Salivary gland derived peptides as a new class of anti-inflammatory agents: review of preclinical pharmacology of C-terminal peptides of SMR1 protein
© Mathison et al; licensee BioMed Central Ltd. 2010
Received: 19 August 2010
Accepted: 28 September 2010
Published: 28 September 2010
The limitations of steroidal and non steroidal anti-inflammatory drugs have prompted investigation into other biologically based therapeutics, and identification of immune selective anti-inflammatory agents of salivary origin. The traditional view of salivary glands as accessory digestive structures is changing as their importance as sources of systemically active immunoregulatory and anti-inflammatory factors is recognized. Salivary gland involvement in maintenance of whole body homeostasis is regulated by the nervous system and thus constitutes a "neuroendocrine axis". The potent anti-inflammatory activities, both in vivo and in vitro, of the tripeptide Phe-Glu-Gly (FEG) are reviewed. FEG is a carboxyl terminal peptide of the prohormone SMR1 identified in the rat submandibular salivary gland, The D-isomeric form (feG) mimics the activity of its L-isomer FEG. Macropharmacologically, feG attenuates the cardiovascular and inflammatory effects of endotoxemia and anaphylaxis, by inhibition of hypotension, leukocyte migration, vascular leak, and disruption of pulmonary function and intestinal motility. Mechanistically, feG affects activated inflammatory cells, especially neutrophils, by regulating integrins and inhibiting intracellular production of reactive oxygen species. Pharmacodynamically, feG is active at low doses (100 μg/kg) and has a long (9-12 hour) biological half life. As a therapeutic agent, feG shows promise in diseases characterized by over exuberant inflammatory responses such as systemic inflammatory response syndrome and other acute inflammatory diseases. Arthritis, sepsis, acute pancreatitis, asthma, acute respiratory inflammation, inflammatory bowel disease, and equine laminitis are potential targets for this promising therapeutic peptide. The term "Immune Selective Anti-Inflammatory Derivatives" (ImSAIDs) is proposed for salivary-derived peptides to distinguish this class of agents from corticosteroids and nonsteroidal anti-inflammatory drugs.
Saliva, best known for its digestive and protective properties in the maintenance of the health and integrity of the oral and gastric mucosa , is becoming increasingly recognized for its important role in regulating whole body homeostasis . Although over the past half century many bioactive proteins and peptides have been identified in saliva [3, 4], salivary glands are still viewed primarily as accessory digestive structures that provide lubrication and digestive enzymes. However, it is now becoming clear that salivary endocrine factors play an important role in the modulation of systemic immune and inflammatory reactions. Classically, the salivary glands are generally considered as exocrine glands that dispense their protein and fluid externally into a lumen or a duct. However, investigations dating from 60 years ago suggested an unorthodox view that salivary and other exocrine glands, such as the pancreas, are capable of endocrine secretion, dispensing their secretions internally, i.e. directly into the blood stream. It has been suggested that these glands be called "duacrine" glands .
Salivary glands produce various immunoregulatory [6, 7] and anti-inflammatory  agents. The importance of the salivary gland in maintaining homeostasis has been clarified in recent decades by demonstration of neuroendocrine interactions between the nervous, endocrine, and immune systems . The salivary glands, as well as the thymus and cervical lymph nodes, are innervated by noradrenergic fibers from the sympathetic trunk [10, 11], which were shown to modulate lymphocyte function within lymph nodes and thymus [12, 13].
This paper reviews the published pharmacologic and immunopharmacologic evidence that salivary gland derived peptides, with particular emphasis on the D-isomeric tripeptide feG, deserve consideration as potentially therapeutically useful anti-inflammatory agents.
The Neuroendocrine Axis
Bioactivity of Salivary Gland Extracts: SGP-T
On the basis of the findings that salivary glands participate in modulating systemic inflammatory responses, bioactive factors were sought in saliva. Extracts of submandibular glands were subjected to molecular weight cut-off filtration and tested for bioactivity. A novel seven amino acid peptide with sequence Thr-Asp-Ile-Phe-Glu-Gly (TDIFEGG) was isolated, named submandibular peptide-T (SGP-T), and shown to express anti-allergic and anti-endotoxin activities[16, 17]. SGP-T was identified as the carboxyl terminal of SMR1, a 146-amino acid, multipotent prohormone product of the VCSa1 (variable coding sequence A1) gene , which is also identified as RATSMR1A, Smr1, SMR1 protein and VCS-alpha 1. Recent studies have shown that SMR1 is secreted into saliva in response to intraperitoneal administration of β-adrenergic and cholinergic agonists, and removal of the cervical sympathetic ganglia that innervate the salivary glands resulted in increased levels of SMR1 protein in the submandibular glands . These observations are in keeping with a cervical sympathetic trunk - submandibular gland axis propounded previously .
Before considering the pharmacology of SGP-T and its analogues a brief summary of the VCSa1 gene family and its products is presented as this subject was recently reviewed .
The VCSa1 Gene Family
Pharmacology of the Tripeptide D-PHE-D-GLU-GLY (feG)
During SGP-T isolation and testing procedures, the truncated sequence Phe-Glu-Gly (FEG) was identified, which itself showed bioactivity, as did its D-isomeric form (feG) . This tripeptide sequence was synthesized and characterized pharmacologically in various models.
Several rat models of systemic inflammatory disease, and in vitro or ex vivo immunopharmacologic assays were utilized to test the bioactivity of feG as follows.
Endotoxemia models. Injection of lipopolysaccharide (LPS) in rats results in rapid transient decreases in blood pressure, increases in circulating leukocytes, migration of leukocytes into peritoneal fluid, accumulation of neutrophils in cardiac tissue, disrupted intrinsic rhythmicity of migrating myoelectric complexes (MMC) in intestines, etc.
Anaphylaxis. Rats sensitized to ovalbumin (OA) or larvae of Nippostrongylis braziliensis (Nb) and subsequently challenged with these same antigens by injection, orally, or intra-nasally depending on the purposes of the experiment, develop rapid drops in blood pressure; accumulation of leukocytes in cardiac tissue; increases in vascular permeability; increased circulating leukocytes; diarrhea and disrupted MMCs; and IgE-mediated migration of eosinophils, neutrophils, and monocytes into airways.
Pulmonary bronchoconstriction (measured by specific lung resistance) and airway hyper-responsiveness to methacholine or carbachol in sheep naturally allergic to Ascaris suum or in rats sensitized with either OA or with larvae of Nb and challenged by aerosol administration of the sensitizing antigens was measured after aerosol challenge with the antigen.
Spinal cord injury in rats induced by 60 second clip compression of the spinal cord was measured by lesion site histology and histochemistry as well as recovery of locomotor function.
Pancreatitis induced in mice by intravenous injection of caerulein was measured histologically, by determination of plasma amylase and lipase activity, and by immunoassays.
In vitro and ex vivo studies on leukocyte migration, adhesion, cell surface marker expression, and reactive oxygen species production.
Infusion of LPS in rats also has acute effects on the intestine by disrupting the standard MMCs and produces a pattern of intense, irregular myoelectricity  Intravenous injection of feG 20 minutes before LPS dose-dependently reduced the length of time of disruption of jejunal MMCs. Interestingly, the carboxamide derivative, feG(NH2), was found to be more potent than feG in this endotoxemia model. feG given orally 20 minutes before LPS challenge inhibited disruption of MMCs in a bell shaped, dose-dependent manner, with 65 μg/kg providing maximal inhibition.
Effects on pulmonary inflammation and function
Effects of feG treatment were further studied in pulmonary inflammation models in rats sensitized with either OA or with larvae of Nippostrongylis braziliensis (Nb) and challenged by aerosol administration of the sensitizing antigens , Oral treatment with feG at 1 mg/kg 30 minutes prior to OA challenge significantly reduced airway hyper-responsiveness to methacholine measured 24 hours after challenge. In Nb sensitized rats feG significantly reduced tracheal smooth muscle contraction in response to aerosol Nb challenge.
In cats sensitized to Bermuda grass allergen, administration of feG orally at 1 mg/kg immediately prior to allergen challenge resulted in a significant reduction in accumulation of eosinophils in bronchoalveolar lavage fluid . However, daily treatment for 2 weeks in experimentally asthmatic cats had no measurable effect on airway inflammation . This latter result suggests that further studies will be necessary to evaluate dosing regimens and formulation for feG (see Pharmacodynamic/pharmacokinetic considerations below).
The effects of feG on vascular permeability induced by antigen challenge and histamine have been studied in both rats and dogs. With both species intradermal injection of feG (10-6M to 10-9M) significantly reduced the increase in vascular leak of a dye (Evans blue) provoked by both active cutaneous anaphylaxis and histamine by up to 40% at high doses to ~20% at lower doses (unpublished observations).
Other disease models: acute pancreatitis, spinal cord injury
From a pharmacodynamic perspective, it appears that feG has a long biological half life. Single intravenous dosages of feG inhibit endotoxin-provoked accumulation of neutrophils in cardiac tissue for at least 24 hours  (see Figure 7). Single oral dosage of feG in OA sensitized challenged rats also inhibits neutrophil and eosinophil migration into airways for at least 24 hours  (see Figure 6). Likewise in asthmatic sheep intravenous, oral, or aerosol administration of feG blocks airway responsiveness for at least 24 hours after antigen challenge .
Pharmacokinetic studies, to our knowledge, have not been performed on feG in any species. However, results of preliminary pharmacokinetic and toxicokinetic studies have been performed on a closely-related salivary tripeptide (D-cyclohexylalanine-D-glutamate-glycine; (cha)eG) in rats, dogs, and monkeys (proprietary, in-house data, 2010). In rats and dogs oral dosages of 2,500 μg/kg of (cha)eG were required to achieve detectable plasma concentrations (>5 ng/mL). Oral bioavailability was estimated to be less than 1% in the rat. In monkeys detectable plasma levels of (cha)eG persisted for 24 hours following a single intravenous dosage of 10 mg/kg, with an apparent terminal half life of approximately 9 hours, consistent with pharmacodynamic findings in rats (see Figure 8). However, noting that in vitro feG is active within a window of concentrations of about 0.0035 to 0.35 ng/mL, and that in model studies in rats feG dosage of 100 μg/kg was consistently found to be effective regardless of route of administration, it must be concluded that the systemic bioactivity of feG occurs at concentrations well below minimum detectable plasma concentrations of current assays. In other words, the dosage riddle is unlikely to be solved by pharmacokinetics.
Mechanism studies: Effect of feG on neutrophil chemotaxis, adhesion, and function
Results of in vivo studies point to the neutrophil as the primary target cell for the immunopharmacologic actions of feG and other bioactive factors produced by the salivary gland. Early results showed that SGP-T treatment inhibited neutrophil chemotaxis  as well as rolling .
Effect on adhesion
In peritoneal neutrophils collected from OA sensitized rats 24 hours after challenge, pre-treatment with feG had no effect on expression of the alpha integrin CD 11b but down regulated expression of the beta 1 integrin CD49 d (Alpha-4 integrin chain) . In vitro incubation of human neutrophils with feG inhibited PAF induced neutrophil migration (see Figure 12) as well as expression of CD 11b . In normal (unstimulated) neutrophils feG had no effect on neutrophil adhesion to gelatin, whereas in PAF-activated cells feG at 10-11 and 10-10M significantly inhibited adhesion of human neutrophils. However, within molar concentrations of 10-11 to 10-9 M, feG had no effect on PAF-stimulated superoxide release or on phagocytotic activity, suggesting that feG modulates primarily neutrophil adhesion and migratory responses. Peritoneal neutrophils from OA sensitized rats 24 hours after challenge were also tested for expression of CD11b and CD16b (Fc-gamma RIIIb: Low affinity immunoglobulin gamma Fc region receptor IIIB). feG treatment (100 μg/kg orally) inhibited CD 11b antibody binding to peritoneal neutrophils in unchallenged but not in OA challenged rats. CD 16b binding, however, was inhibited by feG treatment in both challenged and unchallenged rats. In vitro (microtiter plates) feG inhibits adhesion of rat peritoneal leukocytes, but only if the cells were stimulated with PAF, indicating that feG's actions require cell activation. feG treatment also completely blocked the expression of the beta 1-integrin CD49 d on circulating neutrophils which was up regulated by OA challenge, but had no effect on CD11b expression. These and other findings led to the conclusion, that when administered in vivo feG prevents inflammation-induced reduction in cell adhesion as well as restoring its inhibitory effect in vitro.
Effect on oxidative activity
Saliva, in addition to its role as a digestive aid, contributes significantly to lubrication, protection, defence and wound healing in the mouth. The importance of salivary glands and their secretions are poorly appreciated, and they are only taken seriously when salivary gland dysfunction results in decreased saliva flow. In humans this dysfunction contributes to difficulties in tasting, eating, swallowing, and speaking, and results in sores of the soft tissues of the mouth and periodontal disease. These pathologies also manifest in human patients with a variety of systemic diseases including - Sjögren's syndrome, rheumatoid arthritis, juvenile idiopathic (rheumatoid) arthritis, systemic lupus erythematosus (an inflammatory connective tissue disease), systemic sclerosis (sceloderma), primary bilary cirrhosis (an autoimmune disease of the liver), sarcidosis (a multisystem granulomatous disorder), infections with human immunodeficiency virus, herpes virus, hepatitis C, ectodermal dysplasia, chronic pancreatitis and depression .
Nonetheless, it should be recognized that the relationship between salivary glands and systemic health is bidirectional. "Oral infection may represent a significant risk-factor for systemic diseases, and hence the control of oral disease is essential in the prevention and management of these systemic conditions" . Chronic inflammatory periodontal diseases are among the most prevalent chronic infections in humans, and many investigators have established a significant, albeit modest, positive association between periodontal disease and cardiovascular disease, which includes atherosclerosis, myocardial infarction and stroke. In addition, epidemiological associations have been made between periodontal diseases and chronic diseases such as diabetes, respiratory diseases and osteoporosis .
Likewise in veterinary medicine epidemiologic studies reveal that oral disease is the most common disease in all age groups of dogs and cats . Moreover, there is evidence that oral infection also has systemic effects including renal, hepatic, pulmonary, and cardiac diseases; osteoporosis, adverse pregnancy effects, and diabetes mellitus , and can lead to systemic inflammation . The severity of periodontal disease was found to be positively correlated with histological changes in kidneys, myocardium, and liver .
In this review we focused on SGP-T and its derivatives namely FEG and its D-isomeric derivative feG, which in themselves demonstrate the significant physiological and immunological modulation exerted by salivary gland peptides. These peptides have significant anti-inflammatory actions, as shown in animal models of endotoxic shock (Figures 1 & 7), allergic and anaphylactic reactions (Figures 4, 6, 8 & 9), pancreatic (Figure 10) and spinal cord injury (Figure 11).
feG, and its analogues, exhibit a distinctly different mechanism of anti-inflammatory action from corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs and corticosteroids have become the mainstay of anti-inflammatory agents in human and veterinary medicine. NSAIDs are popular owing to their immune sparing effect, especially since the discovery that they act by inhibiting cyclooxygenase (COX), an enzyme that catalyses the arachidonic acid cascade resulting in production of pro-inflammatory eicosanoids . In contrast to enzymatic blockade, the tripeptide feG has multimodal activity and acts directly on activated leukocytes, specifically down regulating expression of integrins, thereby inhibiting chemotaxis (Figures 2 & 12) and cell migration (Figure 5). Furthermore, feG inhibits the function of neutrophils by specifically inhibiting intracellular superoxide production by activated neutrophils (Figure 13), probably as a consequence of interruption of the signaling cascade that induces superoxide generation .
Hence feG and its analogues appear to represent a new class of anti-inflammatory agents which act on immune cells, the central regulators of all inflammation. The term "Immune Selective Anti-Inflammatory Derivatives" (ImSAIDs) is proposed for salivary-derived peptides to distinguish this class of agents from corticosteroids and NSAIDs. A closely-related salivary tripeptide ((cha)eG) is currently under investigation as an anti-asthmatic therapeutic in humans.
Based on its mechanism of action and demonstrable in vivo pharmacologic activity, feG deserves evaluation in a number of situations characterized by over-exuberant or chronic inflammatory responses of human and veterinary significance associated with several major organ systems:
Whole body and circulatory: sepsis, endotoxemia, SIRS ;
Gastrointestinal: pancreatitis, hepatitis, gastroenteritis, enteritis;
Oral cavity: stomatitis
Respiratory: asthma, acute pulmonary inflammation of diverse etiologies;
Musculo-Skeletal: fibromyalgia, rheumatoid arthritis, equine laminitis (now characterized as a neutrophil-mediated inflammatory disease );
Nervous: spinal cord injury, peripheral nerve injury;
Urinary tract: cystitis
Aside from these therapeutic potentials, feG may eventually prove to be useful as a vetraceutical or a nutraceutical [the term coined by Stephen DeFelice ] to reduce the incidence and severity of systemic and localized inflammations caused by intense exercise, poor oral health and other causes.
List of Abbreviations
bronchoalveolar lavage fluid
AlphaM integrin chain
Fc-gamma RIIIb - Low affinity immunoglobulin gamma Fc region receptor IIIB
- CD49 d:
Alpha-4 integrin chain
D-cyclohexylalanine-D-glutamate-glycine COX: cyclooxygenase
Immune Selective Anti-Inflammatory Derivatives
migrating myoelectric complexes
platelet activating factor
protein kinase C
phorbol myristate acetate
systemic inflammatory response syndrome
specific lung resistance
variable coding sequence-1
ventricular peak systolic pressure
The financial assistance of Allergen NCE Inc. is gratefully acknowledged.
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