Thrombin action on NST astrocytes disrupts glycemic and respiratory control

Abstract

Burns and severe trauma can produce a post‐injury “metabolic self‐destruction” characterized by catabolic metabolism and hyperglycemia. The severity of the hyperglycemia is highly correlated with post‐trauma morbidity and mortality. No mechanism has been posited to connect severe trauma with a loss of autonomic control over metabolism. However, traumatic injury causes other failures of autonomic function; one of those, gastric stasis and ulceration (“Cushing's Ulcer”) has recently been connected with the generation of thrombin. As a protease, thrombin (produced as a consequence of tissue injury) acts on G‐protein‐coupled protease‐activated receptors (PAR). Our previous work established that PAR1 receptors located on astrocytes in the autonomically critical nucleus of the solitary tract (NST) are responsible for modulating gastric control circuit neurons. The NST is at the center of a homeostatic control nexus that receives vast quantities of visceral afferent data from cranial nerve afferents including the vagus. This region of the hindbrain is also outside the “blood‐brain barrier” and is accessible to large molecules from the circulation. The NST uses this neural and chemical information to regulate gastrointestinal, metabolic, cardiorespiratory, endocrine, and behavioral functions. Astrocytes in the hindbrain have been also been implicated as important detectors of low glucose or glucose utilization and when activated, these astrocytes trigger CRR. There may be a convergence between the effects of thrombin to derange hindbrain gastrointestinal control and the hindbrain circuitry that initiates counter‐regulatory responses (CRR) to increase glycemia in reaction to critical hypoglycemia. We tested the hypothesis that administration of thrombin to the floor of the fourth ventricle (4V) or directly into the NST could trigger increases in glycemia through the mediation of astrocytes. Pre‐exposure of the 4V to fluorocitrate (FC; a selective blocker of astrocyte metabotropic signaling) was used to evaluate astrocyte involvement in thrombin‐triggered changes in glycemia. Our results suggest that thrombin acts within the NST to increase glycemia through an astrocyte dependent mechanism. Blockade of purinergic, but not glutamatergic, gliotransmission pathways interrupted the effect of thrombin to increase glycemia. Our studies also revealed that thrombin, acting in the NST, produces a rapid, dramatic and potentially lethal suppression of respiratory rhythm that was also a function of purinergic gliotransmission. These results suggest that the critical connection between traumatic injury and a general collapse of autonomic regulation involves thrombin action on astrocytes.Support or Funding InformationNIH NIDDK 108765, NIH NINDS 96113This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.