Thrombin action on astrocytes in the hindbrain of the rat disrupts glycemic and respiratory control.

Richard C Rogers,Eileen M Hasser,Gerlinda E Hermann

doi:10.1152/ajpregu.00033.2020

Abstract

Severe trauma can produce a postinjury “metabolic self-destruction” characterized by catabolic metabolism and hyperglycemia. The severity of the hyperglycemia is highly correlated with posttrauma morbidity and mortality. Although no mechanism has been posited to connect severe trauma with a loss of autonomic control over metabolism, traumatic injury causes other failures of autonomic function, notably, gastric stasis and ulceration (“Cushing’s ulcer”), which has been connected with the generation of thrombin. Our previous studies established that proteinase-activated receptors (PAR1; “thrombin receptors”) located on astrocytes in the autonomically critical nucleus of the solitary tract (NST) can modulate gastric control circuit neurons to cause gastric stasis. Hindbrain astrocytes have also been implicated as important detectors of low glucose or glucose utilization. When activated, these astrocytes communicate with hindbrain catecholamine neurons that, in turn, trigger counterregulatory responses (CRR). There may be a convergence between the effects of thrombin to derange hindbrain gastrointestinal control and the hindbrain circuitry that initiates CRR to increase glycemia in reaction to critical hypoglycemia. Our results suggest that thrombin acts within the NST to increase glycemia through an astrocyte-dependent mechanism. Blockade of purinergic gliotransmission pathways interrupted the effect of thrombin to increase glycemia. Our studies also revealed that thrombin, acting in the NST, produced 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.

Highlights

Critical injuries, including head trauma, surgery-related bleeding, gunshot wounds, and burns can produce a posttraumatic “metabolic self-destruction” [26]
Data from our studies demonstrate that the injections of thrombin in the hindbrain can provoke systemic hyperglycemia
Whereas acute hypoxia can produce hyperglycemia [38, 69], the current study demonstrated that artificial ventilation did not prevent the hyperglycemic response to thrombin

Summary

INTRODUCTION

Critical injuries, including head trauma, surgery-related bleeding, gunshot wounds, and burns can produce a posttraumatic “metabolic self-destruction” [26]. The extreme and prolonged hyperglycemia associated with the global metabolic collapse of severe trauma is not adaptive or helpful Rather, it is better described as a pathophysiology in those individuals who would not have survived the initial insult had there not been timely clinical intervention. We hypothesized that the gastric stasis of traumatic injury occurred as a consequence of the activation by thrombin of PARs located on neurons in the autonomically critical nucleus of the solitary tract (NST) in the dorsal hindbrain. Preliminary studies revealed that thrombin caused increases in glycemia and produced a rapid, dramatic, and potentially lethal suppression of respiratory rhythm Both the glycemic and respiratory effects were mediated by purinergic gliotransmission

MATERIALS AND METHODS

RESULTS

DISCUSSION

DISCLOSURES