Autonomic Regulation of Anti-Inflammatory Activities from Salivary Glands

Abstract

The cervical sympathetic nerves which innervate the medial basal hypothalamus-hypophyseal complex, primary and secondary lymph organs, and numerous glands, such as the pineal, thyroid, parathyroid and salivary glands form a relevant neuroimmunoendocrine structure that is involved in the regulation of systemic homeostasis. The superior cervical ganglia and the submandibular glands form a 'neuroendocrine axis' called the cervical sympathetic trunk submandibular gland (CST-SMG) axis. The identification of this axis usurps the traditional view of salivary glands as accessory digestive structures and reinforces the view that they are important sources of systemically active immunoregulatory and anti-inflammatory factors whose release is intimately controlled by the autonomic nervous system, and in particular the sympathetic branch. An end component of the CST-SMG axis is the synthesis, processing and release of submandibular rat-1 protein (SMR1), a prohormone, that generates several different peptides, one from near its N-terminus called sialorphin and another from its C-terminus called - submandibular gland peptide-T (SGP-T). SGP-T formed the template for tripeptide fragment (FEG) and its metabolically stable D-isomeric peptide feG, which are potent inhibitors of allergy and asthma (IgE-mediated allergic reactions) and several non-IgE-mediated inflammations. The translation from rat genetics and proteomics to humans has yielded structural and functional correlates that hopefully will lead to the development of new medications and therapeutic approaches for difficult to treat disorders. Although the CST-SMG axis has barely been explored in humans recognition of the importance of this axis could facilitate an understanding and improved management of periodontal disease, and other diseases with a more systemic and nervous system basis such as asthma, autoimmunity, graft-versus-host disease and even Parkinson's disease.

Opiorphin is a master regulator of the hypoxic response in corporal smooth muscle cells

“…The mechanism described here, where hypoxic upregulation of sialorphin results in transcriptional activation of Hif-1a and A2BR, may be restricted to CSM tissue, which under normal physiological conditions expresses high levels of vcsa1 relative to other tissues (15)(16)(17)(18). However, we have previously demonstrated that changes in expression of vcsa1 in rat corporal tissue are reflected by circulating levels of sialorphin in the blood (47).…”

“…2A, B, respectively). To further demonstrate the dependence of Hif-1a and a2br expression on sialorphin, we performed geneknockdown experiments using siRNA against vcsa1 (vcsa1-siRNA) in the CSM cells, which have been reported to have high levels of endogenous vcsa1 expression compared to other cell types (15)(16)(17)(18). Treating CSM cells with vcsa1-siRNA caused a significant decrease of ϳ50% Hif-1a and a2br expression ( Fig.…”

“…In rats, the opiorphin homologue, called sialorphin, is encoded by the variable coding sequence a1 (vcsa1) gene (14). The vcsa1 gene has tissue-specific expression, being highly expressed in the submandibular gland, lung, prostate, and corporal tissue (15)(16)(17)(18). The mouse contains Ն3 genes with homology to vcsa1.…”

Changes in PGE2 signaling after submandibulectomy alter post–tooth extraction socket healing

“…Wounds in the oral cavity are repaired relatively easily, likely due to the involvement of saliva in oral tissue repair processes. Nevertheless, the described endocrine function of the salivary glands should not be disregarded as a possible mediator in oral tissue repair …”

“…Nevertheless, the described endocrine function of the salivary glands should not be disregarded as a possible mediator in oral tissue repair. 1 Saliva is very important to oral health. A lack of saliva has been shown to bring serious problems to oral health, and delay the repair of mouth lesions.…”