Differential Innervation of Secretory Coils and Ducts in Human Eccrine Sweat Glands.

BACKGROUND: Previous studies demonstrate that eccrine sweat glands are innervated by both cholinergic and adrenergic nerves. However, it is still unknown whether the secretory coils and ducts of eccrine sweat glands are equally innervated by the sympathetic nerve fibers. To well understand the mechanisms on sweat secretion and reabsorption, the differential innervation of secretory coils and ducts in human eccrine sweat glands was investigated in the study. METHODS: From June 2016 to June 2017, six human skins were fixed, paraffin-embedded, and cut into 5 µm-thick sections, followed by costaining for nerve fiber markers protein gene product 9.5 (PGP 9.5), tyrosine hydroxylase (TH) and vasoactive intestinal peptide (VIP), and eccrine sweat gland markers K7, S100P, and K14 by combining standard immunofluorescence with tyramide signal amplification (IF-TSA). Stained sections were observed under the microscope, photographed, and analyzed. RESULTS: The fluorescent signals of PGP 9.5, TH, and VIP were easily visualized, by IF-TSA, as circular patterns surrounding eccrine sweat glands, but only PGP 9.5 could be observed by standard IF. The IF-TSA method is more sensitivity than standard IF in detecting antigens expressed at low levels. PGP 9.5, TH, and VIP appeared primarily surrounding the secretory coils and sparsely surrounding the sweat ducts. CONCLUSION: Sweat secretion is mainly controlled by autonomic nerves whereas sweat reabsorption is less affected by nerve activity.

Three-dimensional reconstructed eccrine sweat glands with vascularization and cholinergic and adrenergic innervation.

Functional integrity of the regenerated tissues requires not only structural integrity but also vascularization and innervation. We previously demonstrated that the three-dimensional (3D) reconstructed eccrine sweat glands had similar structures as those of the native ones did, but whether the 3D reconstructed glands possessing vascularization and innervation was still unknown. In the study, Matrigel-embedded eccrine sweat gland cells were implanted under the inguinal skin. Ten weeks post-implantation, the vascularization, and innervation in the 10-week reconstructed eccrine sweat glands and native human eccrine sweat glands were detected by immunofluorescence staining. The results showed that the fluorescent signals of general neuronal marker protein gene product 9.5, adrenergic nerve fiber marker tyrosine hydroxylase, and cholinergic nerve fiber markers acetylcholinesterase and vasoactive intestinal peptide embraced the 3D reconstructed glands in circular patterns, as the signals appeared in native eccrine sweat glands. There were many CD31- and von Willebrand factor-positive vessels growing into the plugs. We demonstrated that the 3D reconstructed eccrine sweat glands were nourished by blood vessels, and we for the first time demonstrated that the engineering sweat glands were innervated by both cholinergic and adrenergic fibers. In conclusion, the 3D reconstructed eccrine sweat glands may have functions as the native ones do.

Neural control of sweat secretion: a review.

BACKGROUND: Humans have 4 million exocrine sweat glands, which can be classified into two types: eccrine and apocrine glands. Sweat secretion, a constitutive feature, is directly involved in thermoregulation and metabolism, and is regulated by both the central nervous system (CNS) and autonomic nervous system (ANS). OBJECTIVES: To explore how sweat secretion is controlled by both the CNS and the ANS and the mechanisms behind the neural control of sweat secretion. METHODS: We conducted a literature search on PubMed for reports in English from 1 January 1950 to 31 December 2016. RESULTS AND CONCLUSIONS: Acetylcholine acts as a potent stimulator for sweat secretion, which is released by sympathetic nerves. ß-adrenoceptors are found in adipocytes as well as apocrine glands, and these receptors may mediate lipid secretion from apocrine glands for sweat secretion. The activation of ß-adrenoceptors could increase sweat secretion through opening of Ca2+ channels to elevate intracellular Ca2+ concentration. Ca2+ and cyclic adenosine monophosphate play a part in the secretion of lipids and proteins from apocrine glands for sweat secretion. The translocation of aquaporin 5 plays an important role in sweat secretion from eccrine glands. Dysfunction of the ANS, especially the sympathetic nervous system, may cause sweating disorders, such as hypohidrosis and hyperhidrosis.

Peripheral choline acetyltransferase in rat skin demonstrated by immunohistochemistry.

Conventional choline acetyltransferase immunohistochemistry has been used widely for visualizing central cholinergic neurons and fibers but not often for labeling peripheral structures, probably because of their poor staining. The recent identification of the peripheral type of choline acetyltransferase (pChAT) has enabled the clear immunohistochemical detection of many known peripheral cholinergic elements. Here, we report the presence of pChAT-immunoreactive nerve fibers in rat skin. Intensely stained nerve fibers were distributed in association with eccrine sweat glands, blood vessels, hair follicles and portions just beneath the epidermis. These results suggest that pChAT-positive nerves participate in the sympathetic cholinergic innervation of eccrine sweat glands. Moreover, pChAT also appears to play a role in cutaneous sensory nerve endings. These findings are supported by the presence of many pChAT-positive neuronal cells in the sympathetic ganglion and dorsal root ganglion. Thus, pChAT immunohistochemistry should provide a novel and unique tool for studying cholinergic nerves in the skin.

Blocking the beta-adrenergic system does not affect sweat gland function during heat acclimation.

The purpose of the current study was to test the hypothesis that the beta-adrenergic innervation of the human eccrine sweat gland facilitates greater sweat production following heat acclimation. Eight healthy subjects (mean ± SD age: 25.1 ± 4.1 years, weight: 79.0 ± 16.1 kg, and VO(2)max: 48.5 ± 8.0 ml/kg/min) underwent active heat acclimation by walking at 40% of their VO(2)max for 8 days (90 min a day) in an environmental chamber (35.3 ± 0.8°C and 40.2 ± 2.1% rH). To test the hypothesis, the adrenergic component of sweat gland innervation was inhibited by continuously administering a 0.5% solution of the beta-adrenergic antagonist propranolol via iontophoresis to a 5 cm(2) area of one forearm during each 90-min exercise bout. The opposing control forearm underwent iontophoresis with a saline solution. Following heat acclimation, mean sweat rate in the inhibited and control forearm was 0.47 ± 0.30 mg/cm(2)/min and 0.44 ± 0.25mg/cm(2)/min, respectively. Findings of the current study fail to support the hypothesis that adrenergic innervation facilitates human eccrine sweat gland function during heat acclimation, as no significant differences in sweating were observed. In light of the above, the physiological significance of the dual cholinergic and adrenergic innervation of the eccrine sweat gland has yet to be determined.

Is active sweating during heat acclimation required for improvements in peripheral sweat gland function?

We investigated whether the eccrine sweat glands must actively produce sweat during heat acclimation if they are to adapt and increase their capacity to sweat. Eight volunteers received intradermal injections of BOTOX, to prevent neural stimulation and sweat production of the sweat glands during heat acclimation, and saline injections as a control in the contralateral forearm. Subjects performed 90 min of moderate-intensity exercise in the heat (35 degrees C, 40% relative humidity) on 10 consecutive days. Heat acclimation decreased end-exercise heart rate (156 +/- 22 vs. 138 +/- 17 beats/min; P = 0.0001) and rectal temperature (38.2 +/- 0.3 vs. 37.9 +/- 0.3 degrees C; P = 0.0003) and increased whole body sweat rate (0.70 +/- 0.29 vs. 1.06 +/- 0.50 l/h; P = 0.030). During heat acclimation, there was no measurable sweating in the BOTOX-treated forearm, but the control forearm sweat rate during exercise increased 40% over the 10 days (P = 0.040). Peripheral sweat gland function was assessed using pilocarpine iontophoresis before and after heat acclimation. Before heat acclimation, the pilocarpine-induced sweat rate of the control and BOTOX-injected forearms did not differ (0.65 +/- 0.20 vs. 0.66 +/- 0.22 mg x cm(-2) x min(-1)). However, following heat acclimation, the pilocarpine-induced sweat rate in the control arm increased 18% to 0.77 +/- 0.21 mg x cm(-2) x min(-1) (P = 0.021) but decreased 52% to 0.32 +/- 0.18 mg x cm(-2) x min(-1) (P < 0.001) in the BOTOX-treated arm. Using complete chemodenervation of the sweat glands, coupled with direct cholinergic stimulation via pilocarpine iontophoresis, we demonstrated that sweat glands must be active during heat acclimation if they are to adapt and increase their capacity to sweat.

Effects of topiramate on mouse eccrine sweat gland responsiveness to heat exposure.

Young mice (2 weeks old) were given topiramate daily for 1 month, and sudomotor function was evaluated utilizing impression mould techniques to determine the number of sweat glands reactive to heat exposure and sweat output per gland on the plantar surface of mice hind-paws. Immunohistochemical quantitation of protein gene product 9.5, choline acetyltransferase and tyrosine hydroxylase in footpads was determined after topiramate treatment. While a 25% decrease in the number of secreting sweat glands and a 42% decline in sweat output per gland were observed following topiramate treatment, no significant differences were noted in sudomotor innervation, expressed as length of choline acetyltransferase, tyrosine hydroxylase and protein gene product 9.5 immunoreactive nerve profiles in single secretory coils or in sweat gland sizes within the secretory coil area. Long-term topiramate stimulation resulted in a reduction in the number of reactive sweat glands, without changes in sweat gland innervation, suggesting that the diminished responsiveness of the glands to heat exposure induced by topiramate might have resulted from a decrease in the intrinsic regulatory activity of sweat glands, as opposed to the loss of periglandular neurotransmitters or the impairment of the structure of the glands.

[Colorimetric determination of eccrine sudoriferous glands functional condition in case of hyperhidrosis and their correction by belladonna].

For study of the sweat secretion in 27 patients suffered by local hyperhidrosis method of colorimetric determination of functioning sudoriferous glands number and a Minor's tests were used. The confines and intensity of sweat secretion have been determined. Study was carried out before and during the treatment as well as at the moment of clinical recovery. Revealing of vegetative syndromes was provided by Vein's inquirer. In patients with hyperhidrosis vegetative abnormalities were combined with asthenic disorders. Duration of illness had impact on frequency and character of neurasthenic syndrome manifestation. Offered scheme of local hyperhidrosis treatment with staged use of belladonna and antihistaminic preparation "hydroxyzine" (having antimuscarinic action) could be characterized as a well endurable and significantly ameliorative of patient's clinical status.

Neural control and mechanisms of eccrine sweating during heat stress and exercise.

In humans, evaporative heat loss from eccrine sweat glands is critical for thermoregulation during exercise and/or exposure to hot environmental conditions, particularly when environmental temperature is greater than skin temperature. Since the time of the ancient Greeks, the significance of sweating has been recognized, whereas our understanding of the mechanisms and controllers of sweating has largely developed during the past century. This review initially focuses on the basic mechanisms of eccrine sweat secretion during heat stress and/or exercise along with a review of the primary controllers of thermoregulatory sweating (i.e., internal and skin temperatures). This is followed by a review of key nonthermal factors associated with prolonged heat stress and exercise that have been proposed to modulate the sweating response. Finally, mechanisms pertaining to the effects of heat acclimation and microgravity exposure are presented.

Congenital insensitivity to pain with anhidrosis.

Congenital insensitivity to pain with anhidrosis is an autosomal-recessive disorder resulting from defective neural crest differentiation with loss of the first-order afferent system, which is responsible for pain and temperature sensation. There is also a neuronal loss in the sympathetic ganglia. Lack of sweating, hyperthermia, and infections of bones are main features of the disorder; however, contradictory results have been published regarding eccrine sweat gland innervation. A 5-year-old male patient with typical clinical manifestations of congenital insensitivity to pain with anhidrosis is presented. Immunohistochemistry with antibodies against S100 protein and neuron-specific enolase failed to reveal nerve fibers in the vicinity of the eccrine sweat glands. The roles of the nerve growth factor and tyrosine kinase receptor gene mutations in the pathogenesis of the disease are also discussed.

Denervation of eccrine glands in patients with familial amyloidotic polyneuropathy type I.

OBJECTIVE: To study the alterations in the structure and innervation of eccrine glands in familial amyloidotic polyneuropathy (FAP) type I with Val 30 Met transthyretin mutation. BACKGROUND: Anhidrosis of the distal lower limbs is a prominent feature of FAP type I. METHODS: Qualitative and morphometric study of amyloid deposition, eccrine glands, and their innervation in nine patients with FAP type I (duration of sensory symptoms, 8.4 +/- 3.9 years [mean +/- SD]; range, 3 to 15 years) and seven control subjects. RESULTS: On light microscopy, the endoneurium of cutaneous nerve fascicles had no definite amyloid deposition. Amyloid deposition was observed around eccrine glands in seven of nine patients. On electron microscopy, no focal destruction and degeneration of eccrine glands or ducts and of Schwann cell processes with or without nerve terminals or unmyelinated axons were observed in relation to adjacent amyloid deposition. Secretory vacuoles and granules of dark cells were markedly decreased in some secretory coils. Nerve terminals and unmyelinated axons of eccrine glands were considerably fewer in patients than in control subjects, and denervation was prominent in all patients. A few nerve terminals and unmyelinated axons of eccrine glands were present in patients who had experienced sensory symptoms for 3, 5, and 6 years, but were absent in patients with sensory symptoms for more than 7 years. CONCLUSIONS: Eccrine glands are markedly to totally denervated in patients with FAP type I and chronic sensory symptoms. The extent of denervation indicates the severity of autonomic denervation and therefore may suggest the timing of liver transplantation.

The development of cholinergic sympathetic neurons: a role for neuropoietic cytokines?

The sympathetic neurons that innervate eccrine sweat glands undergo a phenotypic switch from noradrenergic to cholinergic and peptidergic. The changes in neurotransmitter choice are retrogradely specified by interactions with the target tissue that are mediated by a secreted differentiation factor. Production of the target-derived differentiation factor requires noradrenergic innervation. The switch from noradrenergic to cholinergic and peptidergic is reproduced in culture when neonatal sympathetic neurons are treated with members of the neuropoietic cytokine family, leukemia inhibitory factor (LIF) or ciliary neurotrophic factor (CNTF), suggesting that these cytokines might be responsible for the target-induced change in neurotransmitter properties. Analysis of transgenic mice that lack either LIF or CNTF or both, however, does not support their candidacy: the transmitter properties of the sweat gland innervation is indistinguishable from that of wild-type mice. It seems likely that another and novel member of the, family is responsible.

[Idiopathic acquired generalized anhidrosis with normal numbers of eccrine gland nerve terminals and unmyelinated axons. A case report].

A 37-year-old man with acquired generalized anhidrosis but without other autonomic or somatic abnormalities (idiopathic acquired generalized anhidrosis) is described with special reference to histologic and morphometric findings of the eccrine gland and its nerve terminals and unmyelinated axons. The patient was admitted to our hospital in August 1989 with complaints of heat intolerance and anhidrosis of the face, trunk, and both limbs. General physical and neurological examinations revealed no abnormalities except generalized anhidrosis. Sweating tests revealed anhidrosis of most surfaces of the body except the axillae, mammary areolae, forearms, hands, popliteal fossae, and plantar surfaces. Sympathetic skin responses were absent in the axillae, and were decreased on the palms. Iontophoretically applied pilocarpine revealed a complete absence of active eccrine glands on the dorsal surface of the right foot. No other abnormalities were revealed by autonomic function tests. Light and electron microscopic studies of the eccrine glands of the distal and lateral aspects of the left leg were performed in this patient and six control subjects. Infiltration of mononuclear inflammatory cells around the duct and secretory coil of a limited number of eccrine glands on multiple sections was found only in this patient. Electron microscopic morphometric evaluation of the eccrine glands, associated nerve terminals and unmyelinated axons of this patient revealed no definite alterations when compared with those of the six control subjects. Therefore, we concluded that the nerves innervating the eccrine glands were not affected in this patient and suspect that either the cholinergic receptors or the function of secretory cells of the eccrine glands were involved.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell interactions that determine sympathetic neuron transmitter phenotype and the neurokines that mediate them.

The transmitter properties of both developing and mature sympathetic neurons are plastic and can be modulated by a number of environmental cues. Cell culture studies demonstrate that noradrenergic neurons can be induced to become cholinergic and that the expression of neuropeptides can be altered. Similar changes in transmitter phenotype occur in vivo. During development, noradrenergic neurons that innervate eccrine sweat glands acquire cholinergic and peptidergic function. This change is dependent upon interactions with the target tissue. Following injury of sympathetic neurons in developing and adult animals, striking alterations take place in peptide expression. Ciliary neurotrophic factor and cholinergic differentiation factor/leukemia inhibitory factor, members of a family that includes several hematopoietic cytokines, induce cholinergic function and modulate neuropeptide expression in cultured sympathetic neurons. Studies in progress provide evidence that members of this new cytokine family influence the transmitter phenotype of sympathetic neurons not only in vitro but also in vivo.

Cholinergic sensitivity of the eccrine sweat gland in trained and untrained men.

The purpose of this study was to compare the cholinergic responsiveness of the human sweat gland in trained and untrained men. Eighteen healthy male volunteers (9 trained, 9 sedentary) served as subjects. Pilocarpine concentration vs. sweat rate dose-response curves were obtained from each subject using iontophoresis. From these measurements, maximal iontophoretic sweat rate (SRmax) was determined and correlated with each subject's maximal oxygen uptake (VO2max). The trained group had a significantly (P less than 0.05) greater mean SR max and their mean dose-response curve was shifted up and to the left, as compared to the sedentary controls. Furthermore, VO2max was significantly correlated with SRmax (r = 0.76). These findings suggest that the modification occurring in the human sweat gland after training may include improvements in both SRmax and cholinergic sensitivity, and support the hypothesis that the potentiation in sweating following training is achieved via a peripheral mechanism.