The stress response to injury

3.1.1 An overview of the stress response to injury- 

The stress response to acute tissue injury consists of the simultaneous activation of multiple physiological systems within the body that promote survival of the host following life threatening tissue injury. Any tissue injury of sufficient magnitude resulting in tissue ischaemia or necrosis will trigger this survival response.  The stress response to acute tissue injury refers principally to the combined actions of the immune, endocrine and nervous systems that are activated following injury to mediate this host survival response. The activation of the innate immune system, the release of multiple stress hormones into the circulation and the actions of the sympathetic nervous system produce a complex series of physiological changes within the host that are referred to as the stress response to injury. 

The stress response to tissue injury is a fundamentally important biological survival response that is highly evolutionarily conserved across all animal species. The stress response can be considered as the coordinated activation of multiple stress mechanisms that form essential protective functions to promote host survival following life threatening injury. All living organisms possess cellular stress mechanisms that are activated following any noxious insult; in both unicellular and multicellular organisms these stress mechanisms trigger specific repair pathways in an attempt to maintain cellular integrity following injury. The stress response to injury may be considered as a collection of stress mechanisms that have evolved in higher order animals to protect the functional integrity of their different tissues and organs.  Within the animal kingdom the stress response to tissue injury exhibits a level of complexity reflecting the evolutionary hierarchy observed amongst different species. Primates have developed the most complex set of stress mechanisms that protect their body tissues and vital organs following injury. 

Following life-threatening injury the host stress response has two main functions, firstly to preserve vital organ function following injury and secondly to generate an inflammatory response at the site of  injury. Recovery from any life-threatening tissue injury is dependent on the activation of the stress response to preserve vital organ function as well as to generate an inflammatory response to achieve wound healing and ultimately host survival. 

The stress response to injury activates a range of physiological functions that aim to protect the host during the critical period following tissue injury by preventing potentially life-threatening complications. These complications include dehydration, haemorrhage, hypoxia, malnutrition and infection. Whilst modern medical care following life threatening tissue injury has markedly improved survival rates by reducing the incidence of these complications, the host stress response remains vitally important for host survival both in terms of preserving vital organ function and generating an inflammatory response at the site of tissue injury.

The stress response to injury activates a survival response where a significant proportion of the hosts physiological reserves are directed towards both preserving vital organ function and wound healing. The host is consequently highly vulnerable to any further insult during the immediate post injury period. Whilst the host is dependent on this response for wound healing and ultimately survival, the actions of the stress response have the cumulative effect of depleting the hosts physiological reserves during the immediate recovery from injury. In addition, the inflammatory response activated at the site of tissue injury has potentially deleterious effects on uninjured tissues of the body. Therefore following life threatening injury the host is at risk of potential complications which may result in increased morbidity and mortality. 

3.1.2 The factors that determine survival following life-threatening injury-

Survival following life threatening injury is determined by a number of factors that can be broadly classified as those related to the injury and those related to the host (patient factors). Therefore, the severity and nature of the tissue injury are key factors that determine survival. Patient factors that determine survival are age, concomitant comorbid medical diseases and physiological reserve. 

In humans the stress response to life threatening tissue injury is considered to be an important factor determining outcome from life threatening tissue injury. Whilst the stress response is an essential survival response that supports tissue healing and host recovery, this response is also associated with deleterious consequences following injury. The stress response may be considered as a double edged sword with both beneficial as well as adverse effects on the host. 

Adverse effects on the host from the stress response to injury may be categorised as sequelae arising firstly from failure to maintain homeostasis and vital organ function and secondly from deleterious effects of the immune response in response to tissue injury. The former category is linked to the serious clinical condition multiple organ dysfunction syndrome (MODS), whilst the latter group of sequelae is associated with impaired wound healing and the consequences of this outcome .

The double edged sword concept of the stress response to injury becomes more important with increasing severity of tissue injury. Increases in the severity of tissue injury activate a corresponding increase in the magnitude of the stress response necessary to achieve tissue healing and recovery. With increasing severity of tissue injury the host is required to direct a greater proportion of physiological reserves to wound healing and preserving vital organ function . This results in greater depletion of metabolic reserves as well as potentially greater tissue damage resulting from the actions of inflammatory mediators. Consequently increasing severity of tissue injury is associated with increased morbidity and mortality rates as well as greater long term health complications. 

The severity of the injury may be quantified by measuring the concentration of endocrine and inflammatory mediators in the bloodstream. Alternatively factors such as increases in the host metabolic rate or oxygen consumption also reflect the severity of the metabolic response to injury. Both high concentrations of the stress response mediators and increases in metabolic rate are associated with excess morbidity and mortality reflecting greater severity of injury.

Separating the adverse effects from the beneficial effects of the stress response to injury is a goal that has remained elusive to clinicians. Determining the component of overall morbidity and mortality that is attributable to the stress response to injury has been studied in different settings following life threatening injury. The clinical setting of tissue injury associated with surgery is a practical method of studying this important area of clinical practice. Attempts to block the surgical stress response either with pharmacological agents or with regional anaesthetic techniques have been shown to have only a limited effect on reducing mortality. Within surgical practice a strategy that minimises tissue injury has successfully improved mortality and morbidity through limiting tissue damage and reducing the magnitude of the stress response to injury. The introduction of minimally invasive surgical techniques into routine surgical practice has reduced postoperative complications following surgery and improved recovery back to baseline functional status.  However, whilst these surgical techniques reduce the surgical stress response and improve morbidity and mortality, this does not answer the question as to whether the surgical stress response is beneficial or detrimental to the host outcome following life threatening injury.   

Potentially life threatening complications following severe tissue injury are common and may include delayed wound healing, infection or vital organ dysfunction. Common adverse sequelae also include prolonged hospital stay, delayed recovery back to pre-injury baseline health and chronic health complications. Importantly the surgical recovery initiative Enhance Recovery after Surgery (ERAS) highlights the importance of the stress response to injury in determining the outcome following surgery. ERAS aims to minimise the stress response to injury by limiting tissue injury associated with surgery by using minimally invasive surgical techniques. This has transformed modern surgical techniques and justified investment in robotic and laparoscopic surgical techniques.

3.1.3 The key components of the stress response to injury-

A triad of mechanisms regulate the stress response to life threatening injury; these three physiological systems include the endocrine, the immune and the autonomic nervous systems. The activation of these three physiological systems produce a highly complex and integrated physiological response to tissue injury. The combined actions of these physiological systems result in the secretion of an array of different humeral mediators into the bloodstream. A rapid rise in the concentrations of these mediators within the blood results in the multisystem physiological changes observed within the human body following injury.

These chemical signalling mechanisms are a fundamental principle underlying the stress response to injury where the physiological actions of the stress response are produced by changes in the concentrations of stress response mediators released into the blood. These stress response mediators display a characteristic concentration time curve when the concentration of these mediators are measured over time following injury (Fig 2 ). The actions of these mediators occur through endocrine, paracrine or autocrine effects when they are secreted by cells.

The physiological changes mediated by stress response mediators result from cell signalling pathways that are activated through specific cellular receptor mediated pathways. The stress response to injury is a physiological response that has a number of key features following life threatening injury. The time course of this response occurs from the time of injury and continues over a period of days depending on the severity of tissue injury. The host is required to initiate this response rapidly and to adapt the response depending on factors such as the severity of tissue injury and the presence of adverse complications. 

The stress response has a number of regulatory mechanisms that are necessary for successful recovery following tissue injury. These mechanisms ensure that the various physiological systems are activated to produce a coordinated response both in terms of preserving vital organ function and in generating the acute inflammatory response. In particular, acute inflammation involves potentially damaging effects on uninjured body tissues. A dysregulated stress response may result in adverse effects if these regulatory mechanisms do not function correctly

3.1.4 The autonomic nervous system-

The autonomic nervous system is the first of the three physiological systems that is activated following injury and mediates the host “fight or flight” response . Following injury pain and proprioceptive fibres of the peripheral nervous system transmit a range of sensory information to the central nervous system in response to injury. These signals combine with other sensory information through visual, auditory and other signals within the cerebral cortex to activate the autonomic nervous system in the brain stem. The activation of the autonomic nervous system ensures a rapid response to any potential host tissue injury as the speed of activation of the nervous system is measured in milliseconds in contrast to humeral or immune mechanisms that may take minutes or hours to take effect..

The functions of the autonomic nervous system control vasomotor circulatory tone through the  actions of baroreceptors and chemoreceptors in the aorta and carotid body respectively. The role of the autonomic nervous system is key to maintaining vital organ perfusion during the stress response to injury. The release of endocrine mediators into the local circulation including norepinephrine (noradrenaline) from synaptic nerve terminals onto blood vessels increases vasomotor tone.  In addition, the release of epinephrine (adrenaline) from the adrenal medulla into the blood also regulates arterial tone and maintains blood pressure in the face of falling circulating volume. Activation of the sympathetic nervous system produces an increase in blood flow and tissue oxygen delivery to the injured area and ensures that perfusion to the vital organs is prioritised over less critical body tissues.

The sympathetic nervous system produces a range of physiological responses which enables the host to respond to physical stress associated with life threatening injury. In the cardiovascular and respiratory systems the actions of the sympathetic nervous system includes the recruitment of blood from vascular capacitance vessels in the venous side of circulation, redistribution of blood flow from non-essential organs to essential vital organs and increases in cardiac contractility. Within the respiratory system increases in respiratory minute volume aid oxygen and carbon dioxide exchange within the lungs.

3.1.5 The endocrine system-

The endocrine system plays a central role in the host response to tissue injury where the functions of different hormones are required to assist with the recovery from life threatening injury. The endocrine system is  required to maintain vital host homeostatic functions whilst also responding to the needs of the host following injury. This is achieved by a change in the secretion of many of these hormones into the bloodstream from their normal resting state. For example, following injury activation of the hypothalamic/pituitary/adrenal axis increases the secretion of the stress hormone cortisol from the adrenal gland from the normal diurnal secretion of this hormone.

Of all the endocrine mediators released into the circulation following injury cortisol and epinephrine are considered to be the most important stress response mediators. The functions of these two mediators have a wide range of actions to protect the host during the immediate post injury period. The functions of cortisol include a broad range of functions within the human body to promote survival of the host following life-threatening injury. Cortisol is often referred to as the stress hormone where its actions include potentiating the actions of both the catecholamine neurotransmitters norepinephrine and epinephrine. This action assists the host to maintain circulating volume and vital organ perfusion when dehydration and haemorrhage may occur associated with injury . Cortisol also mediates many of the important biochemical pathways involved in the metabolic response to injury. These include the release of metabolic fuel substrates from the host’s energy stores into the blood which provide energy for a range of metabolic pathways. Finally cortisol has anti-inflammatory actions which protect the host by the inhibiting the actions of inflammatory mediators of the immune response to uninjured areas of the body thereby ensuring the local inflammatory response is limited to site of injury. (6).

3.1.6 The immune system-

Following tissue injury the release of cellular constituents within the extracellular space initiates the activation of the innate immune system. These cellular constituents contain damage associated molecular pattern (DAMP) proteins which activate specific pattern recognition receptors (PRR) found on the cell membrane of local immune cells. The activation of these membrane  receptors on resident tissue macrophages intiates an intracellular signalling cascade which results in the activation of these immune cells form their inactive state. This results in the release inflammatory mediators into the surrounding injured area. Examples of these inflammatory mediators include chemokines which attract leucocytes from the bloodstream and cytokines that mediate the characteristic features of a localised inflammatory reaction. Chemokines coordinate the migration of leucocytes from the bone marrow via the bloodstream to the site of tissue injury. These local mechanisms promote the activation of the innate immune system to initiate an acute inflammatory response at the site of tissue injury.

Whilst these local mechanisms may be sufficient to achieve tissue healing for minor tissue injuries  the magnitude of the response required following life threatening injuries is much greater. Life threatening injury requires a correspondingly greater response which includes a systemic inflammatory response necessary to achieve tissue healing. This systemic response is often referred to as the systemic inflammatory response syndrome (SIRS) as it is associated with characteristic host clinical features. A regulated acute inflammatory response at the site of tissue injury is required to ensure successful tissue repair and regeneration. As well as pro-inflammatory mechanisms there are also anti-inflammatory mechanisms that limit the inflammatory response to the site of injury.

Measurements of plasma mediator concentrations have demonstrated an activation phase where plasma mediator concentrations peak within the first 24 hours following injury. This is followed by a recovery phase during which the concentration of these mediators decreases over the following 48-72 hours. More recently these have been referred to as the hyper and hypo-inflammatory phases of the stress response respectively. A feature of the hypo-inflammatory phase is that the host is susceptible to infection during this period; this is thought to reflect the relative paralysis of the immune system following its activation in response to major injury (5).

Modern laboratory assay techniques have enabled the simultaneous measurement of multiple peptide mediator concentrations within the blood.  When repeated measurements are performed over time the concentration profiles of these mediators can be measured following injury. These techniques allow the relationship between different stress response mediators to be analysed to search for potential regulatory mechanisms that control the release of these mediators into the bloodstream. In particular, multiple correlation analysis between mediator concentration profiles may be analysed to search for potential underlying regulatory mechanisms that control the stress response to acute tissue injury.

3.1.7 An overview of the combined actions of these physiological systems-

The stress response to injury has two principal functions which are firstly to preserve vital organ function and secondly to activate an inflammatory response at the site of tissue injury. The combined actions of the endocrine and autonomic nervous systems may preserve vital organ function remarkably effectively following injury. In these circumstances clinical signs indicating abnormalities in vital organ physiology may be absent despite significant loss of blood or body fluids. In the presence of dehydration or haemorrhage these changes may not be clinically detectable until they reach a critical threshold where clinical signs represent late and ominous life threatening injury.

The combined effects of the stress response result in multisystem responses including changes in thermoregulatory, metabolic, coagulation and hepato-renal systems, which are all required to preserve vital organ function. The actions of these different systems is also necessary to support the activation of the innate immune system to generate an acute inflammatory response. Activation of the stress response through the actions of the sympathetic nervous system, the endocrine and innate immune systems result in a transformation of all the major physiological systems in an attempt to protect the host from potentially life-threatening complications associated with tissue injury. The preservation of vital organ function is achieved through increases in oxygen delivery to these organs which aims to protect the host from the life-threatening complications of multiple organ dysfunction syndrome.

During both stressed and unstressed conditions the autonomic nervous system functions to maintain physiological homeostasis through mechanisms that do not require conscious input from the host. Whilst the immune system is activated from its normal quiescent or inactivated state, both the endocrine and autonomic nervous systems produce a stress response that is in addition to their normal resting functional state. Therefore changes in the secretion of various endocrine hormones occurs following injury where the stress response to injury can be quantified by measuring changes in the concentration of these hormones from their resting state.NAMPT in the stress response to acute tissue injury

3.1.8 The role of visceral and subcutaneous adipose tissue in the metabolic response to injury-

Human adipose tissue is classified into two categories namely brown and white adipose tissue. Adipose tissue stores within the body have different functional properties depending on characteristic anatomical or endocrine features. Whilst brown adipose tissue is involved in theromoregulation, white adipose tissue has traditionally been considered to function simply as an energy store for the host that can be utilised when food is scarce. Following life threatening injury white adipose tissue stores are metabolised to provide energy substrates for the host to generate an acute inflammatory response.

White adipose tissue is further classified into visceral and subcutaneous adipose tissue reflecting important functional differences between these two categories. These two classes of adipose tissue have characteristic profiles in the secretion of different adipokines from these adipose sites. Adipokines such as leptin regulate many different physiological functions including satiety, body composition, thermoregulation, reproduction and immunity. Subcutaneous adipose tissue secretes the hormone leptin into the bloodstream and serum leptin concentrations correlate with subcutaneous adipose tissue reserves. Therefore leptin functions as a signal to the host indicating the supply of stored metabolic reserves. This is potentially important in the response to life threatening injury where metabolic reserves are required to generate an inflammatory response and maintain vital organ function.   

The preliminary research ( Preliminary Clinical Research ) has demonstrated  a characteristic pattern in the leptin concentration time curve following life threatening injury. The changes in serum leptin concentrations reveal that this hormone displays characteristic features of a stress response following injury-this is in keeping with previous reports demonstrating that leptin concentrations increase following surgical stress. In addition, these preliminary results demonstrate a correlation between the change in serum concentrations of insulin and leptin following injury. This finding indicates that both these hormones have potentially important functions within the stress response following injury and is an additional factor that supports the insulin stress response theory. In the postprandial state insulin stimulates leptin secretion from adipose tissue to promote satiety following ingestion of a meal. Leptin secretion in turn reduces insulin secretion through the actions of leptin receptors on the surface membrane of pancreatic beta cells. This forms a feedback loop (the adipo-insular axis) which in the unstressed state functions to match caloric energy intake with metabolic reserves. Leptin secretion inhibits insulin secretion In the unstressed state however, in cases of leptin resistance this negative feedback loop malfunctions and is considered to be a causative factor resulting in insulin resistance. In the stressed state insulin secretion is postuiated to increase leptin secretion where insulin has the functions outlined in the section .

Both subcutaneous and visceral adipose tissue stores may provide free fatty acides for ATP energy production to meet the hosts metabolic requirements following life threateining injury. Visceral adipose tissue has a number of properties that potentially are of greater benefit to the host following life threatening injury. The anatomical location of visceral adipose tissue enables FFA's to be directly delivered to the liver via the portal circulation. In contrast subcutaneous adipose tissue supplies these metabolic fuels to the venous systemic circulation and then via the pulmonary circulation to the hepatic artery. The delivery of FFA's to the liver is also potentially preferentially more advantageous from visceral compared to subcutaneous adipose tissue, where the blood supply to the splanchnic circulation supplying visceral adipose tissue is less comprimised compared with the peripheral systemic circulation for subcutaneous adipose tissue. The relative contribution of the delivery of FFAs  to the liver from visceral or subcutaneous adipose tissue will depend on the circulation of blood to these fat deposits. Following haemorrhage and other circulatory shock states the circulation to the vital organs is prioritised over non-essential tissues such as adipose tissue. The blood flow to the liver is preserved as a vital organ, however, the splanchnic circulation is reduced following tissue injury. However, blood flow to subcutaneous adipose tissue may be more compromised compared to reductions in splanchnic blood flow. Therefore, following life threatening injury, visceral provides the host with an alternative source of FFA's in addition to subcutaneous adipose tissue where the former adipose tissue reserves are important in providing metabolic fuels to generate the stress response to injury.        

Adipose tissue physiology is an active area of research where a particular role for both visceral and subcutaneous adipose tissue is emerging as a regulator of metabolism in response to changes in nutritional or caloric needs of the host. For example, during starvation adipose tissue reserves are depleted and  characteristic changes occur in metabolism to adapt to scare nutritional supply. These metabolic adaptations include an increase in tissue insulin sensitivity and a decrease in GSIS reflecting the low glucose availability. The insulin stress response theory postulates that stress response to injury and starvation represent opposing extremes of metabolic regulation where the former is associated with both high insulin concentrations and tissue insulin resistance whereas the latter is associated with low insulin levels and low tissue insulin resistance. Visfatin/NAMPT secreted from visceral adipose tissue, is postulated to have a role in the regulation these metabolic responses. 

3.1.9 Stress hyperglycaemia and the stress response to injury-

The critical role of glycolysis in the initial phase of the acute inflammatory response requires glucose to be delivered to cells involved in generating this inflammatory response. The supply of glucose as the primary metabolic fuel for activated leucocytes is important in determining the ability of the host to generate an acute inflammatory response. A fundamental metabolic requirement of the stress response is to ensure adequate leucocyte transmembrane glucose flux following activation of the innate immune system. Wound healing and recovery from life threatening injury will be impaired by an inability to provide adequate glucose to leucocytes and other cells involved in this acute inflammatory response.

During the stress response to life threatening tissue injury the release of counter regulatory hormones such as catecholamines, glucagon, cortisol and growth hormone all act to maintain glucose concentrations within the blood. The actions of these mediators maintain glucose concentrations within the bloodstream through two mechanisms. These mechanisms are firstly increased production of glucose by the host and secondly through actions that mediate insulin resistance in peripheral tissues. This latter mechanism reduces glucose uptake into the liver, adipose and muscle tissues thereby creating greater glucose availability to other tissues including the immune system and cells of the wound. 

These counter regulatory hormones increase the production of glucose by activating glycogenolysis within the liver and muscle tissues which depletes glycogen stores within these tissues. Following depletion of glycogen stores the primary source of glucose is obtained through hepatic gluconeogenesis from the breakdown of protein. These insulin counter regulatory stress mechanisms provide glucose, amino acids and free fatty acids for cellular ATP production to support the activation of the innate immune system. The actions of stress response mediators including epinephrine, cortisol and cytokines stimulate hepatic gluconeogenesis and mediate tissue insulin resistance in adipose tissue, the liver and muscle which all act to maintain the glucose concentration within the blood. 

The plasma glucose concentration following acute tissue injury will reflect the balance between the rate of glucose production as well as the rate of glucose utilisation by the host. The former will depend on factors such as the rate of hepatic gluconeogenesis whilst the latter will depend on metabolic requirements of the host including the metabolic requirements of the innate immune system and other tissues. In addition, the plasma glucose concentration will depend on the actions of insulin and counter regulatory hormones within the blood. 

(In the setting of acute tissue injury host metabolism has less reserve with which to maintain plasma glucose homeostasis. This occurs because the regulatory mechanisms controlling glucose stimulated insulin secretion have to control blood glucose concentrations when tissue insulin resistance severely impairs the actions of insulin in lowering blood glucose. In addition, the adverse effects of impaired glucose homeostasis (both hypoglycaemia and hyperglycaemia) will be more deleterious under conditions of acute cellular stress.)

The combined effects of high glucocorticoid and inflammatory mediator concentrations may result in elevated blood glucose concentrations following acute tissue injury. A high blood glucose concentration in association with the stress response to acute tissue injury is termed “stress hyperglycaemia”. Stress hyperglycaemia reflects the severity of tissue injury where higher concentrations of both endocrine and inflammatory stress response mediators are observed following more severe forms of injury. However, as the incidence of obesity and T2DM within the surgical population is high, stress hyperglycaemia may also occur due to dysregulated stress response metabolic pathways.

Whether stress hyperglycaemia represents an appropriate physiological response in fit and healthy individuals or is a dysregulated response predisposing to adverse outcomes is fiercely debated. Stress hyperglycaemia following acute tissue injury has been described well before the rise in the incidence of obesity within the general population. Hyperglycaemia following tissue injury may have both beneficial and deleterious actions for the host following major tissue injury. Potentially beneficial actions include the osmotic actions of glucose that maintain circulating volume following injury and the generation of a favourable concentration gradient for glucose to enter leucocytes and other cells involved in the inflammatory response. However, hyperglycaemia has multiple deleterious effects on cells including increased oxidative stress with higher concentrations of ROS species. 

This controversy reflects the different mechanisms regulating blood glucose concentrations during the stress response and their relationship to asymptomatic metabolic factors including obesity and impaired glucose tolerance. In fit and metabolically healthy individuals it remains unclear whether stress hyperglycaemia is an appropriate physiological response to severe tissue injury. It also remains unclear if the temporary deleterious effects of hyperglycaemia are a necessary price the host pays to deliver an adequate glucose load to leucocytes and the innate immune system.