mucosa Neuroendocrine regulation of inflammation and tissue revair by submandibular 1. gland factors Ronald Mathison, Joseph S. Davison ana A. Dean Befus Interactions between the immune, nervous and endocrine systems are important in inflammation and tissue repai~: One neuroendocrine pathu'ay invoh,es polypeptide factors derived from the submandibular glands, whose synthesis and release are controlled by cervical sympathetic nerves. This novel pathway of immune-neuroendocri,te communication is the cervical sympathetic trunk-submandibular gland (CST-SMG) axis. Here, Ronald Mathison, Joseph Davison and Dean Befus di.,cuss the contributions of this axis to the neuroendocrine regulation of inflammation and tissue repai~: The concept of interactions between the nervous, endo- crine and immune systems emerged in the late 1970s and early 1980s (Refs 1,2), and significant advances have been made over the past decade in understanding the molecular aspects of bidirectional communication within immune-neuroendocrine systems 3"4. Concurrent with these developments in neuroendocrinoimmu- nology, the discipline of psychoneuroimmunology has approached the subject from a different perspective and has attempted to relate the central nervous systcm (CNS), and endocrine and immune systems, to psycho- social and physical weil-beingL This review takes a • intcIIHCUlttt¢' I.JI~I.VVUCli the ' ~ '-- neuro- position " ".... a:_._ L........ molecular immunological and the psychoneurolmmunological approaches, and explores a neuroendocrine mechan- ism involved in facilitating tissue repair following an injury, trauma or infection. To achieve this goal, the recently described cervical sympathetic trunk- submandibular gland axis (CST-SMG) (Refs 6,7) is used as a model system (Fig. 1). It is proposed that growth factors released from SMGs help re-establish normal tissue function by promoting cell growth and proliferation and by regulating inflammatory cell function. The CST-SMG axis Within the CST-SMG axis, the sympathetic nerves innervating the SMGs arise from preganglionic neurons residing in the spinal cord s. The axons proiect down the CST to two ganglia: the inferior cervical (i.e. stellate) ganglia and the superior cervical ganglia (SCG) (see Fig. 1). The postganglionic neurons leaving the stellate ganglia predominately innervate the lungs and heart, whereas those projecting from the SCG innervate the upper thoracic, cervical and head regions. The structures of particular relevance to the modulation of inflammatory responses are the hv- pophysis, thymus, thyroid, cervical lymph nodes and salivary glands, including the SMG. Structurally, the SMG comprises four major epi- thelial compartments: acinar cells, intercalated ducts, granular convoluted tubule (GCT) cells and striated excretory ducts" (Fig. 1). The acinar cells secrete amyl- ase, an important digestive enzyme, and produce saliva that is isotonic with plasma. The intercalated duct cells include stern cells that form acinar and GCT cells during normal and hyperplastic development. In the context of this reviex~,; the GCT cells are of particular interest since they are a major source of a variety of biologically active polypeptides. The cells of the striat,d excretory ducts regulate the ionic composition and water content of saliva. While exploring the neural mechanisms that regulate late-phase pulmonary inflammation to antigen challenge in Nippostrongylus brasiliensis (Nb)-sensitized rate, it was discovered that decentralization of the SCG, or bilateral removal of these ganglia (ganglionectomy), (Fig. 1) markedly attenuated the influx of neutrophils and macrophages into the alveolar spaces 8h after induction of the anaphylactic reaction. By contrast, on examination of the decrease in mean arterial blo.,~d pressure induced by intravenous injection of endotoxin in unsensitized, ganglionectomlzed or decentralized rats, it was found that the hypotensive response was exacer- bated-. These contrasting responses to injur.v indicated that the CST modulates inflammatory responses in a complex fashion. The innervation of the SCG is an intriguing area. Since the axons emanating from the SCG are directed to the upper thoracic, cervical and cephalic regions, they cannot directly modulate pulmonary and systemic inflammatory reactions. The concept of a CST-SMG axis "~.ll emerged foilowil~g the observation that regu- lation of anaphylaxis-induced pulmonary inflammation and endotoxin-provoked hypotension by the cervical sympathetic nerves was mediated by fa.ztOrs released from the SMGs (Refs 7,10). In this review, the con- cept is developed that this axis contributes to the © 1+94. I+]+,e+tcr N,:wncc I td I)ll~--+;t+'~q/+4/$ I}'.~)1~ .,.,.,,,olog++. rod.,y 5 2 7 v... is N.. 1119~4