Salivary gland derived peptides as a new class of anti-inflammatory agents: review of preclinical pharmacology of C-terminal peptides of SMR1 protein

Abstract

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.

Figure 1

Neuroendocrine axis and modulation of responses to lipopolysaccharide: Intravenous administration of lipopolysaccharide (LPS) induces rapid reduction in blood pressure in rats. Either bilateral removal of the submandibular salivary glands (sialadenectomized) or the superior cervical ganglia (ganglionectomized) exacerbate the LPS-induced hypotension. (mean ± sem, n = 6 to 8). Adapted from [16].

Figure 2

SGP-T and neutrophil chemotaxis: Neutrophil chemotaxis into carrageenan-soaked sponges over a 24 hour period in rats is inhibited by SGP-T injected intravenously, in a bell-shaped dose-dependent manner, at dosages indicated. (mean ± sem, n = 3 to 12). Adapted from [22].

Figure 3

eptide Products from Submandibular Rat-1 (SMR1) Prohormone: The SMR1 precursor protein contains sialorphin near the N-terminal, and SGP-T (submandibular gland peptide T) near the C-terminal. FEG and FEG(NH₂) are biologically active derivatives of SGP-T.

Figure 4

feG and cardiovascular anaphylaxis: Anaphylaxis induced by ovalbumin (OA) challenge in previously sensitized rats causes rapid reduction in blood pressure (control). feG treatment orally at the time of OA challenge dose-dependently inhibited anaphylaxis-induced hypotension. (mean ± sem, n = 5 to 6). Adapted from [38].

Figure 5

feG and neutrophil migration: Neutrophils migrate into carrageenan-soaked surgical sponges implanted subcutaneously in rats. feG, at a dosage of 100 μg/kg injected intraperitoneally at the time of sponge implantation, significantly inhibited neutrophil migration measured 24 hours after implantation. (mean ± sem, n = 6 to 10). Adapted from [39].

Figure 6

Allergen induced by aerosol challenge with ovalbumin (OA) in previously sensitized rats causes pulmonary airway inflammation: feG treatment orally 30 minutes, 3 hours, or 6 hours after OA challenge inhibited the influx of eosinophils and neutrophils into airways. Adapted from [44].

Figure 7

Neutrophil accumulation in heart tissue: Intravenous administration of lipopolysaccharide (LPS) in rats causes accumulation of neutrophils in heart tissue as detected by myeloperoxidase (MPO) activity in atrial slices 24 hours after LPS infusion. Intravenous treatment with a carboxamide derivative, feG(NH₂), at the time of LPS infusion, dose-dependently inhibited MPO in atrial slices. (mean ± sem, n = 4 to 8). Adapted from [46].

Figure 8

feG and intestinal allergic responses: Oral challenge with ovalbumin (OA) in sensitized rats results in disrupted intrinsic rhythmicity of migrating myoelectric complexes (MMC) in the small intestine. feG injected intravenously at 100 μg/kg up to 8 hours before challenge significantly reduced disruption in MMCs, suggesting a long biological half life (mean ± sem, n = 4 to 8). Adapted from [49]

Figure 9

feG and asthma in sheep: In asthmatic sheep naturally sensitized to Ascaris suum, bronchoconstriction determined by measuring specific lung resistance (SR_L) increased rapidly immediately after aerosol challenge, decreased to baseline values over 4 hours, but was followed by a secondary increase in SR_L 5 after hours post challenge. Inhaled feG at a dose of 30 mg/sheep reduced early as well as late increases in SR_L, whereas treatment with feG intravenously (1 mg/kg) or orally (2 mg/kg) inhibited only late phase bronchoconstriction. (mean ± sem, n = 4 to 8). Adapted from [51].

Figure 10

feG and acute pancreatitis. In acute pancreatitis, induced in mice by 12 hourly injections of caerulein, a single intraperitoneal dose of feG (100 μg/kg) administered at start of caerulein induction or 3 hours after start of induction, inhibited plasma lipase and amylase activity. Adapted from [40].

Figure 11

feG and spinal cord injury: In a spinal cord injury model induced by 60 second clip compression of the spinal cord, rats given feG intravenously at 200 μg/kg twice daily for 5 days had higher BBB locomotor scores compared to controls (p = 0.043) over 7 weeks following cord injury. Adapted from [54].

Figure 12

feG and human neutrophils: Incubation of human neutrophils with feG within a window of molar concentrations between 10^-11 to 10^-9 M downregulated platelet activating factor-(PAF) induced neutrophil migration in vitro. (mean ± sem, n = 3 to 7). Adapted from [39].

Figure 13

feG and the oxidative burst: - Dose-response for phorbol myristate acetate- (PMA) stimulated intracellular oxidative activity of circulating neutrophils 18 hours after ovalbumin (OA) challenge in OA sensitized rats. feG was injected intraperitoneally at 100 μg/kg at the time of challenge. Oxidative activity was measured using flow cytometry for a marker of oxygen free radicals, 123-dihydrorhodamine. (mean ± sem, n = 6 to 7). Adapted from [57].