FEBRUARY 1973
Circulation Research VOL. XXXII NO. 2
An Official Journal of the American Mi ear t Association
Brief Reviews
Blood-Borne Humoral Factors In the Pathophysiology
of Circulatory Shock
By Allan M. Lefer
• The concept of a toxic humoral substance
produced within an animal during a stressful
event such as circulatory shock represents an
attractive mechanism to explain the pathophysiol-
ogy of shock states. Indeed, toxic factors have been
proposed as an explanation of the lethal effects of
circulatory shock for some time. In 1943, two
reports appeared (I, 2) indicating the presence of
toxic substances in thoracic duct lymph during
tourniquet shock. Lymph from normal dogs had no
observable effect when it was injected into normal
animals. The presence of toxic factors in lymph was
subsequently confirmed in 1964 by Tice and
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Dumont (3), using shock induced by splanchnic
artery occlusion. None of these studies clarified the
nature of the toxic factor(s) present in the lymph of
animals in shock. However, in 1970, Glenn and
Lefer (4) showed that the thoracic duct lymph of
cats in postoligemic shock contained cardiotoxic
activity, and this activity was related to the
presence of both lysosomal hydrolases and a
myocardial depressant factor. These data help to
clarify some of the earlier findings, since both of
these substances are now recognized as toxic agents
in shock.
Historically, other investigators have inferred the
existence of toxic factors in shock but have not
attempted to isolate or identify the toxic principle.
Thus, Selkurt (5) postulated the presence of a
vasotoxic material in splanchnic artery occlusion
shock, which originated in the ischemic intestine.
Baez et al. (6) also found a substance(s) under
From the Department of Physiology, University of
Virginia School of Medicine, Charlottesville, Virginia
22901.
Dr. Lefer is an Established Investigator of the American
Heart Association.
Received September 1, 1972. Accepted for publication
November 30, 1972.
CtrcuUtion Rtsttrcb, Vol. XXXII, Fikrutrj 197}
similar conditions which exhibited vasoactive prop-
erties in isolated test systems, although no direct
toxic effect was shown. In addition to these factors
which were presumed to act on the peripheral
vasculature, Gomez and Hamilton (7) postulated
that a cardiotoxic material was released into the
blood during hemorrhagic shock. This cardiode-
pressant substance was thought to contribute to the
severe myocardial depression observed in the late
stages of shock.
These studies called attention to the possibility
that toxic factors may play a role in the pathogene-
sis of circulatory shock by acting on components of
the cardiovascular system in a positive feedback
fashion (i.e., impairment of the circulatory system
results in the elaboration of humoral substances
which further impair overall circulatory function,
even though the humoral substance may correct one
of the defects in circulatory function).
Many well-known substances, particularly the
neurohumoral transmitters and the vasoactive sub-
stances (i.e., norepinephrine, acetylcholine, hista-
mine, vasopressin, serotonin, ferritin, and angioten-
sin II), have been considered as mediators of shock
(8-10). Recently, lactic acid (11) and bradykinin
(12) also were suggested as toxic agents in
circulatory shock. Although these substances in-
crease transiently in the blood, they never achieve
very high concentrations except perhaps in certain
organs. Conceivably, this accumulation could
prove to be toxic at some critical site, but no
compelling evidence has been obtained to verify
this assumption. More likely, the release of the
neurohumors or the vasoactive agents is a compen-
satory response to the trauma of the shock-inducing
event (e.g., hemorrhage, myocardial infarction,
ischemia of tissues, etc.). From this viewpoint, the
vasoactive agents can be considered substances
which aid in the mobilization of the body's defense
129
 130
mechanisms to either maintain mean arterial blood
pressure or preserve blood flow in face of a
traumatic event, much like the release of cortico-
steroids is thought to mobilize substrates in
metabolic terms. Thus far, no definitive toxic effect
has been ascribed to these substances in concentra-
tions which exist in plasma during shock. Although
they may participate in the formation of other toxic
factors, perhaps by inducing regional ischemia,
these substances do not appear to be primary toxic
factors themselves.
CRITERIA FOR SHOCK FACTORS
It is essential that a toxic factor satisfy specific
criteria before it can be judged to be a true shock
factor. Although every criterion may not be
assigned equal weight, most investigators would
probably agree with the following criteria.
A toxic factor in shock should not be present in
animals that are not in shock at concentration levels
which exert deleterious effects. A toxic factor could
be a metabolite which accumulates to toxic
concentrations, or it could be a substance which is
formed only during shock (i.e., breakdown product
of a cellular component). In the former case it
probably would be present in small amounts of
plasma from normal animals, whereas in the latter
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case it probably would not occur in normal
animals.
A toxic factor in shock should also be produced in
a variety of types of shock. This criterion is a test of
the factor's universality, and the criterion presup-
poses that a common pathophysiological mecha-
nism exists for many forms of circulatory shock.
Many investigators in the field contest this notion as
being a simplistic view of the problem and claim
that no single mechanism is prevalent in all forms of
shock. However, there are many striking similarities
among the various types of circulatory shock (e.g.,
hemorrhagic, endotoxic, splanchnic artery occlu-
sion, cardiogenic, acute pancreatitis, and bum
shock), although each form has its hemodynamic
differences. One such common reaction to shock
stimuli appears to be the activation of the
sympathetic adrenergic system and the resultant
peripheral vasoconstriction. Regardless of the
hemodynamic response to shock, a single humoral
factor could exist in these types of shock.
It should be possible to isolate a toxic factor
in a partially purified form from animals in
shock. No factor has been completely purified,
identified, and synthesized. These steps would be
LEFER
the ultimate validation of a shock factor. However,
a goal that can be more readily achieved is the
isolation and partial purification of a factor from
the plasma of animals in shock.
The toxic factor should exert a severe pathophys-
iological effect on some vital organ or essential
metabolic pathway. Several substances have been
proposed as shock factors, but not all are associated
with a deleterious effect on an essential system in
the body. It is not sufficient to demonstrate the
action of a substance on an isolated tissue or organ;
one must show that the action compromises the
animal's chances of survival. Thus, an important
test of a shock factor would be to inject it in the
amounts present in plasma from animals in shock
into test animals not in shock and to demonstrate
the production of shock or at least of a severe
impairment of an important organ or system.
Finally, a toxic factor in shock should be present
in man as well as in experimental animals during
shock. If one is to ascribe clinical significance to a
toxic factor, it must be found in patients during
clinical shock. The problems of species variability
and of idiosyncratic reactions in certain species
have been intensively discussed among investi-
gators in the field of shock. Nevertheless, shock
represents a common defect in all species, namely a
critical reduction in blood flow to the systemic
organs. Therefore, it would not be completely
surprising if, despite differences in the precise
homeostatic adjustments to the shock stimulus,
some mechanism was common to most mammalian
species including man.
GENERAL CHARACTERISTICS OF SHOCK FACTORS
A summary of the known characteristics, proper-
ties, and actions of proposed toxic factors in shock is
presented in Table 1. The factors are quite diverse
in their chemical properties. They range from
simple small molecules with molecular weights less
than 1,000 to complex molecules with molecular
weights of 1,000,000 or more. Some of the factors
are partially characterized chemically (e.g., hemo-
chromogen, some of the lysosomal hydrolases, and
to some degree myocardial depressant factor
[MDF] and reticuloendothelial depressant sub-
stance [RDS]), whereas the others are not.
However, none of the toxic factors is completely
characterized in specific molecular terms. Knowl-
edge of the chemical structure could lead to infor-
mation about the metabolism and the clearance of a
Circulation Rtiurcb, Vol. XXXII, Pihrutrj 1973
 HUMORAL FACTORS IN CIRCULATORY SHOCK
toxic factor and ultimately to the synthesis of mo-
lecular analogues which could be useful in the treat-
ment of circulatory shock. Despite the lack of com-
plete information about the toxic factors, one can
attempt to evaluate each factor in terms of its ful-
fillment of the criteria and thus determine its signif-
icance in the pathophysiology of shock.
The first criterion for a shock factor (i.e., that the
factor not be present in high amounts in control
animals) is essentially satisfied by all of the factors
in Table 1. Any factor that failed to satisfy this
elementary requirement could not be seriously
considered further.
The finding that certain factors occur in so many
types of shock having diverse etiologies is striking.
Moreover, of all the investigators who have studied
a specific toxic factor in shock, none have reported a
type of shock in which they failed to find that
factor.
At present, the factors reported by Fukuda (58,
59), Thai and co-workers (60, 61), and Clowes and
colleagues (62-64) as well as by others (19, 65)
have not been isolated in sufficient purity to
warrant further consideration of their chemical
nature. However, those factors which have been
partially purified (i.e., lysosomal hydrolases, RDS,
and MDF) and those about which chemical
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properties are known (i.e., hemochromogen and
endotoxin) can be said to have partially satisfied
the third criterion.
All of the factors listed induce shock or at least ex-
ert severe disturbances in the normal functioning of
the cardiorespiratory or the reticuloendothelial sys-
tem when injected into normal animals. Thai and co-
workers (60, 61) have not injected their factor into
intact normal animals, but they have perfused the
lungs of the shock animal, thereby partially
fulfilling this requirement. Although all the factors
are capable of exerting a biological effect that can
be considered detrimental to survival, the degree of
toxicity of the factors is variable. Thus, hemo-
chromogen, endotoxin, and, to some extent, lysoso-
mal enzymes appear to exert part or all of their
detrimental effects indirectly by releasing other
agents, which act as toxic factors, and thus in a
sense are secondary toxic factors. These factors also
have high molecular weights and thus may be
degraded further to produce a toxic factor. The
other factors either depress the heart directly (28,
42, 44, 45, 62), induce hypotension (56, 58), which
may be a cardiac or a peripheral vascular effect, or
impair phagocytosis (38-42). Some of the factors
Circulation Rlltarcb, Vol. XXXII, Ftbnur) 1973
131
also exert effects on other organs or loci in addition
to the ones cited above (i.e., MDF also constricts
the splanchnic vasculature [56], Thai's factor
stimulates vascular smooth muscle [61], etc.).
However, these actions probably are not of primary
importance in the direct actions of the factors,
although they may play some role in their overall
effectiveness.
Regarding the final criterion, namely the presence
of the factors in plasma from human subjects in
shock, only MDF (57) and endotoxin (66) have
been identified in the plasma of patients having a
variety of forms of shock, although Thai's factor (61)
and hemochromogen (27) have each been found in
one shock patient.
CRITIQUE OF SHOCK FACTORS IN GENERAL
One type of criticism is often proposed against
toxic factors in general, and that is the question of
how the homeostatic balance is so overwhelmed in
shock that it produces a substance which is lethal to
itself. There are two kinds of answer to this
question. (1) The priorities that are designated in
the homeostatic regulation of the circulatory system
sometimes conflict with one another. For example,
vasodilation of the cutaneous vessels (i.e., to effect
heat loss) appears to have priority over vasomotor
regulation of systemic mean arterial blood pressure,
so that sometimes in heat stress syncope results.
This condition, of course, is usually a temporary
situation, which can be brought into balance by an
alteration in position or temperature of the body. In
the case of shock (e.g., brought about by severe
hemorrhage), the coronary and the cerebral circula-
tions invoke a higher priority than do the
splanchnic, renal, and cutaneous vasculatures for
blood flow. The significance of this priority system
is obvious as a short-term adjustment (i.e.,.protec-
tion of the heart and brain). However, if the
situation is prolonged and not alleviated, the
resultant splanchnic ischemia will induce irreversi-
ble autolytic changes in the cells of the splanchnic
organs (e.g., activation of lysosomal and zymogenic
enzymes) which can lead to destruction of these
organs. Richards (67) has eloquently discussed and
classified these errors in homeostasis and has cited
numerous examples of inappropriate or excessive
responses to a change in an organism's status quo.
(2) The second answer is that homeostasis is not
omnipotent. It works within finite limits, and these
limits can be reached under prolonged adverse
conditions. Thus, there are homeostatic mechanisms
 132 LEFER

TABLE

Summary of Properties of Toxic Factors in Plasma of Animals in Circulalory Shock

Name of factor Specie* Form* of shock Chemical properties Type of molecule

Ly.sosomal hydrolases Dog SAO (13, 14) M.W. 25,000-200,000 Proteins

Cat Hemorrhagic (15) Water soluble
Endotoxic (16) Heat labile
Cardiogenic (17) Nondialyzable

Hemoehromogen Dog SAO (24, 25) M.W. 68,000 Hemoglobin derivativ

Acute pancreatitis (24) Nondialyzable
Hemorrhagic (26)
Endotoxin Rabbit Endotoxic M.W. 200,000-2,000,000 Lipopolysaccharide
Dog Hemorrhagic (29, 30) Nondialyzable
SAO (31, 32)
Catecholamine (32)

Reticuloendothelial depressant Dog Hemorrhagic (36, 37) M.W. 10,000 Unknown

substance (RDS) Cat SAO (38) Dialyzable (39)
Can be frozen (39)
Soluble in methylene
chloride (39)
Myocardial depressant factor Cat Hemorrhagic (44-16) M.W. .500-1,000 (52, 53) Peptide, glycopeptide
(MDF) Dog Endotoxic (16) Dialyzable (25) (27, 45, 52, .53)
Baboon SAO (14, 47-49) Can be frozen (28)
Man Cardiogenic (17) H,O soluble (28, 45)
Pancreatitis (50) Not soluble in methylene
Burn (51) chloride (27)
Fukuda's factor Dog Hemorrhagic (58) H.0 soluble (59) Appears to be protein
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Endotoxic (59) Heat labile (58)

Precipitated by ammonium
sulfate (58)
Probably large M.W.
Thai's factor Dog SAO (60, 61) Unknown Unknown

Clowes's factor Dog Septic (62, 63) M.W. 1,000-3,000 Possibly peptide

SAO " splanchnic artery occlusion, M.W. — molecular weight, MDF = myocardial depressant factor, and RE = reticuloendothelia

available to protect against these enzymes and
other substances which induce cellular autolysis,
but this second line of defense can also be
overwhelmed in untreated shock. These protective
mechanisms include the compartmentalization of
the enzymes within subcellular particles (e.g.,
lysosomes and zymogen granules), the presence of
local inhibitors and enzymes which degrade these
enzymes (e.g., pancreatic trypsin inhibitors and
certain proteases), and the occurrence of unfavor-
able conditions which prevent the optimal activa-
tion of these enzymes (e.g., neutral or basic pH).
However, cell damage, binding of inhibitors, and
the acidosis of shock act to override these protective
mechanisms.
Another general criticism that can be applied to
the toxic factors is that to date none have been
identified and synthesized. This deficiency is
undoubtedly due to the difficulty of such a task and
does not necessarily detract from the validity of
toxic factors. Of course, identification and synthesis
of any of these factors will enable a much more
rigorous testing of its role in shock, as mentioned
previously.
CircmJrtio* Ruttrcb, Vol. XXXII, ?thru*n '973
 HUMORAL FACTORS IN CIRCULATORY SHOCK 133

Origin in body Biological actions Prevention of formation of factor

schemic splanchnic region
-iver (18-20)
'ancreas (14, 15)
Ipleen (18)
nt€stine (13, 21)
udney (22)
Jlood absorbed by damaged
intestinal mucosa (26)
schemic intestine
absorbed through damaged
intestinal mucosa (31, 32)
schemic splanchnic region
(possibly intestine [36, 40])
Sensitize heart to other toxic
factors (18)
Cause hypotension (14, 18)
Constrict pancreatic vessels (23)
Participate in the formation
of MDF (15, 17, 18)
Unclear whether there are
direct effects
Hypotension
Unclear, may release
vasoactive agents
Depresses phagocytosis by fixed
macrophages (37, 40, 41)
May depress heart (42)
Impairs survival (43)
Pharmacological doses of
glucocorticoids (14)
Unknown
Nonabsorbable antibiotics (32)
(challenged by others
[33-35])
Unknown
Found in lymph in shock (4)
Slight hemodynamic effect
in presence of intact RE
system (18)
Action not blocked by
glucocorticoids (15)
Occurs in patients (27)
Does not depress
myocardium (28)
Does not depress
myocardium (16)
Found in lymph (30)
Germ-free animals not
protected in shock (34)
Passively transferred to
another animal (36, 41)
Formed despite absence of
intestinal flora (38)

schemic splanchnic region (52)
'ancreas is major source
(15, 23, 47)
Negative inotropic effect
(44, 45, 54, 55)
Constricts splanchnic
resistance vessels (56)
May depress RE system (42)
Pharmacological doses of
glucocorticoids (52)
Trasylol (.53)
Lymph diversion (4)
Found in lymph (4) and in
pancreatic autolysates in
shock (15)
Occurs in plasma of patients
in shock (57)

Ischemic splanchnic region Hypotension (59) Pharmacological doses of Passively transferred to

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(particularly liver) glucocorticoids (59) another animal (57)

Not blocked by
glucocorticoids (59)

[schemic splanchnic region
(60, 61)
Probably splanchnic region (64)
Induces lesion in lung (59) Phenoxybenzamine (60) May not be one factor
Stimulates vascular smooth
muscle (61)
Increases pulmonary vascular Glucocorticoids Activity is free of
resistance Trasylol (partially endotoxin (63)
Induces focal alveolar collapse effective) (63)
and right heart failure
(63,64)

One hazard of a lack of knowledge of the precise
molecular structure of each factor is that investiga-
tors may separately discover the same factor. For
example, Fukuda's factor (58, 59) and one which
has been described only on a preliminary basis (19)
appear to be similar to lysosomal hydrolases. They
appear to be proteins which are released from
either the ischemic or the damaged liver, but this
release can be prevented by large doses of
glucocorticoids (59), drugs which are known to
stabilize splanchnic lysosomes (14). In another
instance RDS was compared with MDF (42), and
each purified plasma extract contained high activity
CircuUsitm Rtsurch, Vol. XXXII, V.bfuMr, 197}
of both factors. Of course, both factors could have
been present together in the same plasma extract
rather than being a single entity. Nevertheless, the
chemical properties of RDS and MDF are strikingly
similar except for their apparent difference regard-
ing their solubility in methylene chloride (42).
Further work is necessary to clarify whether any
two or more of these factors are truly identical or
whether they represent separate but similar sub-
stances.
CRITIQUE OF THE INDIVIDUAL SHOCK FACTORS
Lysosomal hydrolases appear to be involved in
the pathogenesis of circulatory shock indirectly by
 134
sensitizing the heart (18) and perhaps other target
organs to the effects of other toxic factors and by
aiding in the formation of at least one toxic factor
(15, 18). However, lysosomal hydrolases exert little
hemodynamic effect acutely in an animal with a
normal reticuloendothelial system (18, 22), partial-
ly because of the rapid clearance of the enzymes by
this system (18). Specific inhibitors of lysosomal
enzymes would be useful agents to clarify the role
of these enzymes in shock and to determine
whether they have a direct toxic action.
Hemochromogen is formed as a consequence of
denaturation of hemoglobin liberated during the
hemolysis that frequently occurs in shock (26). This
abnormal pigment is presumably absorbed across
the necrotic mucosal surface of the intestine during
shock (26). This hemorrhagic necrosis is a phenom-
enon that is not generally considered to occur in all
species and appears to be a peculiarity of the dog.
The one shock patient in which hemochromogen
was found had intestinal bleeding from multiple
foci (27) so that intestinal absorption of hemo-
chromogen was facilitated and hence resulted in
increased concentrations of this substance. It should
be determined whether hemochromogen can be
absorbed in the cat or the primate when frank
intestinal necrosis does not occur during shock or in
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clinical shock when the complications of intestinal
bleeding do not occur. Furthermore, although
injection of a large amount of hemochromogen can
cause hypotension (24), it is not clear how this
dose (i.e., 0.015 mM/kg body weight) relates to the
amount actually present in the plasma of animals in
shock. Moreover, the directness of this effect and its
actual toxic mechanism are completely unknown.
Endotoxin has been proposed by Fine and co-
workers (29-32) as the primary shock factor in
several types of shock. These workers have
presented considerable data to show that there is
absorption of live gram-negative bacteria or their
endotoxin or both via the intestine during shock and
that endotoxin induces toxic effects in animals in
shock. One of the problems with verifying this
hypothesis has been the detection of endotoxin in
the plasma of animals in shock. Recently, Fine and
co-workers (32) have demonstrated endotoxin-
positive material in the plasma of animals in shock
induced by splanchnic artery occlusion and in man
with a variety of septic and nonseptic disorders
(66). However, others have not been able to find
endotoxin in the blood of animals in shock (68).
Moreover, no data are presently available showing
LEFER
actual endotoxin titers in normal control nonseptic
patients. The concentration of endotoxin detected
in peripheral plasma by the assay technique must
eventually be related to the concentration required
to produce shock in animals before this work can be
evaluated. Furthermore, the endotoxin hypothesis
has been challenged on a number of other points:
(a) the finding that chronic administration of
nonabsorbable antibiotics, which should eliminate
the organisms that produce endotoxin, either failed
to stop a bacteremia (33) or did not prevent the
ultimate lethality of shock (34, 38), (b) animals
rendered "bacteria-free" developed shock similar to
that in ordinary animals (34), (c) no endotoxin
was found in hepatic portal venous blood of
animals in lethal shock induced by splanchnic
artery occlusion, although a toxic factor was
present in the blood (68), (d) endotoxemia per se
did not necessarily sensitize animals to other forms
of shock (35), and (e) extracts of spleen from
normal animals, which are supposed to detoxify
circulating endotoxin in animals in shock (69),
actually were toxic themselves due to their high
endogenous lysosomal enzyme content (18). Endo-
toxin does not appear to exert a direct toxic action
on the circulatory system but may release vasoac-
tive agents which alter circulatory function. Finally,
the mechanism of absorption of endotoxin from the
damaged intestine to the peritoneal space and then
to the blood (70) is not completely clear at present.
Until all these questions are satisfactorily answered,
there will be reservations about endotoxin as a
primary toxic factor in shock.
RDS is another toxic factor in shock which is
identifiable with a serious deleterious effect. The
depression of the reticuloendothelial system is well
documented in a variety of forms of shock (37, 71),
and this event represents a serious challenge to the
survival of the animal. Although the exact chemical
structure of RDS is unknown, it is a small molecule
and therefore is less likely to release other factors or
be hydrolyzed into smaller active agents in the
blood than are the larger toxic factors. The major
problem with evaluating the role of RDS is the
differentiation of other conditions which may
depress the reticuloendothelial system in shock
(e.g., depletion of plasma opsonins and ischemia of
the liver) from the RDS effect. In this regard, Saba
(72) and Schildt and Bouveng (73) have called
attention to plasma proteins and other substances
which promote phagocytosis, and they claim that
the opsonins decrease during shock. These workers
CircuUiiom Rtjurcb, Vol. XXXII. ftbrutrt 1973
 HUMORAL FACTORS IN CIRCULATORY SHOCK
suggest that this decrease may mislead one to
presume the presence of RDS. However, these
studies were done only on rats and mice, and RDS
may still be important in higher mammals. Also, the
possibility exists that RDS may actually act to
deplete the opsonins in the blood. Clarification of
these points would enable a more direct evaluation
of the significance of RDS in shock.
MDF has been found in a variety of shock states
by various groups including those of Lefer and
Glenn (14-18, 28, 44, 45, 47, 50, 52-56), Ledingham
(46), Shires (51), and Williams (48, 49). A large
body of information concerning its chemical prop-
erties, mechanism of formation, origin in the body,
biological actions, and methods of prevention has
been collected. MDF appears to be a small peptide
(47, 52, 53) which originates in the ischemic
pancreas (15, 23, 47) largely due to the hydrolytic
actions of lysosomal (14, 15, 18, 50) and perhaps
zymogenic proteases (50). It exerts a prominent
negative inotropic effect in isolated heart tissue (45,
54, 55) and in the whole animal (15). In addition,
it constricts the resistance vessels of the splanchnic
region (56) and perhaps depresses the reticuloen-
dothelial system (42). These latter two effects
would tend to set up positive feedback loops by
further enhancing MDF production (i.e., splanch-
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nic vasoconstriction) and preventing the clearance
of MDF from the plasma (i.e., reticuloendothelial
depression).
MDF cannot explain the entire picture observed
in shock and is not the only shock factor; however,
it appears to have considerable merit as a toxic
substance. One question which arises regarding
MDF is whether cardiac depression occurs in the
absence of MDF due to direct ischemia of the
myocardium or to other cardiotoxic substances.
Although the data are by no means complete, it
appears that the coronary circulation usually
exhibits adequate autoregulation during shock to
protect the heart from direct ischemic damage
except at extremely low blood pressures. The fact
that cardiac lysosomes are relatively well preserved
in the late stages of hemorrhagic shock is consistent
with this concept (15). Moreover, no other agent
that acts as a potent cardiodepressant appears in
the plasma of animals in shock.
Urschel et al. (74) failed to find a myocardial
depressant factor in the plasma of dogs in
hemorrhagic shock, but they may not have waited
long enough, since their dogs had not developed
any significant myocardial depression. A similar
CircuUtio* Rti—tcb, Vol. XXXI1, Pihrmtry 1975
135
situation recently occurred in endotoxic shock.
Thus, Hinshaw and co-workers (75) reported that
there was no evidence of cardiac depression 3 hours
after endotoxic shock in dogs. However, these
workers (76) found marked evidence of cardiac
impairment and even cardiac failure 6-9 hours after
administration of endotoxin. This latter time is
consistent with the work of Wangensteen et al.
(16), who reported the appearance of a plasma
myocardial depressant factor 7 hours after the onset
of endotoxic shock. Therefore, it appears that in the
early stages of shock cardiac performance is
relatively stable and that plasma MDF has not yet
accumulated to high levels. However, as shock pro-
gresses, MDF accumulates and cardiac impairment
ensues. The concept of a gradual cardiac impair-
ment becoming important in the late stages of
shock has been well documented by Crowell and
Guyton (77) and by Gomez and Hamilton (7).
Not enough information is presently available on
the factors of Fukuda (58, 59), Thai (60, 61), or
Clowes (62-64) to accurately assess their overall
significance in shock or to determine whether any of
these factors are identical with any of the more
well-established factors. Nevertheless, the fact that
two of these factors adversely affect the lung is of
great significance, since recent developments indi-
cate that pulmonary damage may be important
in shock (75).
There are many interesting similarities among the
various shock factors. Figure 1 summarizes the ori-
gin, the route of transport, and the sites of action
of the shock factors discussed in this review. All of
the shock factors listed appear to originate in the
splanchnic region: endotoxin, hemochromogen, and
RDS from the intestine, MDF from the pancreas,
Fukuda's factor from the liver, lysosomal enzymes
from throughout the splanchnic region but pri-
marily from the liver and the pancreas, and Clowe's
and Thai's factors from somewhere in the splanch-
nic region.
Several of the shock factors are transported to the
systemic circulation from their site of origin
primarily through the lymphatic system, particular-
ly the high molecular weight factors (i.e., endotoxin
and lysosomal enzymes). In addition, MDF appears
to be in part transported via the lymphatics, which
may indicate that at some stage in its formation it
is bound to a larger molecule. The other low mo-
lecular weight factors (i.e., RDS and Clowes's fac-
tor) are probably directly taken up by the micro-
circulation in the region in which they are formed.
 136 LEFER

Thoracic lymph duct

FIGURE 1
Schematic diagram of the site of origin, the route of transport, and the target organs of the
Downloaded from http://ahajournals.org by on June 28, 2020

major shock factors. CF = Clowes's factor, Endo = endotoxin, FF = Fukuda's factor, Hemo =
hemochromogen, Lyso = lysosomal hydrolases, MDF = myocardial depressant factor, RDS =
reticuloendothelial depressant substance, and TF = ThaTs factor. In general, the origin of the
factors is the splanchnic organs (i.e., Uver, spleen, pancreas, or intestine), the two major routes
of transport within the body are the intravascular blood stream and the lymphatic system,
and the target organs are the cardiovascular, the respiratory, and the reticuloendothelial systems.

In the cases of hemochromogen and Fukuda's fac-
tor, the routes of transport are not clear, although
some of the hemochromogen is absorbed via the
damaged intestinal mucosa or via mucosal capil-
laries into the systemic circulation.
Once transported to the systemic circulation,
either directly or via the lymphatic system, the
factors are then rapidly and easily delivered to
virtually all the peripheral tissues. However, it is
not known to what extent any of these factors can
penetrate the blood-brain barrier. Figure 1 also
shows that, despite the similar origin of the shock
factors, there is a diversity in the target organs
on which the shock factors exert deleterious effects.
Thus, MDF and to a lesser degree lysosomal en-
zymes have a cardiodepressant action, Thai's and
Clowes's factors primarily exert a damaging effect
on the lungs, RDS acts on the fixed macrophages
of the reticuloendothelial system (i.e., in the liver
and perhaps in the spleen), and lysosomal hy-
drolases (and perhaps endotoxin) appear to exert a
damaging effect on the splanchnic vasculature.
However, the precise target organs of Fukuda's
factor and to some extent endotoxin are not clearly
established at the present time.
The target organs which are known to be
adversely affected by shock factors are clearly
among the more vital organs (i.e., heart, lungs,
peripheral vasculature, and reticuloendothelial sys-
tem ) and are obviously necessary for the continuing
functioning of the organism. Perhaps the brain may
be spared because of its unique situation (i.e., the
blood-brain barrier), although there is no evidence
that the brain is in fact free of humorally induced
effects.
OrcnUtiom Rtsurcb, Vol. XXXll, Ftbrutn 1973
 HUMORAL FACTORS I N CIRCULATORY SHOCK
It appears that an appropriate therapeutic
management of circulatory shock should involve
prevention of the splanchnic ischemia which
engenders toxic factors as well as the specific
antagonism of the pathological actions of these
humoral factors. A comprehensive regimen such as
this has not been adequately tested, and thus an
important application of basic laboratory knowl-
edge to an important clinical problem remains to be
achieved.
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