[Skip to Content]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 54.211.168.204. Please contact the publisher to request reinstatement.
Sign In
Individual Sign In
Create an Account
Institutional Sign In
OpenAthens Shibboleth
[Skip to Content Landing]
Basic Science for Surgeons
October 1998

NeuropeptidesMediators of Inflammation and Tissue Repair?

Author Affiliations

From the Departments of Surgery, Eberhard-Karls-Universit[[auml]]t, T[[uuml]]bingen, Germany (Drs Sch[[auml]]ffer and Becker and Mr Beiter), and University of California at San Francisco (Dr Hunt).

Arch Surg. 1998;133(10):1107-1116. doi:10.1001/archsurg.133.10.1107

Successful repair of injured tissues requires diverse interactions between cells, biochemical mediators, and the cellular microenvironment.13 Much has been learned about the individual events that are involved in this process, but their integration is clearly far more complex than has been imagined, and the important role of neurogenic stimuli is only recently being recognized.

Neurogenic stimuli profoundly affect cellular events that are involved in inflammation, proliferation, and matrix, as well as cytokine and growth factor synthesis. Immune cells regulated by neuropeptides include lymphocyte subsets, macrophages, and mast cells. In addition, neuropeptides may affect the proliferative and synthetic activity of epithelial, vascular, and connective tissue cells. Furthermore, a close interaction between the nervous and the immune systems has become obvious.4

The peripheral nervous system (PNS), acting through neuropeptides, not only relays sensory information to the central nervous system (CNS) but also plays an effector role in the inflammatory, proliferative, and reparative processes after injury. These effects range from growth factor and cytokine responses to control of local blood flow. Neuropeptides mediate many of the actions important in tissue–nervous system communication.

We review the accumulated knowledge about the role of neuropeptides in inflammation as it pertains to tissue repair.

NEUROPEPTIDES OF THE PNS

Neuropeptides constitute one of the largest families of extracellular messengers, having a long phylogenetic history. They can act as neurotransmitters, hormones, and paracrine factors.

In contrast to the classic low molecular weight neurotransmitters, neuropeptides are exclusively produced in the cell soma without local synthesis in nerve endings.5 In most instances, several different neuropeptides are encoded by a single continuous messenger RNA (mRNA), which is translated into 1 large protein precursor (polyprotein). Like other secretory proteins, neuropeptides or their precursors are processed in the endoplasmatic reticulum and then move to the Golgi apparatus to be processed further. They leave the Golgi apparatus within secretory granules and are transferred to terminals by fast axonal transport.6

In the PNS, neuropeptides occur in the perivascular terminals of noradrenergic (sympathetic) and cholinergic nerve fibers, as well as in the free nerve endings of primary afferent neurons.7,8

Numerous neuropeptides are localized in nociceptive afferent nerve fibers, including thinly myelinated Aδ pain fibers and unmyelinated C fibers.9 Antidromic stimulation of these fibers induces the release of the stored neuropeptides, resulting in vasodilation, increased vascular permeability, and edema (neurogenic inflammation).8,10 These effects are not only restricted to the point of the initial stimulus but also can be observed in the surrounding area, indicating that the nerve impulses travel not only centrally but at the collateral branches they also pass antidromically to unstimulated nerve endings to cause release of neuropeptides (axon reflex).8

Two neuropeptides playing an essential role in repair mechanisms are introduced in more detail below. An overview of the most important neuropeptides of the PNS is given in Table 1.

Table 1. 
Important Neuropeptides of the Peripheral Nervous System*
Important Neuropeptides of the Peripheral Nervous System*
Substance P

Substance P (SP), an 11–amino acid peptide, is a member of a family of structurally related peptides called tachykinins, which are characterized by a conserved carboxyl terminal sequence of Phe-X-Gly-Leu-Met-NH2 (in the mammalian forms of these peptides, X represents Phe or Val).18 Mammalian tachykinins are encoded by 2 distinct genes: the preprotachykinin (PPT)-A gene and the PPT-B gene. The PPT-A gene is transcribed to an mRNA precursor that undergoes alternative splicing to give rise to at least 4 forms, of which α– and δ–PPT-A mRNAs encode SP only, whereas β– and γ–PPT-A mRNAs encode both SP and neurokinin (NK) A.19,20 The PPT-B gene, which encodes NKB only, is expressed in the CNS but not in sensory neurons.21

Substance P is present in many areas of the CNS and PNS. In the periphery, SP is located especially in areas of immunologic importance, such as the skin, gastrointestinal tract, and respiratory tract.22 Substance P is synthesized in the dorsal root ganglia, from which it migrates centrally to the dorsal horn of the spinal cord and peripherally to nerve terminals of sensory neurons.23

The tachykinins bring about their actions mainly by activating 3 primary types of receptors: NK1, NK2, and NK3. Each receptor has been defined pharmacologically by the rank order of potencies of tachykinins in bioassays and in radioligand binding studies.24,25 The pharmacological definition of these 3 receptors has been confirmed by the molecular cloning and heterologous expression of the genes encoding each receptor type. All 3 receptors are members of the superfamily of receptors coupled to G-regulatory proteins. Receptor stimulation leads to the activation of phospholipase C and thus to the generation of inositol triphosphate and diacylglycerol and to the release of Ca2+ from internal stores.26,27

Substance P and other tachykinins are able to cause vasodilation because of direct actions on vascular smooth muscle and enhanced production of nitric oxide by the endothelium.28,29 In addition, SP can initiate increased vascular permeability and protein extravasation after tissue injury.22,30,31 Many of the inflammatory actions of SP, such as plasma leakage, are mediated by NK1 receptors, which are rapidly desensitized after exposure to agonists and then gradually become resensitized.11,32 The receptors are internalized after ligand binding, which may be a limiting factor in the inflammatory response.33

Neurokinin 1 tachykinin receptors are expressed by neurons and glia in the CNS, neurons within the mesenteric plexus, smooth muscle cells, acinar cells, endothelial cells, fibroblasts, keratinocytes, and various types of circulating immune cells and inflammation-activated immune cells.26,34,35

Calcitonin Gene-Related Peptide

Calcitonin gene-related peptide (CGRP), a 37–amino acid peptide, is known to exist in 2 forms, α and β. In humans, they differ from each other by 3 amino acid residues.36 α–Calcitonin gene-related peptide is encoded by the calcitonin gene. The expression of either CGRP in the CNS or calcitonin in the thyroid is tissue related. In contrast, β-CGRP is the sole biologically active product of a separate gene.36,37

Binding sites for CGRP with properties consistent with those of receptors are present in central and peripheral tissue. Stimulation of CGRP receptors in various cells and tissue has been shown to increase intracellular cyclic adenosine monophosphate concentration and to activate adenylate cyclase.38,39 Pharmacologically, a division into CGRP1 and CGRP2 receptor subtypes has been proposed.40,41 Recently, 2 proposed CGRP receptors have been cloned.42,43 Conceivably, these findings will promote studies of how the CGRP receptors are to be classified.

Calcitonin gene-related peptide is present mainly in small sensory neurons partially colocalized with SP.8,44 Peripheral secretion of CGRP causes prolonged increases in blood flow.45 Unlike SP, CGRP is not capable of enhancing vascular permeability on its own but potentiates the protein extravasation induced by tachykinins.46,47

EFFECTS OF NEUROPEPTIDES ON THE IMMUNE SYSTEM

It has been recognized since the early part of the century that stimulation of afferent nerve fibers is associated with peripheral inflammatory responses such as vasodilation and plasma extravasation.48 This observation has led to the notion that afferent neurons not only serve a sensory role but also take part in local effector systems that are involved in inflammatory responses to tissue irritation and injury.8 The hypothesis that neuropeptides act as a link between the immune and nervous systems has been supported by the demonstration of (1) a direct peptidergic innervation of primary and secondary lymphoid organs, (2) a close proximity between sensory nerve endings and immune cells, and (3) specific neuropeptide receptors on immune effector cells.4,49 It has become clear that neuropeptides are capable of interacting with virtually all components of the immune system.

A host inflammatory response is necessary to orchestrate tissue repair following injury.3 There is increasing evidence that neuropeptides participate in many of the inflammatory processes that are crucial for normal wound healing.

INFLAMMATORY CELL FUNCTIONS
Polymorphonuclear Leukocytes

Polymorphonuclear leukocytes (PMNs) are the first inflammatory cells to enter the wound space from the intact microcirculation at the edge of the wound, peaking at 24 to 48 hours.2,50 Their main function seems to be the phagocytosis of bacteria and cellular debris to prevent wound infection. The presence of PMNs does not seem to be essential for normal healing of uncontaminated wounds.51

Adhesion to endothelial cells is an initial step in the recruitment of leukocytes to sites of inflammation. Tachykinins are capable of inducing adhesion of PMNs to the endothelium.12,52,53 Neurokinin 1 receptors are present on the endothelial cells of capillaries that become leaky in response to tachykinins.33,54 Stimulation of these receptors causes the rapid mobilization of adhesion molecules for PMNs (eg, P selectin) to the cell surface, presumably by increasing the intracellular Ca2+ concentration.55 Furthermore, neuropeptides have the capacity to affect neutrophil transendothelial migration. Substance P has been shown to exert direct chemotactic actions on PMNs.5658 There are conflicting data concerning the chemotactic capacity of vasoactive intestinal peptide (VIP) and somatostatin. These neuropeptides have been reported to both inhibit and stimulate neutrophil chemotaxis.59,60 In contrast, Carolan and Casale56 were unable to show that VIP and somatostatin had any direct chemotactic effects. These neuropeptides may not directly affect neutrophil chemotaxis, but they do inhibit neutrophil chemotaxis induced via inflammatory mediators.

Monocytes and Macrophages

Monocytes appear at the site of injury within 48 to 96 hours.1 In the wound, they mature into wound macrophages. Initially, macrophages participate in the inflammatory process and débridement; later, they play a pivotal role in regulating the proliferative phase through the release of growth factors and cytokines.50

Several studies have been carried out to elucidate the actions of neuropeptides on monocyte and macrophage functions. Somatostatin and CGRP were found to prevent macrophage activation and to profoundly inhibit the ability of macrophages to produce hydrogen peroxide.61,62 Using allogenic monocytes as stimulator cells, Fox and coworkers63 demonstrated that CGRP has the ability to inhibit the proliferation of peripheral blood mononuclear cells, suggesting that CGRP exerts a direct effect on the monocyte stimulator population. Somatostatin has been shown to have direct inhibitory effects on tumor necrosis factor α (TNF-α), interleukin (IL)-1β, and IL-6 secretion by lipopolysaccharide-activated monocytes.64

Substance P seems to exhibit proinflammatory actions, including activation of arachidonic acid metabolism, chemotaxis, and oxidative burst.65

There are contradictory reports concerning the potential of SP to affect the synthesis and release of cytokines in mononuclear phagocytes. In 1988, Lotz and coworkers66 demonstrated that SP induced the release of IL-1, IL-6, and TNF-α from human monocytes. Similar results were obtained by Rameshwar et al,67 who showed that SP mediated the release of IL-1 and IL-6 by bone marrow mononuclear cells. In contrast, Bahl and Foreman68 demonstrated that SP did not cause either the release or the accumulation of IL-1 from murine peritoneal macrophages. Similarly, Lieb and coworkers69 showed that SP and other neuropeptides were unable to induce the synthesis of IL-1 and IL-6 in human peripheral blood monocytes. These authors69 suggested that undetected levels of endotoxin or lipopolysaccharide in the culture medium may have been primarily responsible for results suggesting an inductive effect of neuropeptides on monocytes and macrophages. However, the cited studies used different cell types and species. Possibly, there are differences in the activation requirements and in the sensitivity of mononuclear cells from different species and different tissues in their response to neuropeptides. Furthermore, the stage of differentiation and maturation of mononuclear phagocytes may be important for the ability of neuropeptides to render the cells sensitive to secondary stimulation, eg, by lipopolysaccharide, and determines to what extent monocyte and macrophage subpopulations contribute to inflammatory responses in vivo. In addition, the physical state of the animal from which the cells are recovered may have a profound affect on macrophage function in vitro. Chancellor-Freeland and coworkers70 were able to show that stress alters macrophage functions and induces the expression of SP binding sites in peritoneal macrophages.

Results of investigations of the biochemical properties of the SP binding sites revealed that monocytes express a specific non–NK receptor for SP, which is functionally coupled to a glutamyl transpeptidase binding protein of the Giclass.71,72 Triggering of this receptor results in stimulation of mitogen-activated protein kinase, mobilization of calcium, and activation of phospholipase D.72

T Lymphocytes

T lymphocytes, the second arm of the cellular immune system, appear in significant numbers in wound sites on about the fifth day.73 They affect wound healing through the release of numerous chemical mediators.1,2

Neuropeptides specifically bind to and modulate the function of lymphocytes. Substance P promotes T-lymphocyte endothelial cell adhesion by preferentially up-regulating lymphocyte function–associated antigen-1 and intercellular adhesion molecule-1 interactions.74 In human T lymphocytes, SP and its C-terminal fragment SP4-11 stimulate [3 H]-thymidine and [3 H]-leucine uptake in the presence and absence of other mitogens.75 Proliferative responses of lymphocytes from spleen, mesenteric lymph nodes, and Peyer patches are enhanced by SP, whereas VIP and somatostatin significantly decrease DNA synthesis.76 Furthermore, CGRP and VIP exert an inhibitory effect on the proliferative response of CD4+ and CD8+ T-murine lymphocytes and induce a rapid and dose-dependent increase in intracellular cyclic adenosine monophosphate.77 Vasoactive intestinal peptide also inhibits the production of IL-2 and IL-4 in murine thymocytes.78 In contrast, SP can act as a cosignal to enhance the expression of specific IL-2 mRNA and IL-2 secretion in T cells.79,80 Substance P also increases synthesis of immunglobulins from mixed lymphocyte cultures, the major effect being on IgA synthesis.76

Mast Cells

Mast cells play an important role in a variety of biological responses. They are critical effector cells in certain forms of IgE-dependent hypersensitivity reactions in which mediators such as histamine, proteoglycans, prostaglandin D2, proteases, and acid hydrolases are released.81 Furthermore, they participate in the modulation of late-phase inflammatory responses, including the augmentation of vascular permeability, fibrin deposition, tissue swelling, and leukocyte infiltration.82 In addition to immediate hypersensitivity mediators such as histamine, mast cells express a number of multifunctional cytokines, including IL-1, IL-3, IL-4, IL-6, and TNF-α.83,84

Mast cells have been suggested as one of the principal effector cells responding to neuropeptides because nerve cell stimulation caused degranulation of mast cells and histamine release.85 Peptidergic nerve fibers and mast cells are associated anatomically in several tissues, and IgE-activated mast cell mediators may amplify an inflammatory response by directly stimulating nerve terminals and initiating an axon reflex.8689 Several neuropeptides (eg, SP, VIP, and neuropeptide Y) can bind to and activate mast cells, resulting in degranulation and histamine release.9092 Furthermore, Ansel and coworkers93 demonstrated that mast cell TNF-α mRNA is selectively up-regulated by SP in a dose-dependent manner. Substance P increased TNF-α secreted from cloned murine mast cells and freshly isolated peritoneal mast cells.93

Mast cells, however, are not just passive responders to neuropeptides. Mast cell secretory products also have been implicated to excite various portions of the nervous system. For example, tryptase, the most abundant secretory granule protein in all subsets of human mast cells, has been shown to activate proteinase-activated receptor (PAR)–2.94 Proteinase-activated receptor–2 belongs to a growing subfamily of G-protein–coupled receptors that are activated by proteolysis. The first PAR described, PAR-1, is a receptor for thrombin.95 Trypsin, mast cell tryptase, and probably other trypsinlike proteases activate PAR-2. Proteases cleave within the extracellular N-termini of PARs, exposing tethered ligand domains that bind to and activate the cleaved receptors. Proteolytic activation of these receptors represents a new concept in receptor signaling mechanisms because the ligand is physically attached to its own receptor. In other words, unlike traditional soluable ligand-to-receptor interactions, PARs are activated by removal of part of the receptor protein.

Proteinase-activated receptors are expressed in many different tissues and cell types. In addition to its central role in coagulation, thrombin has numerous biological functions that are related to inflammation, tissue remodeling, and wound healing. Many of these effects are mediated by PAR-1. Proteinase-activated receptor–2 is also widely distributed. It is expressed in the kidney, pancreas, intestine, stomach, prostate, eye, spleen, heart, and several cell types. The proteases that activate PAR-2 in these tissues and cells and the biological functions of PAR-2 remain to be clarified. As mentioned above, mast cell tryptase represents 1 possibility. It has recently been shown that a large proportion of myenteric neurons express PAR-1 and PAR-2. Thrombin and mast cell tryptase have been shown to excite PAR-1 and PAR-2, respectively, on myenteric neurons.96 Thus, during trauma and inflammation, when prothrombin is activated and mast cells degranulate, thrombin and tryptase may excite myenteric neurons by cleaving and triggering PAR-1 and PAR-2, respectively, perhaps contributing to the neuro-inflammatory response.94 The consequences of this unique observation are not yet clear, but they promise to provide a direct path from mast cells to the sympathetic nervous system. This is critical to wound healing in several ways, not the least being regulation of blood flow in injured tissue.94

REGULATION OF NEUROPEPTIDE ACTIVITY

The diverse actions of neuropeptides in injury and inflammation are under the control of a complex pattern of a variety of chemical mediators that operate together in either antagonistic or synergistic manners (Table 2). The intricate regulatory processes that have to be orchestrated comprise generation, release, and metabolism of neuropeptides, as well as expression of neuropeptide receptors on target cells. The precise spatial and temporal interweaving of the reaction pathways involved is still poorly understood.

Table 2. 
Some of the Naturally Occurring Agents That Affect Neuropeptide Release
Some of the Naturally Occurring Agents That Affect Neuropeptide Release
Enzymatic Catabolism

The biological actions of classic neurotransmitters such as acetylcholine are terminated by enzymatic degradation, re-uptake into nerve endings, or diffusion away from target cells.34 Because no re-uptake mechanisms seem to operate for neuropeptides, enzymatic catabolism represents the major mechanism by which biological activity of neuropeptides is regulated.5,97 Accumulating evidence suggests that neuropeptides are degraded and inactivated mainly by cell surface peptidases.

The best-studied membrane-bound surface peptidase, neutral endopeptidase (EC 3.4.24.11; NEP), also known as enkephalinase or CD10, was identified as the main degrading enzyme for several neuroactive peptides. Neutral endopeptidase, which has been localized on the surface of epithelial, endocrine, and connective tissues; Schwann cells; subpopulations of neurons; immunocytes; and smooth muscle cells and fibroblasts, cleaves 5– to 37–amino acid residue peptides at bonds involving preferentially hydrophobic residues (eg, tachykinins, enkephalins, somatostatin, VIP, and CGRP).13,98101

Neutral endopeptidase activity in the trachea is reduced by up to 50% by infection,102 and NEP is down-regulated by intestinal inflammation.103 Consequently, inhibition of NEP by specific inhibitors (phosphoramidon and thiorphan) has been shown to potentiate tracheal neurogenic inflammation.104 Glucocorticoids are able to stimulate expression of NEP105 and to down-regulate NK receptor,106 and these actions may constitute additional mechanisms by which corticosteroids exert anti-inflammatory effects.

By now, several membrane-bound surface peptidases (eg, dipeptidylaminopeptidase IV; EC 3.4.14.5, aminopeptidase N; and EC 3.4.11.2 [EC signifies enzyme classification]) have been implicated in the metabolism of bioactive peptides in various tissues.94,95 In addition, Jackman and coworkers107 discovered an enzyme, released from human platelets by thrombin, that deamidizes protected peptides, such as SP and other tachykinins.

Peptidases and their cleavage sites may be potential targets for the development of inhibitors as vasoactive drugs or of metabolically stable peptide agonists.

Kinins

Kinins are a group of small peptides formed in blood and biological fluids by the action of proteolytic enzymes (kallikreins) on α2-globulins (kininogens). When an appropriate physiologic or pathophysiological stimulus activates the kallikreins, the nonapeptide bradykinin is formed in the blood from high molecular weight kininogens (plasma pathway). Similarly, the decapeptide kallidin (lysyl bradykinin) is released in tissues by the actions of the kallikreins on low molecular weight kininogens (tissue pathway).108

Kinins are among the naturally occuring agents involved in inflammatory reactions, eg, vasodilation, increase of vascular permeability, and mobilization of blood and tissue cells.108 There is increasing evidence that these kinin effects are, at least in part, mediated by tachykinins released from sensory nerve endings. Blockade of the kinin B2 receptors with a selective antagonist had an inhibitory effect on plasma extravasation in the trachea and nasal mucosa caused by antigen challenge in the guinea pig.109,110 A similar effect was seen when a tachykinin receptor antagonist was used,109 suggesting that kinins and tachykinins may use a common final pathway. Pharmacological and biochemical evidence confirms that kinins released by the anaphylactic reaction and tissue injury are powerful stimulants of sensory nerves and exert at least part of their actions through the release of sensory neuropeptides.111

Endogenous Opioids

The opioid peptide family comprises many distinct peptides with opioid activity. All of these so-called endogenous opiates contain a common sequence of Tyr-Gly-Gly Phe and bind to the same cell-surface receptors as morphine. Triggering of cell-surface opiate receptors activates Giproteins that inhibit adenylate cyclase and thereby cause a decrease in intracellular cyclic adenosine monophosphate levels.112

Opioid antinociception usually has been associated with the activation of opioid systems within the CNS. Recently, however, evidence has accumulated that opioid peptides and receptors in the periphery may play an important role in such phenomena. Endogenous opioids can interact with opiate receptors located on primary afferent neurons in inflamed tissue, resulting in antinociception and decreased release of neuropeptides.113 Furthermore, it seems that these opioid peptides are released from immunocompetent cells (T and B lymphocytes and monocytes and macrophages) infiltrating the inflamed tissue.114116 Consequently, opioids may alter inflammatory processes by inhibiting the release of neuropeptides from sensory nerve terminals. Receptors for opioid peptides are also present on lymphocytes and macrophages, and, thus, opioids are capable of directly modulating immune cell responses such as chemotaxis, proliferation, cytokine production, and cytotoxicity.117120 The observed effects, however, are highly diverse, and further studies have to be undertaken to elucidate the role of opioids in immunoregulation. The effects of opioids in enhancing local blood flow that has been impaired because of vasoconstriction is, however, well known.

Nerve Growth Factor

Nerve growth factor (NGF), a 118-acid polypeptide hormone, is the best-characterized member of the neurotrophin family.121 The role of NGF in the development and maintenance of peripheral sympathetic and nociceptive sensory neurons is well established.122,123 Nerve growth factor binds to the high-affinity receptor tyrosine kinase on neurons, and, after internalization, it is transported retrogradely to the cell body. Through the activation of second messenger signals and changes in transcription factor expression, NGF controls the survival, growth, and phenotype of immature neurons.124128 In addition to this specific neurotrophic action during development, a constant supply of NGF from the periphery may be important for the maintenance of normal phenotype in tyrosine kinase receptor–expressing nociceptive adult sensory neurons.122

A variety of cell types are capable of producing NGF. The main cellular source in normal skin seems to be keratinocytes.14,129 In addition, NGF may be synthesized by immunocompetent cells (lymphocytes, macrophages, and mast cells), fibroblasts, smooth muscle cells, and Schwann cells.130134 Nerve growth factor levels have been found to be elevated in inflammatory exudates, inflamed skin, and the nerves innervating inflamed tissue.135137

Nerve growth factor may directly or indirectly affect tissue immune reactivity. Indirect effects of NGF may result from its cytokinelike actions, including stimulation of the release of inflammatory mediators from lymphocytes138,139 and degranulation of mast cells.140 Furthermore, NGF is capable of directly modulating neuropeptide expression in tyrosine kinase–expressing neurons.132,136 After inflammation, synthesis of SP and CGRP has been shown to be up-regulated in dorsal root ganglion cells by NGF.135,141144 We are just beginning to understand, however, the molecular mechanisms that allow neuropeptide genes to respond to transsynaptic, humoral, and trophic stimuli.145

The elevation of NGF during the inflammatory response is mediated by several different cytokines and growth factors.143 There is strong evidence that 2 cytokines, TNF-α and IL-1β, are necessary intermediates leading to the production of NGF in inflammation.132,136 As mentioned before, SP can stimulate the release of these mediators from inflammatory cells, which, in turn, increases NGF levels in inflamed tissues. Thus, it is conceivable that a positive feedback mechanism exists in which SP induces synthesis of NGF by cytokines, leading to increased production of SP in the dorsal root of ganglion cells (Figure 1).

Figure 1.
Postulated feedback mechanism between substance P (SP) and nerve growth factor (NGF) in inflammation. Activation of nociceptors leads to the release of SP and other peptides. Substance P acts on inflammatory cells in the vicinity of sensory endings to stimulate the release of cytokines. At least 2 of them—interleukin 1 (IL-1) and tumor necrosis factor α (TNF-α)—are responsible for the elevation of NGF in the inflamed tissue. Nerve growth factor is capable of directly activating primary sensory nociceptors by increasing synthesis of SP in dorsal root ganglion cells.

Postulated feedback mechanism between substance P (SP) and nerve growth factor (NGF) in inflammation. Activation of nociceptors leads to the release of SP and other peptides. Substance P acts on inflammatory cells in the vicinity of sensory endings to stimulate the release of cytokines. At least 2 of them—interleukin 1 (IL-1) and tumor necrosis factor α (TNF-α)—are responsible for the elevation of NGF in the inflamed tissue. Nerve growth factor is capable of directly activating primary sensory nociceptors by increasing synthesis of SP in dorsal root ganglion cells.

NEUROPEPTIDE EFFECT ON CELL PROLIFERATION AND TISSUE REPAIR

Injury induces a sequence of neuropeptide responses in wounds. The initial ones involve vasomotor activity through nociceptive influences and the initial events in inflammation. Vasomotor tone lies in the balance, and in this balance, resistance to infection, collagen deposition, and angiogenesis are regulated through the supply of blood and, in particular, oxygen. These influences continue in more subtle ways, for instance, injury induces a reversible sprouting of peptidergic nerve fibers adjacent to the injury site, which increases in proportion to the severity of the injury.146148 The significance of this sprouting has not yet been fully determined. The ability to affect proliferation of various types of target cells34 and to improve healing of experimentally malperfused tissues149,150 suggest a regulatory role of neuropeptides in tissue repair.

Substance P has been shown to act through the NK receptor to stimulate proliferation of cultured keratinocytes.151,152 Vasoactive intestinal peptide can exert both stimulatory and inhibitory effects on the proliferation of keratinocytes.153 There is increasing evidence that neuropeptides play an important role in angiogenesis, including formation of new vessels in inflammation and wound healing. Substance P stimulates DNA synthesis in cultured arterial smooth muscle cells.154 Similarly, CGRP increases both cell number and DNA synthesis in cultured endothelial cells.155 In vivo, SP, CGRP, and VIP have been shown to stimulate angiogenesis.156158 Using an in vitro model, Wiedermann and coworkers159 showed that SP stimulated endothelial cell differentiation into capillarylike structures. Furthermore, SP and CGRP exert potent proliferative stimuli on cultured fibroblasts.154,160,161 These data suggest that neuropeptides released from peripheral nerve endings in association with tissue injury may not only affect vasodilation and the inflammatory response but may also stimulate proliferation of epithelial, vascular, and connective tissue cells (Figure 2).

Figure 2.
Main targets of neuropeptide action in tissue repair.

Main targets of neuropeptide action in tissue repair.

In vivo experiments support the hypothesis that tissue–nervous system interactions promote healing. More than 70 years ago, it was noted that damage to the PNS may alter skin repair, leading to chronic wounds at the affected area.162 Experimentally, denervation of skin was shown to decrease mechanical strength and collagen content of incisional wounds in rabbits.163 Capsaicin-induced depletion of neuropeptides in corneas delayed cornea wound healing.164 Also, rats treated with capsaicin showed greater severity of experimentally induced skin ulcers.165 After a scalding injury of a dog's paw, an increase in SP immunoreactivity was demonstrated, indicative of SP release after trauma.166 In healing ligamentous tissue, more SP- and CGRP-containing nerve fibers were found compared with normal ligaments.167 Similarly, elevated neuropeptide levels were found in healing bones by others.147,168 In wounded rat skin, however, diminished content of SP, CGRP, and somatostatin was reported.169 Whether this decrease in neuropeptide levels represented an increased release from terminals to the wound site, decreased synthesis and transport to terminals, or loss of terminals remained unclear. In a different study,170 when rats were treated with SP, their skin wounds healed more rapidly. Clearly, in wound healing there is an increased tissue–nervous system interaction that may modulate repair mechanisms and thus affect the outcome of healing.

Last, neurogenic mechanisms that govern local blood perfusion and oxygenation may literally govern the rate of healing. The affected processes include angiogenesis, collagen deposition, bacterial killing, and epithelialization.

CONCLUSIONS

Complex mechanisms controlling neuropeptide activity include not only their synthesis and secretion but also their tissue availability and interactions with receptors on target cells and their degradation by peptidases. The rate of tissue reinnervation in healing critically affects availability of neuropeptides.

Recent advances in neuropeptide research, including the cloning of neuropeptide receptors and the introduction of highly potent and specific receptor antagonists, have provided new insights into the pathogenesis of inflammatory diseases and chronic wounds. Clinically, diseases and injuries with impaired tissue–nervous system integrity are known to be associated with poor outcome of healing (eg, patients with diabetes, herpes zoster, or spinal cord injury). The rapidly accumulating body of knowledge on the pathophysiological role of neuropeptides in tissue repair may open new therapeutic options to treat clinical states of impaired tissue–nervous system interaction.

Back to top
Article Information

Reprints: Thomas K. Hunt, MD, Department of Surgery, University of California at San Francisco, 513 Parnassus Ave, HSW-1652, San Francisco, CA 94143-0522.

References
1.
Barbul  A Immune aspects of wound repair. Clin Plast Surg. 1990;17433- 442
2.
Cioffi  WGBurleson  DGPruitt  BA Leukocyte responses to injury. Arch Surg. 1993;1281260- 1267Article
3.
Guirao  XLowry  SF Biologic control of injury and inflammation: much more than too little or too late. World J Surg. 1996;20437- 446Article
4.
Payan  DG Neuropeptides and inflammation: the role of substance P. Annu Rev Med. 1989;40341- 352Article
5.
Hökfelt  TJohansson  OLjungdahl  ALundberg  JMSchultzberg  M Peptidergic neurones. Nature. 1980;284515- 521Article
6.
Jessell  TMKelly  DDKandel  ERedSchwartz  JHedJessell  TMed Pain and analgesia. Principles of Neural Science New York, NY Elsevier Science Inc1991;385- 399
7.
Felten  DLFelten  SYBellinger  DL  et al.  Noradrenergic sympathetic neural interactions with the immune system: structure and function. Immunol Rev. 1987;100225- 258Article
8.
Holzer  P Local effector functions of capsaicin-sensitive sensory nerve endings: involvement of tachykinins, calcitonin gene-related peptide and other neuropeptides. Neuroscience. 1988;24739- 768Article
9.
Hökfelt  TedSchaible  HGedSchmidt  RFed Neuropeptides, Nociception and Pain.  Weinheim, Germany Chapman & Hall1994;
10.
Kenins  P Identification of the unmyelinated sensory nerves which evoke plasma extravasation in response to antidromic stimulation. Neurosci Lett. 1981;25137- 141Article
11.
Sakamoto  TBarnes  PJChung  KF Effect of CP-96,345, a non-peptide receptor antagonist, against substance P-induced, bradykinin-induced and allergen-induced airway microvascular leakage and bronchoconstriction in the guinea pig. Eur J Pharmacol. 1993;23131- 38Article
12.
Peretti  MAhluwalia  AFlower  RJManzini  S Endogenous tachykinins play a pivotal role in IL-1-induced neutrophil accumulation: involvement of NK-1 receptors. Immunology. 1993;8073- 77
13.
Mentlein  RRoos  T Proteases involved in the metabolism of angiotensin II, bradykinin, calcitonin gene-related peptide (CGRP), and neuropeptide Y by vascular smooth muscle cells. Peptides. 1996;17709- 720Article
14.
Di Marco  EMarchisio  PCBondanza  SFranzi  ATCancedda  RDe Luca  M Growth-regulated synthesis and secretion of biologically active nerve growth factor by human keratinocytes. J Biol Chem. 1991;26621718- 21722
15.
Pernow  J Co-release and functional interactions of neuropeptide Y and noradrenaline in peripheral sympathetic vascular control. Acta Physiol Scand Suppl. 1988;5681- 56
16.
Saria  A Neuropeptide. Hautarzt. 1992;43745- 752
17.
Trantor  IRMesser  HHBirner  R The effects of neuropeptides (calcitonin gene-related peptide and substance P) on cultured human pulp cells. J Dent Res. 1995;741066- 1071Article
18.
Maggi  CAPatacchini  RRovero  PGiachetti  A Tachykinin receptors and tachykinin receptor antagonists. J Auton Pharmacol. 1993;1323- 93Article
19.
Krause  JEChirgwin  JMCarter  MSXu  ZSHershey  AD Three rat preprotachykinin mRNAs encode the neuropeptides substance P and neurokinin A. Proc Natl Acad Sci U S A. 1987;84881- 885Article
20.
Mägert  HJHeitland  ARose  MForssmann  WG Nucleotide sequence of the rabbit r-preprotachykinin I cDNA. Biochem Biophys Res Commun. 1993;195128- 131Article
21.
Lundberg  JM Pharmacology of cotransmission in the autonomic nervous system: intergrative aspects on amines, neuropeptides, adenosine triphosphate, amino acids and nitric oxide. Pharmacol Rev. 1996;48113- 178
22.
Pernow  B Substance P. Pharmacol Rev. 1983;3585- 141
23.
Barber  RVaughn  JSlemmon  JSalvaterra  PRoberts  ELeeman  S The origin, distribution and synaptic relationship of substance P axons in rat spinal cord. J Comp Neurol. 1979;184331- 351Article
24.
Maggio  JE Tachykinins. Annu Rev Neurosci. 1988;1113- 28Article
25.
Quirion  RDam  TV Multiple neurokinin receptors: recent developments. Regul Peptides. 1988;2218- 25Article
26.
Krause  JETakeda  YHershey  AD Structure, functions, and mechanisms of substance P receptor action. J Invest Dermatol. 1992;98(6 suppl)2S- 7SArticle
27.
MacDonald  SGDumas  JJBoyd  ND Chemical cross-linking of the substance P (NK-1) receptor to the α subunits of the G proteins Gq and G11. Biochemistry. 1996;352909- 2916Article
28.
Bolton  TClapp  L Endothelial-dependent relaxant actions of carbachol and substance P in arterial smooth muscle. Br J Pharmacol. 1986;87713- 715Article
29.
Hökfelt  TKellerth  JNilsson  GPernow  B Substance P: localization in the central nervous system and in some primary sensory neurones. Science. 1975;190889- 890Article
30.
Devillier  PRegoli  DAsseraf  ADescours  BMarsac  JRenoux  M Histamine release and local responses of rat and human skin to substance P and other mammalian tachykinins. Pharmacology. 1986;32340- 347Article
31.
Lundberg  JMSaria  ABrodin  ERosell  SFolkers  K A substance P antagonist inhibits vagally induced increase in vascular permeability and bronchial smooth muscle contraction in the guinea pig. Proc Natl Acad Sci U S A. 1983;801120- 1124Article
32.
Baluk  PBowden  JJLefevre  PLMcDonald  DM Increased expression of substance P (NK1) receptors on airway blood vessels of rats with Mycoplasma pulmonis infection. Am J Respir Crit Care Med. 1994;151A719- A729
33.
Bowden  JJGarland  AMBaluk  P  et al.  Direct observation of substance P-induced internalization of neurokinin 1 (NK1) receptors at sites of inflammation. Proc Natl Acad Sci U S A. 1994;918964- 8968Article
34.
Ansel  JCKaynard  AHArmstrong  CAOlerud  JBunnett  NPayan  D Skin–nervous system interactions. J Invest Dermatol. 1996;106198- 204Article
35.
Bowden  JJBaluk  PLefevre  PMVigna  SRMcDonald  DM Substance P (NK1) receptor immunoreactivity on endothelial cells of the rat tracheal mucosa. Am J Physiol. 1996;270 ((3 pt 1)) L404- L414
36.
Emerson  RBGeppetti  PedHolzer  Ped Posttranscriptional regulation of calcitonin-gene-related peptide (CGRP) mRNA. Neurogenic Inflammation Boca Raton, Fla CRC Press Inc1996;15- 20
37.
Emerson  RBHedjran  FYeakley  JMGuise  JWRosenfeld  MG Alternative production of calcitonin and CGRP mRNA is regulated at the calcitonin-specific splice acceptor. Nature. 1989;34176- 80Article
38.
Van Valen  FPiechot  GJurgens  H Calcitonin gene-related peptide (CGRP) receptors are linked to cyclic adenosine monophosphate production in SK-N-MC human neuroblastoma cells. Neurosci Lett. 1990;119195- 198Article
39.
Yamaguchi  AChiba  TYamatani  T  et al.  Calcitonin gene-related peptide stimulates adenylate cyclase activation via a guanine nucleotide-dependent process in rat liver plasma membranes. Endocrinology. 1988;1232591- 2596Article
40.
Hall  JMBrain  SDGeppetti  PedHolzer  Ped Pharmacology of calcitonin gene-related peptide. Neurogenic Inflammation Boca Raton, Fla CRC Press Inc1996;101- 106
41.
Poyner  DR Pharmacology of receptors for calcitonin gene-related peptide and amylin. Trends Pharmacol Sci. 1995;16424- 428Article
42.
Kapas  SClark  AJ Identification of an orphan receptor gene as a type 1 calcitonin gene-related peptide receptor. Biochem Biophys Res Commun. 1995;217832- 838Article
43.
Luebke  AEDahl  GPRoos  BADickerson  IM Identification of a protein that confers calcitonin gene-related peptide responsiveness to oocytes by using a cystic fibrosis transmembrane conductance regulator assay. Proc Natl Acad Sci U S A. 1996;933455- 3460Article
44.
Navarro  XVerdu  EWendelschafer-Crabb  GKennedy  WR Innervation of cutaneous structures in the mouse hind paw: a confocal microscopy immunohistochemical study. J Neurosci Res. 1995;41111- 120Article
45.
Brain  SDWilliams  TJTippins  JRMorris  HRMacIntyre  I Calcitonin gene-related peptide is a potent vasodilatator. Nature. 1985;31354- 56Article
46.
Gamse  RSaria  A Potentiation of tachykinin-induced plasma protein extravasation by calcitonin-gene-related peptide. Eur J Pharmacol. 1985;11461- 66Article
47.
Louis  SMJamieson  ARussell  NJWDockray  GJ The role of substance P and calcitonin gene-related peptide in neurogenic plasma extravasation and vasodilatation in the rat. Neuroscience. 1989;32581- 586Article
48.
Bruce  NA über die Beziehung der sensiblen Nervenendigungen zum Entzündungsvorgang. Arch Exp Path Pharmak. 1910;63424- 433Article
49.
Felten  DLFelten  SYCarlson  SLOlschowka  JALivnat  S Noradrenergic and peptidergic innervation of lymphoid tissue. J Immunol. 1985;135755s- 765s
50.
Knighton  DRFiegel  VD Regulation of cutaneous wound healing by growth factors and the microenvironment. Invest Radiol. 1991;26604- 611Article
51.
Simpson  DWRoss  R The neutrophilic leukocyte in wound repair: a study with anti-neutrophil serum. J Clin Invest. 1972;512009- 2023Article
52.
Thureson-Klein  AHedqvist  PÖhlen  ARaud  JLindbom  L Leukotriene B4, platelet-activating factor and substance P as mediators of acute inflammation. Pathol Immunopathol Res. 1987;6190- 206Article
53.
Zimmerman  BJAnderson  DCGranger  DN Neuropeptides promote neutrophil adherence to endothelial cell monolayers. Am J Physiol. 1992;263 ((5 pt 1)) G678- G682
54.
Greeno  EWMantyh  PVercellotti  GMMoldow  CF Functional neurokinin 1-receptors for substance P are expressed by human vascular endothelium. J Exp Med. 1993;1771269- 1276Article
55.
Baluk  PBertrand  CGeppetti  PMcDonald  DMNadel  JA NK1 receptors mediate leukocyte adhesion in neurogenic inflammation in the rat trachea. Am J Physiol. 1995;268 ((2 pt 1)) L263- L269
56.
Carolan  EJCasale  TB Effects of neuropeptides on neutrophil migration through noncellular and endothelial barriers. J Allergy Clin Immunol. 1993;92589- 598Article
57.
Marasco  WAShowell  HJBecker  EL Substance P binds to the formylpeptide receptor on the rabbit neutrophil. Biochem Biophys Res Commun. 1981;991065- 1072Article
58.
Roch-Arveiller  MRegoli  DChanaud  B  et al.  Tachykinins: effects on motility and metabolism of rat polymorphonuclear leukocytes. Pharmacology. 1986;33266- 273Article
59.
Bodesson  LNorolind  KLiden  SGafvelin  GTheodorsson  EMutt  V Dual effects of vasoactive intestinal peptide (VIP) on leucocyte migration. Acta Physiol Scand. 1991;141477- 481Article
60.
Rabier  MDamon  MChanez  P Neutrophil chemotactic activity of PAF, histamine and neuromediators in bronchial asthma. J Lipid Mediat. 1991;4265- 275
61.
Niedermuhlbichler  MWiedermann  C Suppression of superoxide release from human monocytes by somatostatin-related peptides. Regul Peptides. 1992;4139- 47Article
62.
Nong  Y-HTitus  RGRibeiro  JMCRemold  HG Peptides encoded by the calcitonin gene inhibit macrophage function. J Immunol. 1989;14345- 49
63.
Fox  FEKubin  MCassin  M  et al.  Calcitonin gene-related peptide inhibits proliferation and antigen presentation by human peripheral blood mononuclear cells: effects on B7, interleukin 10, and interleukin 12. J Invest Dermatol. 1997;10843- 48Article
64.
Peluso  GPetillo  OMelone  MABMazzarella  GRanieri  MTajana  GF Modulation of cytokine production in activated human monocytes by somatostatin. Neuropeptides. 1996;30443- 451Article
65.
Hartung  H-PWolters  KToyka  KV Substance P: binding properties and studies on cellular responses in guinea pig macrophages. J Immunol. 1986;1363856- 3863
66.
Lotz  MVaughan  JHCarson  DA Effects of neuropetides on production of inflammatory cytokines by human monocytes. Science. 1988;2411218- 1220Article
67.
Rameshwar  PGanea  DGascon  P Induction of IL-3 and granulocyte-macrophage colony-stimulating factor by substance P in bone marrow cells is partially mediated through the release of IL-1 and IL-6. J Immunol. 1994;1524044- 4054
68.
Bahl  AKForeman  JC Stimulation and release of interleukin-1 from peritoneal macrophages of the mouse. Agents Actions. 1994;42154- 158Article
69.
Lieb  KFiebich  BLBusse-Grawitz  MHüll  MBerger  MBauer  J Effects of substance P and selected other neuropeptides on the synthesis of interleukin-1β and interleukin-6 in human monocytes: a re-examination. J Neuroimmunol. 1996;6777- 81
70.
Chancellor-Freeland  CZhu  GFKage  RBeller  DILeeman  SEBlack  PH Substance P and stress-induced changes in makrophages. Ann N Y Acad Sci. 1994;771472- 484Article
71.
Jeurissen  FKavelaars  AKorstjens  M  et al.  Monocytes express a non-neurokinin substance P receptor that is functionally coupled to MAP kinase. J Immunol. 1994;1522987- 2994
72.
Kavelaars  ABroeke  DJeurissen  F  et al.  Activation of human monocytes via a non-neurokinin substance P receptor that is coupled to Gi protein, calcium, phospholipase D, MAP kinase, and IL-6 production. J Immunol. 1994;1533691- 3699
73.
Fishel  RSBarbul  ABeschorner  WEWasserkrug  HLEfron  G Lymphocyte participation in wound healing: morphologic assessment using monoclonal antibodies. Ann Surg. 1987;20625- 29Article
74.
Vishwanath  RMukherjee  R Substance P promotes lymphocyte endothelial cell adhesion preferentially via LFA 1/ICAM 1 interactions. J Neuroimmunol. 1996;71163- 171Article
75.
Payan  DGGoetzl  EJ Modulation of lymphocyte function by sensory neuropeptides. J Immunol. 1985;135(2 suppl)783S- 786S
76.
Stanisz  AMBefus  DBienenstock  J Differential effects of vasoactive intestinal peptide, substance P, and somatostatin on immunglobulin synthesis and proliferation by lymphocytes from Peyerís patches, mesenteric lymph nodes, and spleen. J Immunol. 1986;136152- 156
77.
Teresi  SBoudard  FBastide  M Effect of calcitonin gene-related peptide and vasoactive intestinal peptide on murine CD4 and CD8 T cell proliferation. Immunol Lett. 1996;50105- 113Article
78.
Xin  ZTang  HGanea  D Vasoactive intestinal peptide inhibits interleukin (IL)-2 and IL-4 production in murine thymocytes activated via the TCR/CD3 complex. J Neuroimmunol. 1994;5459- 68Article
79.
Calvo  C-FChavanel  GSenik  A Substance P enhances IL-2 expression in activated human T cells. J Immunol. 1992;1483498- 3504
80.
Nio  DAMoylan  RNRoche  JK Modulation of T lymphocyte function by neuropeptides. J Immunol. 1993;1505281- 5288
81.
Czarnetzki  BM Mechanisms and mediators in urticaria. Semin Dermatol. 1987;6272- 276
82.
Wershil  BKMekori  YAMurakami  TGalli  SJ 125I-fibrin deposition in IgE-dependent immediate hypersensitivity reactions in mouse skin: demonstration of the role of mast cells using mast cell-deficient mice locally reconstituted with cultured mast cells. J Immunol. 1987;1392605- 2614
83.
Burd  PRRogers  HWGordon  JR  et al.  Interleukin 3-dependent and -independent mast cells stimulated with IgE and antigen express multiple cytokines. J Exp Med. 1989;170245- 257Article
84.
Plaut  MPierce  JHWatson  CJHanley-Hyde  JNordon  RPPaul  WE Mast cell lines produce lymphokines in response to cross linkage of Fc∊RI or calcium ionophores. Nature. 1989;33964- 67Article
85.
Goetzl  EJChernov  TRenold  FPayan  DG Neuropeptide regulation of the expression of immediate hypersensitivity. J Immunol. 1985;135(2 suppl)802S- 805S
86.
Muller  SWeihe  E Interrelation of peptidergic innervation with mast cells and ED1-positive cells in rat thymus. Brain Behav Immun. 1991;555- 72Article
87.
Newson  BDahlstrom  AEnerback  LAhlman  H Suggestive evidence for a direct innervation of mucosal mast cells: an electron microscopic study. Neuroscience. 1983;10565- 570Article
88.
Ratzlaff  RECavanaugh  VJMiller  GWOakes  SG Evidence of a neurogenic component during IgE-mediated inflammation in mouse skin. J Neuroimmunol. 1992;4189- 96Article
89.
Stead  RHTomioka  MQuinoez  GSimon  GTFelten  SYBienenstock  J Intestinal mucosal mast cells in normal and nematode-infected rat intestines are in intimate contact with peptidergic nerves. Proc Natl Acad Sci U S A. 1987;842975- 2979Article
90.
Cross  LJMBeck-Sickinger  AGBienert  M  et al.  Structure activity studies of mast cell activation and hypotension induced by neuropeptide Y (NPY), centrally truncated and C-terminal NPY analogues. Br J Pharmacol. 1996;117325- 332Article
91.
Ebertz  JMHirschman  CAKettlekamp  NSUno  HHanifin  JM Substance P induced histamine release in human cutaneous mast cells. J Invest Dermatol. 1987;88682- 685Article
92.
Stewart  MJEmery  DLMcClure  SJBendixen  T The effects of four neuropeptides on the degranulation of mucosal mast cells from sheep. Immunol Cell Biol. 1996;74255- 257Article
93.
Ansel  JCBrown  JRPayan  DGBrown  MA Substance P selectively activates TNF-α gene expression in murine mast cells. J Immunol. 1993;1504478- 4485
94.
Corvera  CUDery  OMcConalogue  KM  et al.  Mast cell tryptase regulates colonic myocytes through proteinase-activated receptor-2. J Clin Invest. 1997;1001383- 1393Article
95.
Coughlin  SR Protease-activated receptors start a family [comment]. Proc Natl Acad Sci U S A. 1994;919200- 9202Article
96.
Corvera  UCMcConalogue  KGamp  PCaughey  GHBunnett  NW Proteinase activated receptors (PARS): myenteric neurons: activators thrombinmast cell tryptase [abstract G4653]. Dig Wk Gasteroenterol. 1998;114 ((pt 2)) A1137
97.
Bunnett  NW The role of neuropeptides in regulating airway function: postsecretory metabolism of peptides. Am Rev Respir Dis. 1987;136(6 suppl)S27- S34Article
98.
Bathon  JMProud  DMizutani  SWard  PE Cultured human synovial fibroblasts rapidly metabolize kinins and neuropeptides. J Clin Invest. 1992;90981- 991Article
99.
Kenny  AJHooper  NMHenrickson  JHed Peptidases involved in the metabolism of bioactive peptides. Degradation of Bioactive Substances: Physiology and Pathophysiology Boca Raton, Fla CRC Press Inc1991;47- 49
100.
Russell  JSChi  HLantry  LEStephens  REWard  PE Substance P and neurokinin A metabolism by cultured human skeletal muscle myocytes and fibroblasts. Peptides. 1996;171397- 1403Article
101.
Shipp  MAStefano  GBDíAdamio  L  et al.  Downregulation of enkephalin-mediated inflammatory responses by CD10/neutral endopeptidase 24.11. Nature. 1990;347394- 396Article
102.
Borson  DBrokaw  JSekizawa  KMcDonald  DNadel  J Neutral endopeptidase and neurogenic inflammation in rats with respiratory infections. J Appl Physiol. 1989;662653- 2658
103.
Hwang  LLeichter  ROkamoto  APayan  DCollins  SBunnett  N Downregulation of neutral endopeptidase (EC 3.4.24.11) in the inflamed rat intestine. Am J Physiol. 1993;264G735- G743
104.
Umeno  ENadel  JHuang  H-TMcDonald  D Inhibition of neutral endopeptidase potentiates neurogenic inflammation in the rat trachea. J Appl Physiol. 1989;662647- 2652
105.
Borson  DGruenert  D Glucocorticoids induce neutral endopeptidase in transformed human tracheal epithelial cells. Am J Physiol. 1990;260L83- L89
106.
Ihara  HNakanishi  S Selective inhibition of expression of the substance P receptor mRNA in pancreatic acinar AR42J cells by glucocorticoids. J Biol Chem. 1990;26522441- 22445
107.
Jackman  HLTan  FTamei  H  et al.  A peptidase in human platelets that deamidates tachykinins. J Biol Chem. 1990;26511265- 11272
108.
Nielsen  OHRask-Madsen  J Mediators of inflammation in chronic bowel disease. Scand J Gastroenterol Suppl. 1996;216149- 159Article
109.
Bertrand  CNadel  JAYamawaki  IGeppetti  P Role of kinins in the vascular extravasation evoked by antigen and mediated by tachykinins in guinea pig trachea. J Immunol. 1993;1514902- 4907
110.
Ricciardolo  FLMNadel  JABertrand  CYamawaki  IChan  BGeppetti  P Tachykinins and kinins in antigen-evoked plasma extravasation in guinea pig nasal mucosa. Eur J Pharmacol. 1994;261127- 132Article
111.
Geppetti  PBertrand  CRicciardolo  FMLNadel  JA New aspects on the role of kinins in neurogenic inflammation. Can J Physiol Pharmacol. 1995;73843- 847Article
112.
Dudel  JedMenzel  RedSchmidt  RFed Neurowissenschaften: Vom Molekül zur Kognition.  Berlin, Germany Springer-Verlag1996;
113.
Przewlocki  RHassan  AHSLason  WEpplen  CHerz  AStein  C Gene expression and localization of opioid peptides in immune cells in inflamed tissue: functional role in antinociception. Neuroscience. 1992;48491- 500Article
114.
Prystowsky  MJAngeletti  RH Preproenkephalin mRNA in T-cells, macrophages, and mast cells. J Neurosci Res. 1987;1882- 87Article
115.
Stein  CHassan  AHSPrzewlocki  RGramsch  CPeter  KHerz  A Opioids from immunocytes interact with receptors on sensory nerves to inhibit nociception in inflammation. Proc Natl Acad Sci U S A. 1990;875953- 5959
116.
Zurawski  GBenedik  MKamb  BJAbrams  JSZurawski  SMLee  FD Activation of mouse T-helper cells induces abundant preproenkephalin mRNA synthesis. Science. 1986;232772- 774Article
117.
Gilmore  WWeiner  LP β-endorphin enhances interleukin-2 (IL-2) production in murine lymphocytes. J Neuroimmunol. 1988;18125- 138Article
118.
Stefano  GB Role of opioid neuropeptides in immunoregulation. Prog Neurobiol. 1989;33149- 159Article
119.
Sibinga  NESGoldstein  A Opioid peptides and opioid receptors in cells of the immune system. Annu Rev Immunol. 1988;6219- 249Article
120.
Van den Berg  PDobber  RRalal  SRamlal  SRozing  JNagelkerken  L Role of opioid peptides in the regulation of cytokine production by murine CD4+ T cells. Cell Immunol. 1994;154109- 122Article
121.
Levi-Montalcini  R The nerve growth factor: thirty-five years later. EMBO J. 1987;61145- 1154
122.
Lindsay  RMHarmar  AJ Nerve growth factor regulates expression of neuropeptide genes in adult sensory neurones. Nature. 1989;337362- 364Article
123.
Rich  KMYip  HKOsbourne  PASchmidt  RFJohnson  EM Role of nerve growth factor in the adult dorsal root ganglia neuron and its responses to injury. J Comp Neurol. 1984;230110- 118Article
124.
Chao  MV Neurotrophin receptors: a window into neural differentiation. Neuron. 1992;9583- 593Article
125.
Glass  DJYancopopoulus  GD The neurotrophins and their receptors. Trends Cell Biol. 1993;3262- 268Article
126.
Kaplan  DHempstead  BMartin-Zanca  DChao  MParada  L The trk prooncogene product: a signal transducing receptor for nerve growth factor. Science. 1991;252554- 558Article
127.
Rich  KMLuszczynski  JROsbourne  PAJohnson  EM Nerve growth factor protects adult sensory neurones from cell death and atrophy caused by nerve injury. J Neurocytol. 1987;16261- 268Article
128.
Stockel  KSchwab  MThoenen  H Specificity of retrograde transport of nerve growth factor (NGF) in sensory neurones: a biochemical and morphological study. Brain Res. 1975;891- 14Article
129.
Tron  VACoughlin  MDJang  DEStanisz  JSauder  DN Expression and modulation of nerve growth factor in murine keratinocytes (PAM 212). J Clin Invest. 1990;851085- 1089Article
130.
Brown  MCPerry  VHLunn  ERGordon  SHeumann  R Macrophage dependence of peripheral sensory nerve regeneration: possible involvement of nerve growth factor. Neuron. 1991;6359- 370Article
131.
Leon  ABuriani  ADal Toso  RFabris  MRomanello  SAloe  L Mast cells synthesize, store, and release nerve growth factor. Proc Natl Acad Sci U S A. 1994;913739- 3743Article
132.
McMahon  SB NGF as a mediator of inflammatory pain. Philos Trans R Soc Lond B Biol Sci. 1996;351431- 440Article
133.
Santambrogio  LBenedetti  MChao  MV  et al.  Nerve growth factor production by lymphocytes. Immunology. 1994;1534888- 4898
134.
Thoenen  HBandtlow  CHeumann  RLindholm  MRohrer  H Nerve growth factor: cellular localization and regulation of synthesis. Trends Neurosci. 1988;17432- 438
135.
Donnerer  JSchuligoi  RStein  C Increased content and transport of substance P and calcitonin gene-related peptide in sensory nerves innervating inflamed tissue: evidence for a regulatory function of nerve growth factor in vivo. Neuroscience. 1992;49693- 698Article
136.
Safieh-Garabedian  BPoole  SAllchorne  AWinter  JWoolf  CJ Contribution of interleukin-1β to the inflammation-induced increase in nerve growth factor levels and inflammatory hyperalgesia. Br J Pharmacol. 1995;1151265- 1275Article
137.
Weskamp  GOtten  U An enzyme-linked immunoassay for nerve growth factor: a tool for studying regulatory mechanisms involved in NGF production in brain and peripheral tissue. J Neurochem. 1987;481779- 1786Article
138.
Bischoff  SCDahinden  CA Effect of nerve growth factor on the release of inflammatory mediators by mature human basophils. Blood. 1992;792662- 2669
139.
Horigome  EPryor  JCBullock  EDJohnson  EM Mediator release from mast cells by nerve growth factor: neutrophin specificity and receptor mediation. J Biol Chem. 1993;26814881- 14887
140.
Pearce  FLThompson  HL Some characteristics of histamine secretion from rat peritoneal mast cells stimulated with nerve growth factor. J Physiol. 1986;372379- 393
141.
Amann  RSirinathsingji  DJDonnerer  JLiebmann  ISchuligoi  R Stimulation by nerve growth factor of neuropeptide synthesis in the adult rat in vivo: bilateral response to unilateral intraplantar injections. Neurosci Lett. 1996;203171- 174Article
142.
Kashiba  HUeda  YSenba  E Coexpression of preprotachykinin-A, α-calcitonin gene-related peptide, somatostatin, and neurotrophin receptor family messenger RNAs in rat dorsal root ganglion neurons. Neuroscience. 1996;70179- 189Article
143.
Leslie  TAEmson  PCDowd  PMWoolf  CJ Nerve growth factor contributes to the up-regulation of growth-associated protein 43 and preprotachykinin A messenger RNAs in primary sensory neurons following peripheral inflammation. Neuroscience. 1995;67753- 761Article
144.
Verge  VMKRichardson  PMWiesenfeld-Hallin  ZHökfelt  T Differential influence of nerve growth factor on neuropeptide expression in vivo: a novel role in peptide suppression in adult sensory neurons. J Neurosci. 1995;152081- 2096
145.
MacArthur  LEiden  L Neuropeptide genes: targets of activity-dependent signal transduction. Peptides. 1996;17721- 728Article
146.
Aldskogius  HHermanson  AJonsson  C-E Reinnervation of experimental superficial wounds in rats. Plast Reconstr Surg. 1986;79595- 599Article
147.
Aoki  MTamai  KSaotome  K Substance P- and calcitonin gene-related peptide-immunofluorescent nerves in the repair of experimental bone defects. Int Orthop. 1994;18317- 324Article
148.
Kishimoto  S The regeneration of substance P-containing nerve fibers in the process of burn wound healing in the guinea pig skin. J Invest Dermatol. 1984;83219- 223Article
149.
Kjartansson  JDalsgaard  C Calcitonin gene-related peptide increases survival of a musculocutaneous critical flap in the rat. Eur J Pharmacol. 1987;142355- 358Article
150.
Kjartansson  JDalsgaard  CJonsson  C Decreased survival of experimental critical flaps after sensory denervation with capsaicin. Plast Reconstr Surg. 1987;79218- 220Article
151.
McGovern  UBJones  KTSharpe  GR Intracellular calcium as a second messenger following growth stimulation of human keratinocytes. Br J Dermatol. 1995;132892- 896Article
152.
Tanaka  TDanno  KIkai  KImamura  S Effects of substance P and substance K on the growth of cultured keratinocytes. J Invest Dermatol. 1988;90399- 401Article
153.
Wollina  UBonnekoh  BKlinger  RWetzker  RMahrle  G Vasoactive intestinal peptide (VIP) acting as a growth factor for human keratinocytes. Neuroendocrinol Lett. 1992;1421- 32
154.
Nilsson  Jvon Euler  AMDalsgaard  C-J Stimulation of connective cell growth by substance P and substance K. Nature. 1985;31561- 63Article
155.
Haegerstrand  ADalsgaard  C-JJonzon  BLarsson  ONilsson  J Calcitonin gene-related peptide stimulates proliferation of human endothelial cells. Proc Natl Acad Sci U S A. 1990;873299- 3303Article
156.
Fan  T-PDHu  D-E Modulation of angiogenesis by inflammatory polypeptides. Int J Radiat Biol. 1991;6071- 76Article
157.
Fan  T-PDHu  D-EGuard  SGresham  GAWatling  KJ Stimulation of angiogenesis by substance P and interleukin-1 in the rat and its inhibition by NK1 or interleukin-1 receptor antagonists. Br J Pharmacol. 1993;11043- 49Article
158.
Ziche  MMorbidelli  LPacini  MGeppetti  PAlessandri  GMaggi  CA Substance P stimulates neovascularization in vivo and proliferation of cultured endothelial cells. Microvasc Res. 1990;40264- 278Article
159.
Wiedermann  CJAuer  BSitte  BReinisch  NSchratzberger  PKähler  CM Induction of endothelial cell differentiation into capillary-like structures by substance P. Eur J Pharmacol. 1996;298335- 338Article
160.
Kähler  CMHerold  MReinisch  NWiedermann  CJ Interaction of substance P with epidermal growth factor and fibroblast growth factor in cyclooxygenase-dependent proliferation of human skin fibroblasts. J Cell Physiol. 1996;166601- 608Article
161.
Ziche  MMorbidelli  LPacini  MDolara  PMaggi  CA NK1-receptors mediate the proliferative response of human fibroblasts to tachykinins. Br J Pharmacol. 1990;10011- 14Article
162.
Lewis  TMarvin  H Observations relating to vasodilatation arising from antidromic impulses, to herpes zoster and trophic effects. Hearts. 1927;1427- 46
163.
Lusthaus  SShoshan  SBenmeir  PLivoff  AAshur  HVardy  D Effect of denervation on incision wound scars in rabbits. J Geriatr Dermatol. 1993;111- 14
164.
Gallar  JPozo  MRebello  IBelmonte  C Effects of capsaicin on corneal wound healing. Invest Ophthalmol Vis Sci. 1990;311968- 1974
165.
Maggi  CABorsini  FSanticioli  P  et al.  Cutaneous lesions in capsaicin-pretreated rats: a trophic role of capsaicin-sensitive afferents? Naunyn Schmiedebergs Arch Pharmacol. 1987;336538- 543
166.
Jonsson  C-EBrodin  EDalsgaard  C-JHaegerstrand  A Release of substance P-like immunoreactivity in dog paw lymph after scalding injury. Acta Physiol Scand. 1986;12621- 24Article
167.
Grönblad  MKorkala  OKonttinen  YKuokkanen  HLiesi  P Immunoreactive neuropeptides in nerves in ligamentous tissue: an experimental neuroimmunohistochemical study. Clin Orthopaed Relat Res. 1991;265291- 296
168.
Rusanen  MKorkala  OGrönblad  MPartanen  SNederström  A Evolution of substance P immunofluorescent nerves in callus tissue during fracture healing. J Trauma. 1987;271340- 1343Article
169.
Senapati  AAnand  PMcGregor  GPGhatei  MAThompson  RPHBloom  SR Depletion of neuropeptides during wound healing in rat skin. Neurosci Lett. 1986;71101- 105Article
170.
Spevak  SShekhter  AHilse  HOehme  PSoloveva  A Aspects of wound healing in spontaneous hypertensive rats: the effect of morphine, substance P and its fragments SP1-4. Biull Eksp Biol Med. 1989;107729- 743Article
×