complex was described as a 2-component system consisting first of the clavicle and scapula, with the second
component composed of the scapula and humerus
(D 159). Elevation of the arms was divided into 4 phases,
and the importance of the serratus anterior as a prime
mover of the shoulder girdle was emphasized.
INFLAMMATION
An outline of the history of inflammation was
presented (R 106). The mediating systems participating
in inflammatory disease, especially immunologic injury
of the glomerulus, were discussed (C162). A concept of
polyclonal activation as a form of primitive immunity,
and its possible role in chronic inflammation, was presented ((2138). Mechanisms of interaction between the
blood coagulation system and mediators of the inflam-
matory response were described (Zl 1). The chemical aspects of inflammation were reviewed briefly (W 102).
Thio complexes of monovalent copper were
shown to be useful antiinflammatory agents in rats
(W 103). Circulating copper levels rose significantly during inflammatory processes. Carrageenan-induced
edema was significantly greater in copper deficient rats
than in normal control animals (M231).
INFLAMMATION
The value and pitfalls of serum complement
measurements in clinical medicine were reviewed
(W96). Evidence was presented that antibody excess favors the complement activating effect of immune complexes (R1 1). The capacity of several agents to activate
the complement system via the alternative pathway paralleled their ability to induce inflammatory responses in
vivo (S100). A brief review of the role of complement in
the pathogenesis of rheumatic diseases appeared (P 14).
Soluble immune complexes did not cause release
from platelets of serotonin, but conversion of soluble
complexes to insoluble immune precipitates by rheumatoid factor induced serotonin release not associated with
platelet aggregation or acid hydrolase release (Y 13).
Horseradish peroxidase (HRP), a small protein antigen,
was shown to pass from capillary lumen to joint space
of rabbits (after intravenous or intraarticular injection)
across fenestrated vessels (M268). Antigen localized to
collagen fibers and synovial lining cells. Presence of fenestrated capillaries may render the synovium particularly vulnerable to antigen deposition.
The possible role of synovial tissue cells and
their products in degradation of joint structures was reviewed (D43). The interaction of circulating cells which
enter sites of inflammation with resident tissue cells
(e.g., synovial cells) was discussed, especially as the interaction relates to rheumatoid arthritis (D44).
The relationship between cell mediated immunity and an inflammatory response was discussed
(C176). The role played by suppressor cells (T and B
cells and monocytes) in immunologic regulatory systems and abnormalities in disease was reviewed (W7).
Responses of lymphocytes to antigens were compared in
mother-neonate pairs and were found to be disparate
(R176). The authors concluded that the relative resistance of the neonate to some infections does not depend
on the transplacental passage of cellular immunity.
The way in which immune thymus-derived lymphocytes (T cells) contribute to development or resolution of disease processes was considered (D121). It was
shown that amethopterin-induced, lymphocyte-mediated
inflammation in rats was blocked by hydrocortisone
and nonsteroidal antiinflammatory agents (G 19). Persistent inflammatory responses induced by complete
Freund’s adjuvant enhanced lymphocyte-mediated inflammation (G20).
Modifications of the sponge implantation technique for inducing acute inflammation were described
(F80). In the carrageenan-induced granuloma, it was
observed that calcium ethylenediamine tetracetate treatment enhanced resorption of granulation tissue as a re-
265
sult of increased degradation of noncollagen protein
(N10). Blood platelets were shown to accumulate early
in development of carrageenan-induced paw edema and
were considered to play an important role in initiation
and perpetuation of the inflammatory response (V51).
Lipid peroxidation in liver was found to be increased in
rats with carrageenan-induced paw edema, and decreased in rats with adjuvant-induced arthritis (R96).
The characteristics of acetic acid-induced
pleural inflammation were outlined (C3). Evidence was
presented that sensory nervous structures contribute to
development of inflammatory responses through release
of an active agent. Calcitonin was shown to inhibit the
inflammation associated with adjuvant arthritis, nystatin edema, and the Arthus reaction (A7). Hydrocortisone, but not deoxycorticosterone, amplified PGEinduced increases in mast cell cyclic AMP and reduced
histamine release (T70).
It was shown that colchicine treatment of human
leukocytes enhanced CAMP concentrations induced by
compounds which stimulate adenylate cyclase (R 1?2).
The authors suggested that cytoplasmic microtubules
interact with the plasma membrane to impose constraints on the expression of hormone-sensitive adenylate cyclase.
Chemotaxis
One group used a new system in which cells can
be viewed by phase microscopy as they are exposed to
controlled concentrations and concentration gradients
of chemotactic factors to investigate the ability of human and rabbit polymorphonuclear leukocytes (PMN)
to orient along the direction of N-formylmethionyl
chemotactic peptides (27). The early events in chemotaxis were viewed directly, and it was shown that PMN
orientation depends upon mean concentration, as well
as the concentration gradient of the chemotactic peptides. Cells were able to discriminate a 1%concentration
difference. [An important advance in the study of PMN
chemotaxis. Ed.]
Colchicine (lo-’ M) was shown to inhibit random (chemokinesis) rather than directed or oriented
(chemotaxis) locomotion of human PMN (V4). Thus
the colchicine effect may be due to alteration in membrane transport of the signal for appropriate locomotion, rather than a microtubule effect. It was shown that
human peripheral blood mononuclear cell chemotaxis,
like PMN chemotaxis, is composed of a direct microtubule insensitive locomotion, and a leukocyte-induced
microtubule dependent locomotion (S2 13). Phago-
INFLAMMATION
266
cytosis-associated chemotaxis of these cells was not inhibited by antitubulin drugs, supporting the hypothesis
of a tubulin insensitive chemotactic mechanism (R185).
Preincubation of human PMN with a monosodium urate crystal-induced serum chemotactic factor
was found to inhibit Con-A capping in colchicinetreated cells. It was proposed that the chemotactic factor
might induce assembly of microtubules, thus preventing
binding of colchicine to tubulin subunits (M49). Accumulation on a bottom filter of the Boyden chamber of
PMN responding to casein measured mainly leukocyteinduced chemotaxis (B4). This locomotion was found to
be antitubulin-sensitive. The antitubulin-induced inhibition was independent of the complement system.
Soluble immune complexes, like insoluble complexes, can act on fresh normal guinea pig serum to induce chemoattractants for PMN. Chemotactic activity
appeared due to serine esterases as well as complement
activation (L81). Inhibition of rheumatoid but not
healthy control leukocyte migration by IgG-IgG complexes was observed. That the inhibitory effect was mediated through the Fc region of the Ig implies some abnormality in Fc receptor function on rheumatoid cells
(H19).
Chemotactic factors (complement fragments and
synthetic tripeptides) induced neutropenia when infused
into rabbits (013). The neutropenia-inducing dose paralleled the chemotactic potency of the synthetic peptides. Neutropenia may have been due to leukocyte
margination and/or agglutination. Tissue extracts from
biopsies of acute skin inflammation induced on the
backs of guinea pigs by dinitrochlorobenzene yielded a
factor @robably a C3 cleavage product) chemotactic for
PMN (at 12 hours) and an inhibitor of PMN chemotaxis (at 48 to 96 hours) (Bl). Thus another system for
limiting acute inflammation has been uncovered.
The effects of a variety of antiinflammatory
drugs on granulocyte emigration in vivo in the rabbit
skin collection chamber were examined (B202). Results
after topical application of some agents correlated well
with those obtained for oral treatment. The authors suggested that the technique may prove useful in screening
antiinflammatory drugs.
Phagocytosis
Phagocytic cells, exemplified by macrophages
and polymorphonuclear leukocytes were well studied:
the role of macrophages in the rheumatic diseases was
reviewed (S274), and the role of macrophage activation
in chronic inflammation was discussed (A63). The in-
volvement of PMN in inflammation and tissue damage
was reviewed (B6). Leukocyte disappearance-probably due to aggregation of PMN and macrophageswas observed during acute nonimmune (e.g., powder
glass-induced) inflammation (S409). The evidence was
reviewed that phagocytosis results from enzymatic and
mechanical interactions attributable to proteins exhibiting structural and functional properties established for
actin and myosin of muscle (S387).
Oxygen consumption by phagocytic leukocytes
from patients with rheumatic diseases was shown to be
less than in similar cells from normal controls (K188).
The initial rate of particle uptake by PMN was accelerated in patients treated with penicillamine (H25). [Perhaps penicillamine therapy facilitates clearance by
PMN of immune complexes. Ed.] Sera from pregnant
women were found to contain a nondialyzable, heatstable factor which suppressed phagocytosis by human
PMN (P93). The finding may help explain why pregnancy induces remission in rheumatoid arthritis (RA)
patients. It was shown that compounds which increased
cellular cyclic AMP reduced release of superoxide anion
(02-)
from human leukocytes engaged in phagocytosis
(L62). The authors suggested that elevation of cyclic
AMP could constitute a natural means of limiting inflammatory tissue damage.
Lysosomes
An elegant review of the role of lysosomes in
rheumatoid joint inflammation appeared (W80). The
actions of lysosomal enzymes on the degradation of cartilage components in relation to rheumatoid and osteoarthritis were outlined clearly and concisely (G71). The
proteoglycan-degrading proteins of rabbit fibroblasts
and leukocytes were described (W87).
Soluble immune complexes (7S-22S), prepared
in vitro or obtained from RA serum and synovial fluid,
were fractionated into 3 pools, and their effect on provoking lysosomal enzyme release from human PMN
was studied (M308). The 7 s pool (in vitro and synovial
fluid) induced enzyme release. Interference with particle
uptake and subsequent lysosomal enzyme release from
guinea pig neutrophils by prostaglandins and several
antiinflammatory agents were documented (S261). It
was shown that extracts from human peripheral blood
polymorphonuclear leukocytes and PMN granule lysates enhance immunoglobulin (Ig) synthesis by autologous peripheral blood lymphocytes (Y3). The effect was
due to proteolytic enzymes, and the findings thus in-
INFLAMMATION
dicate another role for lysosomal enzymes in the pathogenesis of tissue injury.
The action of the serine proteinase of human
PMN on cartilage and tendon was investigated (S342).
The molecular sequence of articular collagen degradation was determined. A serum activator that generates
the chemotactic C5 fragment, C5a, is contained in specific granules of human PMN, whereas a C5a inactivator is restricted to azurophil granules. These molecules were found to be released at different times during
phagocytosis, and may therefore contribute to local regulation of acute inflammatory responses (W194).
Acute pleural exudates were produced in rats
with calcium pyrophosphate dihydrate crystals (D76).
Indiscriminate (nonselective) enzyme (lysosomal and
cytoplasmic) release was not inhibited by intrapleural
administration of cyclic AMP and theophylline. It was
suggested that cyclic AMP is not important to regulation of PMN phagocytic and secretory functions.
Mediators
The mechanisms were reviewed whereby collagen breakdown is controlled. These events were related
to cartilage degradation in RA (H63). The possible role
of neutrophil proteinases in degradation of articular
cartilage was reviewed (B46), as was the nature and regulation of neutral protease secretion by macrophages
(G167).
Human skin collagenase was purified, and its
natural serum inhibitors were studied (W189). The activity of vertebrate collagenase was increased 3-fold by
a heat and pH stable macromolecule found in normal
human serum (S151).
Latent collagenase released from rheumatoid synovial cells in culture was activated by plasminogen.
Thus, rheumatoid synovium probably produces both latent collagenase and plasminogen activator (W88). It
was shown that rheumatoid synovial cells in culture
produce an inhibitor of collagenase as well as latent enzyme; the 2 probably exist in vitro as an enzyme-inhibitor complex (V33). Rheumatoid synovial cells that
have been dissociated enzymatically from synovial tissue and are adherent to culture vessel surfaces are heterogeneous and include fibroblasts, macrophages, large
rounded cells, and striking nonphagocytic “dendritic”
or “stellate” cells with long radial extensions (W190).
Immunofluorescence studies with a monospecific antibody to human collagenase localized the enzyme
around these cytoplasmic extensions, suggesting that the
dendritic cells secrete large quantities of active enzyme.
267
Collagenase has also been immunolocalized to
the cartilage-pannus junction in tissue from patients
with RA (W186). The observations supported the idea
that synovial collagenase participates in cartilage erosion in RA. Greater collagenase activity was found in
RA than degenerative joint disease synovial fluids
(P69).
Collangenase and elastase released from human
neutrophils during phagocytosis formed complexes with
serum a,-antitrypsin (021). Collagenase was found to
be almost exclusively a component of specific granules
in human PMN (M344). Human PMN collagenase attacked type I collagen preferentially (15 times greater
activity) compared with type 111 collagen (H 187).
It was shown that cathepsin B1 plays an important role in collagen breakdown and resorption of granulation tissue (N9). Collagenolytic cathepsin activity
was detected in lysed rabbit peritoneal PMN (G78).
Human PMN azurophil granules contain a neutral protease which can cleave IgG, producing a Fab-like piece
(F73). Evidence was presented that antibodies directed
at hidden antigenic sites in IgG revealed by endogenous
proteolysis take part in the immune reaction and in the
inflammation of rheumatoid joints (F22).
A latent neutral proteinase was found in culture
media of mouse bone explants (Vl). The latent enzyme
was activated by treatments known to activate procollagenase. An aminopeptidase of human neutrophil
lysosomes was partially purified and was found to amplify bradykinin-induced vascular permeability (P45).
A new connective tissue activating peptide
(CTAP) was described (C64). CTAP-111 is made in
platelets. CTAP from lymphocytes (CTAP-I) and from
platelets stimulated ”SO, incorporation into glycosaminoglycans in connective tissue cells in vitro (C65).
Thymus-dependent lymphocytes challenged with
specific antigen produced a factor(s) capable of causing
dermal fibroblasts to undergo DNA and collagen synthesis (W4). Thus, fibroplasia and collagen deposition
associated with chronic inflammatory disease may result from lymphocyte-mediated activation. Evidence
was presented indicating that transformed lymphocytes
produce a molecule which is a specific chemoattractant
for lymphocytes (H193).
It was shown that bradykinin-induced increases
in cAMP in human synovial fibroblasts are due to activation of a phospholipase whose products (arachidonic
acid, prostaglandins) stimulate adenylate cyclase (N43).
The cAMP increments were inhibited by hydrocortisone and indomethacin. Only hydrocortisone prevented release of arachidonic acid. Rheumatoid syno-
INFLAMMATION
vial cells in culture secreted far less plasminogen
activator than nonrheumatoid cells (B 1 11). Thus, rheumatoid cells may be defective in fibrinolysis capability.
Polyethylene glycol was used to produce multinucleated cells in rabbit synovial fibroblast populations
(B242). Collagenase in these cultures was increased 10fold over control cultures. On exposure to sucrose or
neutral polysaccharides, cell cultures from human synovium exhibited ultrastructural changes similar to those
described in rheumatoid synovium (L48). Changes were
accompanied by increased intracellular lysosomal enzyme activity.
An assay system was described that allows the
presence of inflammatory factors in supernatants from
stimulated human peripheral blood lymphocytes to be
demonstrated by induction of an inflammatory exudate
in mouse peritoneal cavity (W39).
Prostaglandins
A lucid, crisp review of the effects of prostaglandins on platelet aggregation appeared (N83). The evidence which led to the discovery that prostaglandins are
mediators of inflammation was reviewed (F69). A commentary on the role of prostaglandins in chronic inflammation appeared (B 196). Most of the existing data were
reviewed. The role of prostaglandins in inflammation
was discussed (B195). The focus was on use of prostaglandin synthetase inhibitors in essential fatty acid
deficient rats. The influence of prostaglandins on connective tissue cell growth and function was reviewed.
PGE 1 was found to enhance glycosaminoglycan synthesis and reduce proliferation of cultured fibroblasts
(P99).
Endogenous prostaglandin production is
markedly decreased in essential fatty acid deficient
(EFAD) rats (P35). Collagen synthesis in granuloma induced by carrageenan-impregnated sponges was much
greater in EFAD than in control rats, suggesting that
prostaglandins may exert a negative feedback effect on
collagen metabolism during proliferative inflammation.
An ether-soluble, indomethacin-inhibitable activity [Presumably prostaglandins. Ed.] produced by
rheumatoid synovium inhibited the metabolism of rabbit articular cartilage (L 153). The authors suggested this
as a mechanism whereby prostaglandins may influence
development of cartilaginous lesions in inflammatory
arthritis.
Human synovial fibroblasts in culture desensitized to PGE respond (increased cyclic AMP) to bradykinin, and those desensitized to bradykinin respond
to PGE (F3). The bradykinin effect appeared to be mediated in part by prostaglandins. [These carefully done
experiments emphasize the complex interaction which
occur between mediators of inflammation in the rheumatoid joint. Ed.]
Particulate materials added to sponges implanted
in rats resulted in leukocyte migration and prostaglandin accumulation (F79). The 2 processes were not related.
Naturally occurring antiiiammatory agents
A summary of knowledge of rheumatoid synovial collagenase and its natural serum inhibitors, PIanticollagenase and a,-macroglobulin, in relation to
cartilage collagen resorption was presented (W187). The
role of endogenous antiinflammatory proteins was commented upon extensively (L106). Normal cartilage contains low molecular weight cationic protease inhibitors
which inhibit collagenase. An analysis of how these
molecules help prevent cartilage degradation was presented (K176).
A radial diffusion assay for tissue collagenase
was devised and used to examine known or potential inhibitors of collagenase (Y7). Thus, the procedure has
potential for clinical determination of naturally occurring collagenase inhibitors. An assay was described for
inhibitors of collagenase produced by rabbit bone, skin,
and uterus in culture (M343).
It was shown that the a m i t y of a,-macroglobulin for human granulocyte collagenase was about 10
times that of a,-antitrypsin, and the concentration of a,antitrypsin in blood exceeds that of a,-macroglobulin
by about 12 times. Thus, the inhibitors appear equally
important for defense against granulocyte collagenase
(022). Human platelet factor 4 was shown to inhibit
collagenase in addition to neutralizing heparin (H143).
An inhibitor of kallekreins was obtained from rat kidney tubules (F121).
Human chemotactic factor inhibitor (CFI) was
shown to have antiinflammatory activity (J59). Small
amounts of CFI suppressed the reversed passive Arthus
reaction and immune complex-induced alveolitis.
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