BASIC SCIENCE FOR SURGEONS Neuropeptides Mediators of and Tissue Repair?

Michael Scha¨ffer, MD; Thomas Beiter, MS; Horst Dieter Becker, MD; Thomas K. Hunt, MD

uccessful repair of injured tissues requires diverse interactions between cells, biochemi- cal mediators, and the cellular microenvironment.1-3 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 recentlyS being recognized. Neurogenic stimuli profoundly affect cel- In contrast to the classic low molecu- lular events that are involved in inflam- lar weight neurotransmitters, neuropep- mation, proliferation, and matrix, as well tides are exclusively produced in the cell as cytokine and growth factor synthesis. soma without local synthesis in nerve end- Immune cells regulated by neuropep- ings.5 In most instances, several different tides include lymphocyte subsets, macro- neuropeptides are encoded by a single con- phages, and mast cells. In addition, neu- tinuous messenger RNA (mRNA), which ropeptides may affect the proliferative and is translated into 1 large protein precur- synthetic activity of epithelial, vascular, sor (polyprotein). Like other secretory pro- and connective tissue cells. Further- teins, neuropeptides or their precursors are more, a close interaction between the ner- processed in the endoplasmatic reticu- vous and the immune systems has be- lum and then move to the Golgi appara- come obvious.4 tus to be processed further. They leave the The peripheral nervous system Golgi apparatus within secretory gran- (PNS), acting through neuropeptides, ules and are transferred to terminals by fast not only relays sensory information to axonal transport.6 the central nervous system (CNS) but In the PNS, neuropeptides occur in also plays an effector role in the inflam- the perivascular terminals of noradrener- matory, proliferative, and reparative pro- gic (sympathetic) and cholinergic nerve fi- cesses after injury. These effects range bers, as well as in the free nerve endings from growth factor and cytokine re- of primary afferent neurons.7,8 sponses to control of local blood flow. Numerous neuropeptides are local- Neuropeptides mediate many of the ac- ized in nociceptive afferent nerve fibers, in- tions important in tissue–nervous sys- cluding thinly myelinated A␦ pain fibers and tem communication. unmyelinated C fibers.9 Antidromic stimu- We review the accumulated knowl- lation of these fibers induces the release edge about the role of neuropeptides in in- of the stored neuropeptides, resulting in flammation as it pertains to tissue repair. vasodilation, increased vascular perme- ability, and edema (neurogenic inflamma- NEUROPEPTIDES OF THE PNS tion).8,10 These effects are not only re- stricted to the point of the initial stimulus Neuropeptides constitute one of the larg- but also can be observed in the surround- est families of extracellular messengers, ing area, indicating that the nerve im- having a long phylogenetic history. They pulses travel not only centrally but at the can act as neurotransmitters, hormones, collateral branches they also pass antidromi- and paracrine factors. cally to unstimulated nerve endings to cause release of neuropeptides (axon reflex).8 From the Departments of Surgery, Eberhard-Karls-Universita¨t, Tu¨bingen, Germany Two neuropeptides playing an essen- (Drs Scha¨ffer and Becker and Mr Beiter), and University of California at San tial role in repair mechanisms are intro- Francisco (Dr Hunt). duced in more detail below. An overview

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 encoded by the calcitonin gene. The Table 1. Important Neuropeptides of the Peripheral Nervous System* expression of either CGRP in the CNS or calcitonin in the thyroid is Neuropeptide Type of Nerve Fibers Function (Peripheral) tissue related. In contrast, ␤-CGRP Primary afferent Enhanced vascular is the sole biologically active prod- permeability uct of a separate gene.36,37 Calcitonin gene–related peptide Primary afferent Vasodilation Binding sites for CGRP with Vasoactive intestinal peptide Cholinergic, primary afferent Vasodilation Somatostatin Noradrenergic, primary afferent Inhibition of endocrine and properties consistent with those of re- paracrine secretion ceptors are present in central and pe- Neuropeptide Y Noradrenergic Vasoconstriction ripheral tissue. Stimulation of CGRP receptors in various cells and tissue *Data from Sakamoto et al,11 Peretti et al,12 Mentlein and Roos,13 Di Marco et al,14 Pernow,15 Saria,16 17 has been shown to increase intracel- and Trantor et al. lular cyclic adenosine monophos- phate concentration and to activate of the most important neuropep- molecular cloning and heterolo- adenylate cyclase.38,39 Pharmacologi- tides of the PNS is given in Table 1. gous expression of the genes encod- cally, a division into CGRP1 and ing each receptor type. All 3 recep- CGRP2 receptor subtypes has been Substance P tors are members of the superfamily proposed.40,41 Recently, 2 proposed of receptors coupled to G-regula- CGRP receptors have been cloned.42,43 Substance P (SP), an 11–amino acid tory proteins. Receptor stimulation Conceivably, these findings will pro- peptide, is a member of a family of leads to the activation of phospho- mote studies of how the CGRP re- structurally related peptides called lipase C and thus to the generation ceptors are to be classified. tachykinins, which are character- of inositol triphosphate and diacyl- Calcitonin gene-related pep- ized by a conserved carboxyl termi- glycerol and to the release of Ca2+ tide is present mainly in small sen- nal sequence of Phe-X-Gly-Leu-Met- from internal stores.26,27 sory neurons partially colocalized 8,44 NH2 (in the mammalian forms of Substance P and other tachy- with SP. Peripheral secretion of these peptides, X represents Phe or kinins are able to cause vasodila- CGRP causes prolonged increases in Val).18 Mammalian tachykinins are tion because of direct actions on blood flow.45 Unlike SP, CGRP is not encoded by 2 distinct genes: the pre- vascular smooth muscle and en- capable of enhancing vascular per- protachykinin (PPT)-A gene and the hanced production of meability on its own but potenti- PPT-B gene. The PPT-A gene is tran- by the endothelium.28,29 In addi- ates the protein extravasation in- scribed to an mRNA precursor that tion, SP can initiate increased vas- duced by tachykinins.46,47 undergoes alternative splicing to give cular permeability and protein ex- rise to at least 4 forms, of which ␣– travasation after tissue injury.22,30,31 EFFECTS OF NEUROPEPTIDES and ␦–PPT-A mRNAs encode SP Many of the inflammatory actions ON THE IMMUNE SYSTEM only, whereas ␤– and ␥–PPT-A of SP, such as plasma leakage, are mRNAs encode both SP and neuro- mediated by NK1 receptors, which It has been recognized since the early kinin (NK) A.19,20 The PPT-B gene, are rapidly desensitized after ex- part of the century that stimulation which encodes NKB only, is ex- posure to agonists and then gradu- of afferent nerve fibers is associ- pressed in the CNS but not in sensory ally become resensitized.11,32 The ated with peripheral inflammatory neurons.21 receptors are internalized after responses such as vasodilation and Substance P is present in many ligand binding, which may be a plasma extravasation.48 This obser- areas of the CNS and PNS. In the pe- limiting factor in the inflammatory vation has led to the notion that af- riphery, SP is located especially in ar- response.33 ferent neurons not only serve a sen- eas of immunologic importance, such Neurokinin 1 tachykinin re- sory role but also take part in local as the skin, gastrointestinal tract, and ceptors are expressed by neurons effector systems that are involved in respiratory tract.22 Substance P is syn- and glia in the CNS, neurons within inflammatory responses to tissue ir- thesized in the dorsal root ganglia, the mesenteric plexus, smooth ritation and injury.8 The hypoth- from which it migrates centrally to muscle cells, acinar cells, endothe- esis that neuropeptides act as a link the dorsal horn of the spinal cord and lial cells, fibroblasts, keratinocytes, between the immune and nervous peripherally to nerve terminals of sen- and various types of circulating im- systems has been supported by the sory neurons.23 mune cells and inflammation- demonstration of (1) a direct pep- The tachykinins bring about activated immune cells.26,34,35 tidergic innervation of primary and their actions mainly by activating 3 secondary lymphoid organs, (2) a primary types of receptors: NK1, Calcitonin Gene-Related Peptide close proximity between sensory NK2, and NK3. Each receptor has nerve endings and immune cells, and been defined pharmacologically by Calcitonin gene-related peptide (3) specific neuropeptide receptors the rank order of potencies of tachy- (CGRP), a 37–amino acid peptide, on immune effector cells.4,49 It has kinins in bioassays and in radioli- is known to exist in 2 forms, ␣ and become clear that neuropeptides are gand binding studies.24,25 The phar- ␤. In humans, they differ from each capable of interacting with virtu- macological definition of these 3 other by 3 amino acid residues.36 ␣– ally all components of the immune receptors has been confirmed by the Calcitonin gene-related peptide is system.

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 A host inflammatory response wound, they mature into wound ent cell types and species. Possibly, is necessary to orchestrate tissue re- macrophages. Initially, macro- there are differences in the activa- pair following injury.3 There is in- phages participate in the inflamma- tion requirements and in the sensi- creasing evidence that neuropep- tory process and de´bridement; later, tivity of mononuclear cells from dif- tides participate in many of the they play a pivotal role in regulat- ferent species and different tissues inflammatory processes that are cru- ing the proliferative phase through in their response to neuropeptides. cial for normal wound healing. the release of growth factors and Furthermore, the stage of differen- cytokines.50 tiation and maturation of mono- INFLAMMATORY CELL Several studies have been carried nuclear phagocytes may be impor- FUNCTIONS out to elucidate the actions of neuro- tant for the ability of neuropeptides peptides on monocyte and macro- to render the cells sensitive to sec- Polymorphonuclear Leukocytes phage functions. Somatostatin and ondary stimulation, eg, by lipopoly- CGRP were found to prevent macro- saccharide, and determines to what Polymorphonuclear leukocytes phage activation and to profoundly in- extent monocyte and macrophage (PMNs) are the first inflammatory hibittheabilityofmacrophagestopro- subpopulations contribute to in- cells to enter the wound space from duce hydrogen peroxide.61,62 Using flammatory responses in vivo. In ad- the intact microcirculation at the edge allogenicmonocytesasstimulatorcells, dition, the physical state of the ani- of the wound, peaking at 24 to 48 Fox and coworkers63 demonstrated mal from which the cells are hours.2,50 Their main function seems that CGRP has the ability to inhibit the recovered may have a profound af- to be the phagocytosis of bacteria and proliferationofperipheralbloodmono- fect on macrophage function in vitro. cellular debris to prevent wound in- nuclearcells,suggestingthatCGRPex- Chancellor-Freeland and cowork- fection. The presence of PMNs does erts a direct effect on the monocyte ers70 were able to show that stress al- not seem to be essential for normal stimulator population. Somatostatin ters macrophage functions and in- healing of uncontaminated wounds.51 has been shown to have direct inhibi- duces the expression of SP binding Adhesion to endothelial cells is tory effects on sites in peritoneal macrophages. an initial step in the recruitment of ␣ (TNF-␣), interleukin (IL)-1␤, and Results of investigations of the leukocytes to sites of inflammation. IL-6 secretion by - biochemical properties of the SP Tachykinins are capable of induc- activated monocytes.64 binding sites revealed that mono- ing adhesion of PMNs to the endo- Substance P seems to exhibit cytes express a specific non–NK re- thelium.12,52,53 Neurokinin 1 recep- proinflammatory actions, includ- ceptor for SP, which is functionally tors are present on the endothelial ing activation of arachidonic acid coupled to a glutamyl transpepti- cells of capillaries that become leaky metabolism, chemotaxis, and oxi- dase binding protein of the Gi in response to tachykinins.33,54 Stimu- dative burst.65 class.71,72 Triggering of this recep- lation of these receptors causes the There are contradictory re- tor results in stimulation of mitogen- rapid mobilization of adhesion mol- ports concerning the potential of SP activated protein kinase, mobiliza- ecules for PMNs (eg, P selectin) to the to affect the synthesis and release of tion of calcium, and activation of cell surface, presumably by increas- cytokines in mononuclear phago- phospholipase D.72 ing the intracellular Ca2+ concentra- cytes. In 1988, Lotz and cowork- tion.55 Furthermore, neuropeptides ers66 demonstrated that SP induced T Lymphocytes have the capacity to affect neu- the release of IL-1, IL-6, and TNF-␣ trophil transendothelial migration. from human monocytes. Similar re- T lymphocytes, the second arm of Substance P has been shown to ex- sults were obtained by Rameshwar the cellular immune system, ap- ert direct chemotactic actions on et al,67 who showed that SP medi- pear in significant numbers in PMNs.56-58 There are conflicting data ated the release of IL-1 and IL-6 by wound sites on about the fifth day.73 concerning the chemotactic capac- bone marrow mononuclear cells. In They affect wound healing through ity of vasoactive intestinal peptide contrast, Bahl and Foreman68 dem- the release of numerous chemical (VIP) and somatostatin. These neu- onstrated that SP did not cause ei- mediators.1,2 ropeptides have been reported to both ther the release or the accumula- Neuropeptides specifically bind inhibit and stimulate neutrophil che- tion of IL-1 from murine peritoneal to and modulate the function of lym- motaxis.59,60 In contrast, Carolan and macrophages. Similarly, Lieb and co- phocytes. Substance P promotes T- Casale56 were unable to show that VIP workers69 showed that SP and other lymphocyte endothelial cell adhe- and somatostatin had any direct che- neuropeptides were unable to in- sion by preferentially up-regulating motactic effects. These neuropep- duce the synthesis of IL-1 and IL-6 lymphocyte function–associated an- tides may not directly affect neutro- in human peripheral blood mono- tigen-1 and intercellular adhesion phil chemotaxis, but they do inhibit cytes. These authors69 suggested that molecule-1 interactions.74 In hu- neutrophil chemotaxis induced via undetected levels of endotoxin or li- man T lymphocytes, SP and its C- inflammatory mediators. popolysaccharide in the culture me- terminal fragment SP4-11 stimulate dium may have been primarily re- [3H]-thymidine and [3H]-leucine up- Monocytes and Macrophages sponsible for results suggesting an take in the presence and absence of inductive effect of neuropeptides on other mitogens.75 Proliferative re- Monocytes appear at the site of in- monocytes and macrophages. How- sponses of lymphocytes from spleen, jury within 48 to 96 hours.1 In the ever, the cited studies used differ- mesenteric lymph nodes, and Peyer

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 patches are enhanced by SP, whereas VIP and somatostatin significantly Table 2. Some of the Naturally Occurring Agents That Affect Neuropeptide Release decrease DNA synthesis.76 Further- more, CGRP and VIP exert an in- Agent Source Effect on Primary Afferent Fibers hibitory effect on the proliferative re- Potassium Damaged cells Activation sponse of CD4+ and CD8+ T- Platelets Activation Bradykinin Plasma kininogen Activation murine lymphocytes and induce a Histamine Mast cells Activation rapid and dose-dependent increase Nerve growth factor Keratinocytes, fibroblasts Activation in intracellular cyclic adenosine Prostaglandins Arachidonic acid–damaged cells Sensitization monophosphate.77 Vasoactive intes- Opioids Inflammatory cells Deactivation tinal peptide also inhibits the pro- duction of IL-2 and IL-4 in murine *Modified from Jessell and Kelly.6 thymocytes.78 In contrast, SP can act as a cosignal to enhance the expres- TNF-␣ mRNA is selectively up- ney, pancreas, intestine, stomach, sion of specific IL-2 mRNA and IL-2 regulated by SP in a dose-depen- prostate, eye, spleen, heart, and sev- secretion in T cells.79,80 Substance P dent manner. Substance P in- eral cell types. The proteases that ac- also increases synthesis of immun- creased TNF-␣ secreted from cloned tivate PAR-2 in these tissues and cells globulins from mixed lymphocyte murine mast cells and freshly iso- and the biological functions of PAR-2 cultures, the major effect being on lated peritoneal mast cells.93 remain to be clarified. As men- IgA synthesis.76 Mast cells, however, are not just tioned above, mast cell tryptase rep- passive responders to neuropep- resents 1 possibility. It has recently Mast Cells tides. Mast cell secretory products been shown that a large proportion also have been implicated to excite of myenteric neurons express PAR-1 Mast cells play an important role in various portions of the nervous sys- and PAR-2. Thrombin and mast cell a variety of biological responses. tem. For example, tryptase, the most tryptase have been shown to excite They are critical effector cells in abundant secretory granule pro- PAR-1 and PAR-2, respectively, on certain forms of IgE-dependent tein in all subsets of human mast myenteric neurons.96 Thus, during hypersensitivity reactions in which cells, has been shown to activate pro- trauma and inflammation, when pro- mediators such as histamine, pro- teinase-activated receptor (PAR)– thrombin is activated and mast cells teoglycans, prostaglandin D2, pro- 2.94 Proteinase-activated recep- degranulate, thrombin and trypt- teases, and acid hydrolases are tor–2 belongs to a growing subfamily ase may excite myenteric neurons by released.81 Furthermore, they par- of G-protein–coupled receptors that cleaving and triggering PAR-1 and ticipate in the modulation of late- are activated by proteolysis. The PAR-2, respectively, perhaps con- phase inflammatory responses, first PAR described, PAR-1, is a re- tributing to the neuro-inflamma- including the augmentation of vas- ceptor for thrombin.95 Trypsin, tory response.94 The consequences cular permeability, fibrin deposi- mast cell tryptase, and probably of this unique observation are not yet tion, tissue swelling, and leukocyte other trypsinlike proteases activate clear, but they promise to provide a infiltration.82 In addition to imme- PAR-2. Proteases cleave within the direct path from mast cells to the diate hypersensitivity mediators extracellular N-termini of PARs, sympathetic nervous system. This is such as histamine, mast cells exposing tethered ligand domains critical to wound healing in several express a number of multifunc- that bind to and activate the ways, not the least being regulation tional cytokines, including IL-1, cleaved receptors. Proteolytic acti- of blood flow in injured tissue.94 IL-3, IL-4, IL-6, and TNF-␣.83,84 vation of these receptors repre- Mast cells have been sug- sents a new concept in receptor REGULATION OF gested as one of the principal effec- signaling mechanisms because the NEUROPEPTIDE ACTIVITY tor cells responding to neuropep- ligand is physically attached to its tides because nerve cell stimulation own receptor. In other words, un- The diverse actions of neuropep- caused degranulation of mast cells like traditional soluable ligand-to- tides in injury and inflammation and histamine release.85 Peptider- receptor interactions, PARs are ac- are under the control of a complex gic nerve fibers and mast cells are as- tivated by removal of part of the pattern of a variety of chemical me- sociated anatomically in several tis- receptor protein. diators that operate together in ei- sues, and IgE-activated mast cell Proteinase-activated receptors ther antagonistic or synergistic mediators may amplify an inflam- are expressed in many different tis- manners (Table 2). The intricate matory response by directly stimu- sues and cell types. In addition to its regulatory processes that have to lating nerve terminals and initiat- central role in coagulation, throm- be orchestrated comprise genera- ing an axon reflex.86-89 Several bin has numerous biological func- tion, release, and metabolism of neuropeptides (eg, SP, VIP, and neu- tions that are related to inflamma- neuropeptides, as well as expres- ropeptide Y) can bind to and acti- tion, tissue remodeling, and wound sion of neuropeptide receptors on vate mast cells, resulting in degranu- healing. Many of these effects are target cells. The precise spatial and lation and histamine release.90-92 mediated by PAR-1. Proteinase- temporal interweaving of the reac- Furthermore, Ansel and cowork- activated receptor–2 is also widely tion pathways involved is still ers93 demonstrated that mast cell distributed. It is expressed in the kid- poorly understood.

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 Enzymatic Catabolism deamidizes protected peptides, such surface receptors as morphine. Trig- as SP and other tachykinins. gering of cell-surface opiate recep- The biological actions of classic neu- Peptidases and their cleavage tors activates Gi proteins that inhibit rotransmitters such as acetylcho- sites may be potential targets for the adenylate cyclase and thereby cause line are terminated by enzymatic development of inhibitors as vaso- a decrease in intracellular cyclic aden- degradation, re-uptake into nerve active drugs or of metabolically osine monophosphate levels.112 endings, or diffusion away from tar- stable peptide agonists. Opioid antinociception usu- get cells.34 Because no re-uptake ally has been associated with the ac- mechanisms seem to operate for Kinins tivation of opioid systems within the neuropeptides, enzymatic catabo- CNS. Recently, however, evidence lism represents the major mecha- Kinins are a group of small pep- has accumulated that opioid pep- nism by which biological activity of tides formed in blood and biologi- tides and receptors in the periph- neuropeptides is regulated.5,97 Ac- cal fluids by the action of proteo- ery may play an important role in cumulating evidence suggests that lytic enzymes (kallikreins) on ␣2- such phenomena. Endogenous opi- neuropeptides are degraded and globulins (kininogens). When an oids can interact with opiate recep- inactivated mainly by cell surface appropriate physiologic or patho- tors located on primary afferent neu- peptidases. physiological stimulus activates the rons in inflamed tissue, resulting The best-studied membrane- kallikreins, the nonapeptide brady- in antinociception and decreased bound surface peptidase, neutral en- kinin is formed in the blood from release of neuropeptides.113 Further- dopeptidase (EC 3.4.24.11; NEP), high molecular weight kininogens more, it seems that these opioid pep- also known as enkephalinase or (plasma pathway). Similarly, the de- tides are released from immunocom- CD10, was identified as the main de- capeptide kallidin (lysyl bradyki- petent cells (T and B lymphocytes grading enzyme for several neuro- nin) is released in tissues by the ac- and monocytes and macrophages) active peptides. Neutral endopepti- tions of the kallikreins on low infiltrating the inflamed tissue.114-116 dase, which has been localized on the molecular weight kininogens (tis- Consequently, opioids may alter in- surface of epithelial, endocrine, and sue pathway).108 flammatory processes by inhibiting connective tissues; Schwann cells; Kinins are among the natu- the release of neuropeptides from subpopulations of neurons; immu- rally occuring agents involved in sensory nerve terminals. Receptors nocytes; and smooth muscle cells inflammatory reactions, eg, vasodi- for opioid peptides are also present and fibroblasts, cleaves 5– to 37– lation, increase of vascular perme- on lymphocytes and macrophages, amino acid residue peptides at bonds ability, and mobilization of blood and, thus, opioids are capable of di- involving preferentially hydropho- and tissue cells.108 There is increas- rectly modulating immune cell re- bic residues (eg, tachykinins, en- ing evidence that these kinin ef- sponses such as chemotaxis, prolif- kephalins, somatostatin, VIP, and fects are, at least in part, mediated eration, cytokine production, and CGRP).13,98-101 by tachykinins released from sen- cytotoxicity.117-120 The observed ef- Neutral endopeptidase activ- sory nerve endings. Blockade of the fects, however, are highly diverse, ity in the trachea is reduced by up kinin B2 receptors with a selective an- and further studies have to be un- to 50% by infection,102 and NEP is tagonist had an inhibitory effect on dertaken to elucidate the role of opi- down-regulated by intestinal inflam- plasma extravasation in the trachea oids in immunoregulation. The ef- mation.103 Consequently, inhibi- and nasal mucosa caused by anti- fects of opioids in enhancing local tion of NEP by specific inhibitors gen challenge in the guinea pig.109,110 blood flow that has been impaired (phosphoramidon and thiorphan) A similar effect was seen when a because of vasoconstriction is, how- has been shown to potentiate tra- tachykinin receptor antagonist was ever, well known. cheal neurogenic inflammation.104 used,109 suggesting that kinins and Glucocorticoids are able to stimu- tachykinins may use a common fi- Nerve Growth Factor late expression of NEP105 and to nal pathway. Pharmacological and down-regulate NK receptor,106 and biochemical evidence confirms that Nerve growth factor (NGF), a 118- these actions may constitute addi- kinins released by the anaphylactic acid polypeptide hormone, is the tional mechanisms by which corti- reaction and tissue injury are pow- best-characterized member of the costeroids exert anti-inflammatory erful stimulants of sensory nerves neurotrophin family.121 The role of effects. and exert at least part of their ac- NGF in the development and main- By now, several membrane- tions through the release of sen- tenance of peripheral sympathetic bound surface peptidases (eg, di- sory neuropeptides.111 and nociceptive sensory neurons is peptidylaminopeptidase IV; EC well established.122,123 Nerve growth 3.4.14.5, aminopeptidase N; and EC Endogenous Opioids factor binds to the high-affinity re- 3.4.11.2 [EC signifies enzyme clas- ceptor tyrosine kinase on neurons, sification]) have been implicated in The opioid peptide family com- and, after internalization, it is trans- the metabolism of bioactive pep- prises many distinct peptides with ported retrogradely to the cell body. tides in various tissues.94,95 In addi- opioid activity. All of these so- Through the activation of second tion, Jackman and coworkers107 dis- called endogenous opiates contain a messenger signals and changes covered an enzyme, released from common sequence of Tyr-Gly-Gly in transcription factor expression, human platelets by thrombin, that Phe and bind to the same cell- NGF controls the survival, growth,

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 Neuropeptides Dorsal Root Ganglion

Blood Flow Inflammatory Cellular and Vascular Response Proliferation Permeability Spinal Cord Figure 2. Main targets of neuropeptide action in tissue repair.

Mast Cell sistance to infection, collagen depo- sition, and angiogenesis are regu- lated through the supply of blood NGF and, in particular, oxygen. These in- IL-1 and TNF-α fluences continue in more subtle SP ways, for instance, injury induces a Fibroblast reversible sprouting of peptidergic nerve fibers adjacent to the injury Macrophage site, which increases in proportion to the severity of the injury.146-148 The Figure 1. Postulated feedback mechanism between substance P (SP) and nerve growth factor (NGF) in significance of this sprouting has not inflammation. Activation of nociceptors leads to the release of SP and other peptides. Substance P acts yet been fully determined. The abil- 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 ␣ (TNF-␣)—are responsible for the elevation of ity to affect proliferation of various NGF in the inflamed tissue. Nerve growth factor is capable of directly activating primary sensory types of target cells34 and to im- nociceptors by increasing synthesis of SP in dorsal root ganglion cells. prove healing of experimentally malperfused tissues149,150 suggest a and phenotype of immature neu- root ganglion cells by NGF.135,141-144 regulatory role of neuropeptides in rons.124-128 In addition to this spe- We are just beginning to under- tissue repair. cific neurotrophic action during de- stand, however, the molecular Substance P has been shown to velopment, a constant supply of mechanisms that allow neuropep- act through the NK receptor to NGF from the periphery may be im- tide genes to respond to transsynap- stimulate proliferation of cultured portant for the maintenance of nor- tic, humoral, and trophic stimuli.145 keratinocytes.151,152 Vasoactive in- mal phenotype in tyrosine kinase re- The elevation of NGF during testinal peptide can exert both stimu- ceptor–expressing nociceptive adult the inflammatory response is medi- latory and inhibitory effects on the sensory neurons.122 ated by several different cytokines proliferation of keratinocytes.153 A variety of cell types are ca- and growth factors.143 There is strong There is increasing evidence that pable of producing NGF. The main evidence that 2 cytokines, TNF-␣ neuropeptides play an important role cellular source in normal skin seems and IL-1␤, are necessary intermedi- in angiogenesis, including forma- to be keratinocytes.14,129 In addi- ates leading to the production of tion of new vessels in inflamma- tion, NGF may be synthesized by im- NGF in inflammation.132,136 As men- tion and wound healing. Substance munocompetent cells (lympho- tioned before, SP can stimulate the P stimulates DNA synthesis in cul- cytes, macrophages, and mast cells), release of these mediators from in- tured arterial smooth muscle cells.154 fibroblasts, smooth muscle cells, and flammatory cells, which, in turn, in- Similarly, CGRP increases both cell Schwann cells.130-134 Nerve growth creases NGF levels in inflamed tis- number and DNA synthesis in cul- factor levels have been found to be sues. Thus, it is conceivable that a tured endothelial cells.155 In vivo, SP, elevated in inflammatory exudates, positive feedback mechanism ex- CGRP, and VIP have been shown to inflamed skin, and the nerves inner- ists in which SP induces synthesis stimulate angiogenesis.156-158 Using vating inflamed tissue.135-137 of NGF by cytokines, leading to in- an in vitro model, Wiedermann and Nerve growth factor may di- creased production of SP in the dor- coworkers159 showed that SP stimu- rectly or indirectly affect tissue im- sal root of ganglion cells (Figure 1). lated endothelial cell differentia- mune reactivity. Indirect effects of tion into capillarylike structures. NGF may result from its cytokine- NEUROPEPTIDE EFFECT Furthermore, SP and CGRP exert like actions, including stimulation of ON CELL PROLIFERATION potent proliferative stimuli on cul- the release of inflammatory media- AND TISSUE REPAIR tured fibroblasts.154,160,161 These data tors from lymphocytes138,139 and de- suggest that neuropeptides re- granulation of mast cells.140 Further- Injury induces a sequence of neu- leased from peripheral nerve end- more, NGF is capable of directly ropeptide responses in wounds. The ings in association with tissue in- modulating neuropeptide expres- initial ones involve vasomotor ac- jury may not only affect vasodilation sion in tyrosine kinase–expressing tivity through nociceptive influ- and the inflammatory response but neurons.132,136 After inflammation, ences and the initial events in in- may also stimulate proliferation of synthesis of SP and CGRP has been flammation. Vasomotor tone lies in epithelial, vascular, and connective shown to be up-regulated in dorsal the balance, and in this balance, re- tissue cells (Figure 2).

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 In vivo experiments support the Recent advances in neuropep- 12. Peretti M, Ahluwalia A, Flower RJ, Manzini S. En- tide research, including the clon- dogenous tachykinins play a pivotal role in IL- hypothesis that tissue–nervous sys- 1-induced neutrophil accumulation: involve- tem interactions promote healing. ing of neuropeptide receptors and ment of NK-1 receptors. Immunology. 1993;80: More than 70 years ago, it was noted the introduction of highly potent and 73-77. that damage to the PNS may alter specific receptor antagonists, have 13. Mentlein R, Roos T. Proteases involved in the skin repair, leading to chronic provided new insights into the metabolism of angiotensin II, bradykinin, calci- 162 pathogenesis of inflammatory dis- tonin gene-related peptide (CGRP), and neuro- wounds at the affected area. Ex- peptide Y by vascular smooth muscle cells. Pep- perimentally, denervation of skin eases and chronic wounds. Clini- tides. 1996;17:709-720. was shown to decrease mechanical cally, diseases and injuries with 14. Di Marco E, Marchisio PC, Bondanza S, Franzi strength and collagen content of in- impaired tissue–nervous system in- AT, Cancedda R, De Luca M. Growth-re- cisional wounds in rabbits.163 Cap- tegrity are known to be associated gulated synthesis and secretion of biologi- with poor outcome of healing (eg, cally active nerve growth factor by human saicin-induced depletion of neu- keratinocytes. J Biol Chem. 1991;266:21718- ropeptides in corneas delayed cornea patients with diabetes, herpes 21722. wound healing.164 Also, rats treated zoster, or spinal cord injury). The 15. Pernow J. Co-release and functional interac- with showed greater se- rapidly accumulating body of knowl- tions of neuropeptide Y and noradrenaline in pe- verity of experimentally induced edge on the pathophysiological role ripheral sympathetic vascular control. Acta 165 of neuropeptides in tissue repair may Physiol Scand Suppl. 1988;568:1-56. skin ulcers. After a scalding in- 16. Saria A. Neuropeptide. Hautarzt. 1992;43:745-752. jury of a dog’s paw, an increase in open new therapeutic options to 17. Trantor IR, Messer HH, Birner R. The effects of SP immunoreactivity was demon- treat clinical states of impaired tis- neuropeptides (calcitonin gene-related peptide strated, indicative of SP release af- sue–nervous system interaction. and substance P) on cultured human pulp cells. ter trauma.166 In healing ligamen- J Dent Res. 1995;74:1066-1071. 18. Maggi CA, Patacchini R, Rovero P, Giachetti A. tous tissue, more SP- and CGRP- Reprints: Thomas K. 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