Chromaffin Reacting Cells in Human Digital Skin
By
G. E. BURCH, M.D.
AND J. H. PHILLIPS, JR.,
M.D.
These studies demonstrated the existence of chromafiin-reacting granules in the human
skin. The ehromaffln reaction was provided by bichromate fixation. Subsequent special
staining by the modified Sevki procedure revealed these granules to be localized usually
to characteristic long, eel-like cells with distinctive tinctorial features. Although the
true significance of these cells is not certain, they are believed to represent the local
source of a vasopressor material for the peripheral tissues. Much indirect physiologic
evidence supports this belief.
Adams-Ray and Nordenstam10' u accepted
the classic definition of the "chromaffin reaction" as the formation of dark brownstaining
compounds by bichromate fixation.10 20 By
using various histochemical technics, but particularly Orth's solution (bichromate) fixation and a modified Sevki stain, they were
able to demonstrate not only the presence of
chromaffin granules in the skin but their apparent localization to characteristic cells.
The Orth solution fixation provided the chromaffin reaction in the typical granules but,
without subsequent staining, cellular characteristics were indistinct. For this reason the
modified Sevki stain, which is known to stain
chromaffin tissue but is not specific for it,
was used after fixation. The characteristic
cells thus identified were typically long, narrow, and eel- or snake-like, with elongated
pale-staining nuclei surrounded by a narrow
zone of cytoplasm. Cytoplasmic protrusions
of pale-staining material were mainly bipolar
and usually contained typical red to bluishred granules under Sevki staining. Occasionally, the cytoplasmic protrusions gathered in
clusters to produce the appearance of "flowering cowslips." The elongated nuclei were
1 to 2 micra wide and 6 to 10 micra long. The
granules had diameters of about 0.2 to 0.3 micron. The cells were irregularly distributed
among collagen fibers in the coriurn of the
skin and of other organs as well, being more
predominant in the vicinity of blood vessels,
nerves, hair follicles, and sebaceous glands.
L
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OG AX/ humoral factors have been known
for many years to influence the peripheral
circulation.1"3 Denervation of the extremities of man and other animals alters the circulation to the part and affects the regulatory
phenomena, hut satisfactory local mechanisms
readily develop to compensate for these alterations. The studies of Lewis1 -with the " H
substance,"' of Cannon2 with "sympathius,"
of Krogh3 with anoxia, of Heymans4 with
anoxia and poisons of oxygen carriers, of von
Euler5"7 with norepinephrine, and of others8' °
have demonstrated the role of various factors
in the local control of the peripheral circulation.
Recently, we have undertaken a more detailed study of the probable sources of vasoactive humoral factors which appear to originate locally in the tissues. During the course
of these studies, we have investigated further
the important discovery of Adams-Ray and
Nordenstam10'11 of chrornaffin-reacting cells
in tissues of man and other animals. The
presence of a related local humoral regtdatory mechanism would be supported by observations that dissolution of chromaffin granules in these particular cells was associated
with release of a vasopressor substance. This
substance may be epinephrine, norepinephrine, or some similar compound.
From the Department of Medicine, Tulane University School of Medicine and Charity Hospital of
Louisiana at Xew Orleans, La.
Supported by grants from the TJ. S. Public Health
Service (no. H-143), the Upjohn Co., and the Thibodeaui Kesearch Foundation.
Dr. Phillips is a U. S. Public Health Service National Heart Institute Research Fellow.
Received for publication March 10, 195S.
Initially, differentiation of the special cells
from mast cells was difficult because they appeared to stain similarly. This, however,
was clarified subsequently by the positive
416
Circulation Research, Volume VI. July
CHROMAFFIN REACTING CELLS
417
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FIG. 2. Characteristic Sevki stained cells adjacent
to small vessel. Approximately X 1000.
FIG. 1. Unstained {Top) and Sevki stained
{Bottom) preparation, showing characteristic cell
granules (a) and cell body (ft). Approximately
X 1000.
results obtained for the chromaffin cells and
negative results for the mast cells to the
following histochemical procedures: argentaffin reaction, azocoupling reaction, indophenol
reaction, ferriferricyanide reduction tests,
and autofiuorescence on ultraviolet illumination (3660 A). In addition, of course, the
mast cells did not contain chromaffin-positive
granules. Furthermore, on Sevki staining,
the mast cell and its granules were larger (0.6
to 0.7 micron) than the chromaffin cell and
its granules. Finally, the general configuration and nuclear structures of the cells differed somewhat.10' n
We have extended the studies of AdamsRay and Nordenstam to include investigations on human digital skin designed to identify these cells even further by locating them
photographically under successive processes
of fixing in Orth's solution, staining with
Sevki solution, destaining, and then restain-
ing. By this means, the chromaffin granules
were shown to be in the special cells and not
in the mast cells; this also served to differentiate artifacts and ectopic melanin.
METHODS
Specimens of skin were obtained by punch
biopsies from the finger and toe tips and from
the legs of patients in the Charity Hospital.
Several additional samples were gathered from
fresh postmortem material. The adrenal glands
of dogs were studied as a positive source of
chromaffin cells.
The tissue was immediately fixed in Orth's
solution (10:1 mixture of Muller's fluid and
neutral formalin)"1 M for 24 to 4S hours. The
tissue was then washed, dehydrated, embedded in
paraffin, sectioned, mounted, and deparaffinated
with xylene, after which a cover slip was placed
over it. The unstained tissue was examined for
cells with chromaffin-appearing granules, and these
areas were photographed.
The tissue was then stained with modified Sevki
stain21 in the following way. After the cover slip
was removed, the tissue was washed consecutively
with xylene, alcohol of graded strength, and distilled water. After application of a modified
Sevki stain (2 drops of Giemsa's solution per
milliliter of distilled water for 2 hours at 50 C.),
418
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Eio. 3. Unstained (Top) and Sevki stained
(Bottom) preparation, showing cell with characteristic
properties but without chromaffin granules. Approximately X 1000.
the tissue was rinsed in distilled water and differentiated, under microscopic guidance, first in a
70 per cent solution of ethyl alcohol, then successively in a 90 per cent solution, a 95 per cent
solution, absolute alcohol, and finally xylene. The
cover slip was then reapplied. The area with
the chroniaffin-appearing granules previously recorded photomicrographically (under Orth bichromate fixation) was again located in the
Sevki-stained tissue. It was photographed again
for comparison with the unstained tissue.
The coverslip was again removed, and the tissue
was destained with acid alcohol, a process analogous to one described elsewhere with reference
to toluidine blue." The same cells in the tissue,
now returned to the Orth's fixed, unstained state,
were identified once more and photographed.
Finally, the tissue was restained with the modified
Sevki solution, and the same cells were rephotographed.
By studying the resultant series of photomicrographs, one could be certain that the chroniaffinappearing granules identified in the Orth's fixed
BURGH AND PHILLIPS
FIG. 4. Unstained (Top) and Sevki stained
(Bottom) preparation, showing cell with atypical
morphologic characteristics, but with characteristic
granules and staining properties: cell granules (a)
and cell body (6). Approximately X 1000.
tissues were the same granules later noted in the
special cells of that particular section on Sevki
staining. As a control, the medulla of the adrenal
gland of a dog was simultaneously processed by
identical methods as the human skin.
RESULTS
These studies not only confirmed, hut also
added further evidence in support of the observation of Adams-Ray and Xordenstam,10' u
who demonstrated the presence of chromaffinreacting granules in characteristic cells of the
human corium. If the cytochemical criterion
of a chromaffin granule is that it stains
brown with bichromate, then the identification of the same cells containing chromaffin
granules in our series of photographs confirmed the presence of these granules within
cells with the morphologic characteristics described (figs. 1-5). It should be strongly em-
CHROMAFFIX REACTING CELLS
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phasized that identification of these special
cells on the orginal histologic sections under
the light microscope was much easier than is
apparent from the photomicrographs because
of the benefits of increased clarity and color
differentiation.
Although the chromaffin cells were not
numerous in the tissues examined, a few were
found in almost all samples of human skin
studied. They appeared to be concentrated
more heavilj"- in the skin of the toe tip and the
region of the calf than in the finger tip and
were more numerous around blood vessels,
nerves, and sweat and sebaceous glands.
Sevki-stained cells with the morphologic
characteristics of the chromaffin cells but
without chromaffin granules were also found
(fig. 3). Whether or not these same cells had
secreted their chromaffin material before the
tissue was collected is not known. The morphologically and tinctorially characteristic
cells contained chromaffin granules of variable numbers and depths of staining. Furthermore, chromaffin granules were sometimes
found dispersed in the extracellular spaces
of the corium. Whether this represents a normal state of distribution, or is the result of
preparation of the tissues, remains unknown.
In addition, cells were found with atypical
morphologic characteristics, but with typical
granules and staining properties (fig. 4).
DISCUSSION
These studies showed the existence in human skin of the digits and legs of positively
reacting chromaffin granules. Although the
granules were localized principally in characteristic cells,10' u some were extracellular.
Many cells had morphologic and tinctorial
characteristics of the special cell but did not
contain chromaffin-reacting granules. Moreover, chromaffin-reacting granules were found
in celLs that were tinctorially, but not morphologically, characteristic of those described
by Adams-Ray and Xordenstam.10' u The
number of chromaffin-reacting granules, the
intensity of their staining, and the number of
special cells varied from tissue to tissue. Conceivably, such variations might all be related
410
\
v
Fia. 5. Sovki stainod cell, showing "flowering
cowslip" morphologic pattern. Approximately X
1000.
to the phase of secretory function of the cells.
Even though cells with chromaffin-reacting
granules exist in the corium of human skin,
their physiologic significance still remains unknown. That the chromaffin-reacting results
from the oxidation, especially by chromates,
of epinephrine, norepinephrine, or related
compounds12' 14~17 is generally accepted. Recent work has indicated that the catechol
amines in chromaffin cells are enclosed in
microspheres (presecretory granules) and
that interference with the integrity of membrane of these granules results in the release
of the active material.7 That the chromaffin
reaction is not specific is well known.13-18' 20
Red blood cells and the entodermal argentaffin
granules have a positive chromaffin reaction,13 as do hydroxytyramine, dioxyphenylaliuine,15 5-hydroxytryptamine23' 2i and possibly other related compounds.16'17 Since all
methods of demonstrating chromaffin tissue
are to some degree nonspecific, the presence
of cells that possibly secrete epinephrine, norepinephrine, or other vasoactive substances
must be confirmed more directly by both his-
420
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toehemieal and pharruacologic approaches.13
Widely distributed outside the adrenal medulla are cells that contain chromaffin material. Thus far, chromaffin tissue has been
demonstrated in the paraganglia (widespread,
small collections of cells in various retroperitoneal structures, including the organs of
Zuckerkandl), in the connective tissue between the aorta and pulmonary artery, in the
coronary sulci (especially the left) and in
the superior cervical ganglia.18' 20 Also of interest are the enterochromaffin cells (argentaffine system) of the gastroentestinal tract,
which demonstrate the classical chromaffin
reaction.13' 17 ' 18 ' 23 ' 24 Some authors consider
the reacting material in these cells to be
5-hydroxytryptamine (enteramine, serotonin), 20 ' 2S but others are not certain.24 That
the reacting substance is not epinephrine or
norepinephrine appears certain.13
Thus, it is not possible to state definitely
that the characteristic chrornaffin cells found
in the human skin are the local source of
epinephrine, norepinephrine, or both. That
these cells may represent atypical mast cells
in completely different stages of development,
or that the granules may represent the local
source Of 5-hydroxytryptamine or some other
related compound, cannot be denied. However, it does appear that these cells may well
represent a local source of a vasopressor substance.
Of the structures in the body that produce
catechol amines (the adrenergic nerves, the
suprarenal medulla, and the chromaffin cells
in the tissue), the adrenal medulla is the major source of epinephrine, whereas adrenergic
nerve terminals, as well as the adrenal medulla, are major sources of epinephrine.6"7'15'16'
26, 27 Possible precursors of norepinephrine
include dihydroxyphenylserine and hydroxytyramine. Epinephrine is apparently formed
by the methylation of norepinephrine, the
methyl group being supplied by such donors
as methionine.20
The sympathomimetic substances derived
from the adrenal medulla appear to originate
from two specific types of chromaffin cells,
one for the production and release of epi-
BURGH AND PHILLIPS
nephrine and another for norepinephrine.7' 15 ' 10 Whether or not this also applies
to extra-adrenal chromaffin cells is not
certain.
It has been suspected for some time that
chromaffin cells exist outside the adrenal medulla and paraganglia, in various organs and
peripheral tissues, and that they are capable
of producing epinephrine, norepinephrine, or
both. According to von Buler,7 almost all
organs that have been examined have been
shown to contain small amounts of epinephrine in addition to norepinephrine. The
source of the epinephrine has been debatable.
In support of the existence of chromaffin cells
in peripheral tissues is the fact that after
sympathetic d enervation to some organs, thp
norepinephrine content drops sharply, whereas the epinephrine content falls only moderately6' 7 This suggests that epinephrine is
derived from chromaffin cells located in the
tissues, which continue to elaborate their specific product even after sympathetic denervation. In addition, it has been shown repeatedly in the past that the peripheral vasomotor
apparatus can re-establish essentially normal
blood pressure after total body sympathectomy.28"30
The presence of cells in human skin capable
of producing a vasoconstrictive effect was predicted a long time ago. This prediction has
been based on observations of the physiologic
mechanism of tone and contractility of the
minute vessels of the skin.1-31' 33 Although
not conclusive, physiologic evidence has been
presented to support the concept of local production of vasopressor substances by cells of
peripheral tissue. For example, despite the
importance of the sympathetic nerve fibers in
the control of the dermal blood vessels, complete severance of these fibers is followed by
only a temporary period of vasodilatatiou.34
This would imply compensation by some
local phenomenon. The vessels may be demonstrating increased sensitivity to circulating
vasopressor agents, but this is not definite.85"37
Vasopressor substances of local origin not only
may exist but may actually be considerably
more important. Furthermore, responses of
CHROMAFFIN REACTING CELLS
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the peripheral circulation that are attributed
to direct action of various agents upon smooth
muscle of the blood vessels could be mediated
with such a special cell as an intermediary
step.
Probably some of the strongest evidence in
support of locally produced vasoconstrictor
substances is that offered by Sir Thomas
Lewis1 in his discussion of Bier's spots. He
observed these red and white spots in the
skin of the lower arm a few minutes after the
brachial artery had been obstructed by a
pneumatic cuff. As noted by Lewis, the vessels participating in this phenomenon were
those responsible for the color of the skin,
capillaries, and in particular, minute venules.
The white spots are of particular interest in
these studies related to the special cell because they are produced by intense contraction of dermal capillaries and venules.1'38
The presence of innervation to these vessels
is unsettled. 1 ' 34 ' 38 The unequivocal statement
that the capillaries and venules are not innervated84 appears to be incorrect. Through
a careful series of experiments, Lewis1 excluded cold temperature as well as central
nervous and local nervous factors as primary
causes of Bier's white spots, which were noted
to form in denervated areas. He concluded
that in cutaneous areas in which the circulation had been sufficiently reduced, vasoconstrictor as well as vasodilator substances
are formed. Through evidence too extensive to be presented here, he concluded
that vasoconstrictor substances are released
locally in the tissue spaces and are not
derived from the blood. These substances
must act against potent vasodilators, which
are known to be released Avhen the circulation
is arrested. As noted by Lewis, Bier's white
spots enlarge and coalesce progressively as
the skin is deprived of its circulation. If
this is continued (as in death), the whole cutaneous surface becomes involved. Furthermore, responses comparable to Bier's spots
have been described for organs other than the
skin.89
Extremely high tone has been demonstrated
in the cutaneous venules of the lower extrem-
421
ity,31 the degree apparently being proportional to the magnitude of the hydrostatic pressure acting locally within the vessels. The
high tone present in the small cutaneous blood
vessels in some disease states, such as congestive heart failure,82' 83 rnay be in part due to
local mechanisms, perhaps in response to impairment of the circulation to the tissues.
Thus, physiologic phenomena are known
which could depend, at least in part, upon
chromaffiin cells located within the tissues,
such as skin
SUMMARY
Confirming the recent original work of
Adams-Ray and Nordenstam, we have demonstrated the presence of chromaffin-reacting
granules localized in characteristic cells of
the human digital corium. On the basis of
both anatomic and physiologic considerations,
these cells are presumably a local source of
some vasoconstrictor substance, probably epinephrine, norepinephrine, or both, but their
true function remains to be demonstrated by
direct evidence.
SUMMAEIO IN
INTERLINGUA
In confirmation del recente labores original
de Adams-Ray e Nordenstam, nos ha demonstrate le presentia de granulos chromaffinoreactive localisate in cellulas characteristic
del corio digital de humanos. • Super le base
de considerationes anatomic e physiologic, il
pote esser supponite que iste cellulas es un
fonte local de un substantia vasoconstrictori
—probabilemente epinephrina o norepinephrina o ambes—sed lor ver function remane a
demonstrar per constatationes directe.
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Chromaffin Reacting Cells in Human Digital Skin
G. E. BURCH and J. H. PHILLIPS, JR.
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Circ Res. 1958;6:416-423
doi: 10.1161/01.RES.6.4.416
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