The metabolic response to injury

3.2.1 The metabolic response to injury-

Any life-threatening injury activates a major transformation in host metabolism reflecting the profound changes in cellular function that occur in many different tissues within the human body. This transformation is required for the host to respond to the challenges presented by life threatening injury to support tissue healing as well as maintenance of vital organ function. This metabolic transformation is referred to as the metabolic response to injury and forms an important component of the host stress response to injury. The function of the metabolic response to injury is to mobilise metabolic fuels from storage sites within the human body. These metabolic fuels provide energy to tissues that are required to generate the stress response including the vital organs, the immune system and the wound. 

The metabolic response to injury includes both catabolic and anabolic metabolic pathways which with increasing severity of injury, comprise a correspondingly greater proportion of total metabolic activity within the host. A fundamental feature of the stress response is the profoundly catabolic nature of this response reflecting the large energy requirements to generate this response. Catabolic pathways involve glycogenolysis, lipolysis and proteolysis which provide the metabolic fuels glucose, FFAs and amino acids respectively for cellular metabolism. The stress response releases these fuels substrates into the bloodstream for cells to synthesise ATP which is the essential energy substrate required for cellular metabolic pathways. The metabolic transformation following injury is mediated by different stress response hormones and inflammatory mediators that are released into the blood following tissue injury

A characteristic feature of the metabolic response to injury is the catabolism of muscle protein which occurs to meet the high metabolic demands of the host. In contrast, the mobilisation of fuel substrates during exercise and the early phases of starvation spares protein catabolism and utlises glycogen and fat as the principal sources of fuels. Proteolysis provides amino acids for anabolic pathways including protein synthesis for cell growth and replication, In addition, protein breakdown is required for gluconeogenesis which occurs in the liver and the kidneys. The breakdown of muscle tissue for these purposes is sometimes referred to as “auto-cannibalism”  and reflects the nature of the highly catabolic changes in metabolism within the host.   

Following life threatening tissue injury increases in host energy demands can be quantified by measuring changes in the metabolic rate. Measurement of resting metabolic rate ~(resting energy expenditure) provides important information to estimate host energy consumption which can also guide host nutritional caloric requirements during the recovery period from injury. Measuring RMR metabolic rate at the bedside following tissue injury is performed using indirect calorimetry. Following life threatening injury there may be increases in basal metabolic rate and resting energy expenditure of between 10-100% with higher values associated with more severe injuries, particularly burns, sepsis or long bone skeletal fractures. These increases in metabolic rate reflect the importance of the metabolic response to injury for survival. Although the role of bedside indirect calorimetry can quantify host energy expenditure following tissue injury, clinical research studies have not demonstrated any benefit in terms of mortality when using this as a guide to administering nutrition to replenish large calorie deficits. Rather, the results of these studies indicate that matching calorie administration with expenditure following injury may result in adverse effects such as hyperglycaemia, hyperlipidaemia, elevated liver enzymes and higher incidence of infections. 

Anabolic pathways that are activated following injury include increases in the production of acute phase proteins such as C-reactive protein and alpha-1 antitrypsin. Protein synthesis is also required for the production of inflammatory mediators including cytokines, chemokines and antibodies. Anabolic metabolic pathways are also required for cell replication and differentiation which occurs as part of the immune response to injury. Anabolic metabolic pathways are also activated witin the wound where cellular regeneration of injured tissues occurs, involving the synthesis of growth factors including fibrinogen growth factors, platelet derived growth factor and vascular endotherial growth factor. The regeneration of injured tissues involves the cell replication and division which require energy for these activities to occur.  In addition, following activation of the innate immune system leucocytes require energy for a wide range of cellular functions such as phagocytosis and oxygen free radical production.

A key feature of the metabolic state following injury is the rapid requirement for readily available metabolic fuel substrates to generate the inflammatory response. Glucose is the metabolic substrate utilised by cells that rely on glycolysis to generate ATP where rapidly dividing cells switch to glycolysis to generate ATP.  Fuel substrates utilised by tissues that are not solely dependent on glycolysis include lactate, ketone bodies, free fatty acids and amino acids. The host metabolic response to injury ensures adequate glucose production by the breakdown of glycogen stores within the liver and by the production of glucose from non-carbohydrate sources (gluconeogenesis) where proteolysis is the main source of glucose.  

Glucose production occurs primarily in the liver, which highlights the important role the liver plays in metabolism following injury. The liver is also has important roles  in protein and fat metabolism follwoing life threatening injury. Insulin counter regulatory mediators of the stress response increase glucose production in the liver and mediate the breakdown of muscle and fat stores within the body to provide the necessary substrates to produce glucose.  The liver performs both glycogenolysis and gluconeogenesis mediated by the actions of cortisol and epinephrine. The liver also converts lactate produced from anaerobic metabolism in peripheral tissues to pyruvate which can be converted to glucose. Ketone body production increases if glucose availability is impaired due to poor nutritional status or liver disease.  

3.2.2 Immunometabolism and the Warburg effect following acute tissue injury-

The stress response to injury releases fuel substrates from energy stores within the body that are utilised by leucocytes, endothelial cells, fibroblasts and other cells involved in the acute inflammatory response. Studies of leucocytes have demonstrated that during the early phase of an acute inflammatory response, monocyte and macrophage activation involves ATP generation primarily through glycolysis . As the acute inflammatory response evolves over time the proportion of ATP generated from free fatty acid metabolism increases. The metabolic pathways that support the immune system during its activation are currently a strong focus of research which is referred to as immunometabolism.

The role of glycolysis as the principal metabolic pathway to provide both ATP and NAD+ for the activation of the innate immune system following tissue injury is important in understanding the metabolic mechanisms underlying the stress response. The activation of leucocytes during an acute inflammatory response induces a “metabolic switch” within these cells to adapt to the needs of the host following injury. This adaptation includes a range of cellular functions including changes in gene expression, protein synthesis and surface membrane expression which require energy to enable the leucocyte to function in the activated state.

The role of glycolysis in the activation of the innate immune system is surprising as this metabolic pathway is less efficient in terms of generating ATP compared to oxidative phosphorylation. The central role of glycolysis during the early activation of monocytes and macrophages in the acute inflammatory response is termed “aerobic glycolysis” as it occurs in the presence of an adequate oxygen supply sufficient for ATP generation through mitochondrial oxidative phosphorylation. Aerobic glycolysis within immune cells of the innate immune system occurs despite the inferior ATP production compared to mitochondrial oxidative phosphorylation. This phenomenon was first observed in tumour cells by Otto Warburg and has been also shown to occur in certain non-cancerous settings such as acute inflammation.

Glycolysis generates a net total of 2 molecules of ATP for each molecule of glucose metabolism compared to 36 molecules of ATP for the TCA cycle. However, although this is a fraction of the ATP produced by OXPHOS glycolysis has a number of features that are advantageous in the setting of tissue injury. Glycolysis can take place without the requirement for oxygen (anaerobic glycolysis) which enables ATP production despite anaerobic conditions following tissue injury.  Glycolysis also provides host cells with other essential anabolic substrates such as nucleotides which are generated through intermediary pathways including the pentose phosphate pathway (PPP).  This pathway is also required to generate NADPH for leucocyte phagocytosis. Finally, the metabolic regulation within the cytoplasm of cells involved in the inflammatory response occurs in part by the redox ratio (NAD+/NADH). In particular pyruvate dehydrogenase which is a key enzyme that controls entry into the TCA cycle is inhibited due to low concentrations of NAD+. Glycolysis provides a fast supply of NAD+ and ATP  which can be activated immediately in response to any noxious insult. Following leucocyte activation by LPS the metabolic switch involves the increased expression of insulin regulated GLUT 4 glucose transporter. In addition, non-insulin regulated glucose transporter expression is also increased on the surface membrane of leucocytes. These changes in leucocyte membrane expression reflect the requirement of activated leucocytes to enhance transmembrane glucose flux for glycolysis.