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.

The functions of human saliva: A review sponsored by the World Workshop on Oral Medicine VI

“…110 The defensins may have antibacterial effects and may also have antiviral effects. [110][111][112] There are a number of bacterial agglutinins in saliva which agglutinate microorganisms, thereby facilitating their removal by swallowing and possibly inhibiting their attachment to oral surfaces. These include the mucin MUC7, proline-rich proteins, and salivary agglutinin, the last of which is identical with GP340 104 and DMBT1.…”

Prevention and amelioration of rodent endotoxin-induced lung injury with administration of a novel therapeutic tripeptide feG

“…These data demonstrate that feG does not require immunological or inflammatory pre-stimulation, such as that provided by the induction of acute pancreatitis in our previous model, to be effective. The tripeptide FEG (PheeGlueGly), derived from submandibular gland peptide T, and its synthetic counterpart, feG, inhibits cardiac, pulmonary and intestinal anaphylactic activity [5], and decreases pulmonary and pancreatic inflammation, with increased potency [4,26]. Previous mechanistic studies suggest that in vitro feG inhibits stimulated human and rat neutrophil expression of CD11b, and inhibits the expression of CD49d and CD16 antibody binding to peritoneal rat neutrophils [5].…”

“…Previous mechanistic studies suggest that in vitro feG inhibits stimulated human and rat neutrophil expression of CD11b, and inhibits the expression of CD49d and CD16 antibody binding to peritoneal rat neutrophils [5]. In vivo feG reduces reactive oxygen species generation by neutrophils via prevention of protein kinase C deregulation following allergic reactions [5,27]. Therefore, feG is classed as an agent acting on immune cells ("Immune Selective Anti-Inflammatory Derivatives"), differentiating it from classical anti-inflammatory agents such as corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDS) [5].…”

“…In vivo feG reduces reactive oxygen species generation by neutrophils via prevention of protein kinase C deregulation following allergic reactions [5,27]. Therefore, feG is classed as an agent acting on immune cells ("Immune Selective Anti-Inflammatory Derivatives"), differentiating it from classical anti-inflammatory agents such as corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDS) [5]. We hypothesise that in the lung intratracheal administration of feG would result in primarily in situ effects upon cell surface molecules and mediators responsible for leukocyte activation, migration and infiltration.…”

“…The tripeptide FEG (PheeGlueGly), derived from submandibular gland peptide T, and its synthetic counterpart, feG, inhibits cardiac, pulmonary and intestinal anaphylactic activity [5], and decreases pulmonary and pancreatic inflammation, with increased potency [4,26]. Previous mechanistic studies suggest that in vitro feG inhibits stimulated human and rat neutrophil expression of CD11b, and inhibits the expression of CD49d and CD16 antibody binding to peritoneal rat neutrophils [5]. In vivo feG reduces reactive oxygen species generation by neutrophils via prevention of protein kinase C deregulation following allergic reactions [5,27].…”