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Cellular pathophysiology. Part 1: changes following tissue injury

Sharon Edwards, MSc, RN, DipN, PGCEA.

Senior Lecturer, Department of Nursing and Midwifery, University of Hertfordshire

The cellular changes that occur following an insult or hypoxic injury are common and an understanding of the underlying physiological principles of these changes is imperative. Once the initial insult has occurred, the neuroendocrine system and the inflammatory response (IR) are stimulated and endothelial damage initiates the clotting cascade.

The cellular changes that occur following an insult or hypoxic injury are common and an understanding of the underlying physiological principles of these changes is imperative. Once the initial insult has occurred, the neuroendocrine system and the inflammatory response (IR) are stimulated and endothelial damage initiates the clotting cascade.


All these processes play a major role in maintaining haemodynamic normality and promoting healing. This paper looks at these physiological processes of injury. The second paper, next month, will concentrate on the physiological responses to hypoxic injury and the implications for practice.


Following hypoxia, cellular respiration has to resort to anaerobic metabolism. There is a reduction in adenosine triphosphate (ATP) for cellular work, leading to cellular membrane disruption. If interventions are not initiated immediately, the injury can lead to intracellular lysosome membrane disruption, resulting in increased levels of intracellular calcium and the production of free radicals, leading to irreversible cell damage and death.


The nursing and medical interventions required following injury relate to ensuring effective oxygen supply to meet the body's demand, maintaining adequate nutrients to meet metabolic requirements, and fluid replacement to sustain a depleted circulating volume. This is necessary to avoid death not only from the immediate effects of the injury but also from later multiple-system organ failure. These practice requirements will be discussed fully in the second paper.


The physiological processes of injury
Patients with a severe insult to the body (Table 1) require care and attention to the primary injury. However, there is now a sophisticated under-standing of the complex metabolic response to such injuries.


Neuroendocrine response and cellular injury
One of the earliest responses to injury is neuro-endocrine activation, which is intimately linked to control of tissue function. The increased sympathetic activity affects almost all elements of the cardiovascular system and triggers a complex series of events that lead to stimulation of the peripheral sympathetic system and adrenal medulla.


This results in the release of numerous substances into the circulation, such as catecholamines (adrenaline, noradrenaline), glucocorticoids (cortisol) and mineralocorticoids (aldosterone, angiotensin) and pro-inflammatory cytokines (Table 2).


The neuroendocrine response is to protect the body from the effects of injury. These processes are used as compensatory mechanisms to stabilise or enhance cardiac performance (Piano et al, 1998). The release of cytokines (lymphokines, monokines, and tissue necrosis factor) promotes cellular immunity. When released at the site of injury they enhance the activity of the body's immune and non-specific responses.


These compensatory mechanisms affect the target organs with extreme rapidity and intensity. Heart rate can double in three to five seconds, cardiac output can increase fourfold, selective vasoconstriction and vasodilatation occur to redistribute circulating volume to vital organs (heart, brain) (Huddleston, 1992).


They are, however, intended to be used by the body for a short time only, so sustained activation of the sympathetic and renin-angiotensin systems leads to haemodynamic abnormalities and can exert direct effects on cellular physiology. A continued stimulation of the stress response leads to:


- Reduced wound healing


- Reduced cardiac function


- Reduced immune response to infection


- Loss of sufficient stores of energy to facilitate healing and general body functions.


Apoptosis Apoptosis is defined as cell death without inflammation or scarring (Hunter and Chien, 1999). It is one of the two basic ways that body cells die; the other is hypoxia, which usually follows a sudden catastrophic event such as myocardial infarction. It is believed that certain neurohormones, such as angiotensin II and catecholemines, promote apoptosis and can occur in many organs, including the heart (Carelock and Clark, 2001).


Cellular damage after injury or damage Cellular damage causes a severe inflammatory response that ends with repair to damaged cells/tissue, and is part of the innate immune response. Following injury, the damaged endothelium releases mediators and stimulates the clotting cascade. The IR and the damaged endothelium work together.


Inflammatory response Activation of the inflammatory response represents a major physiological event in the body (Huddleston, 1992). Following an insult or injury there is a systemic response that produces extensive inflammation by attracting nutrients, fluids, clotting factors and large numbers of neutrophils and macrophages to the damaged site. To attract these to the injury site the damaged tissue releases mediators, which act as a signalling system (chemotaxis). The mediators cause a localised increase in capillary permeability, leading to swelling, oedema, redness, heat and pain, often observed in inflammation (Figure 1).


The most important mediators in this instance are histamine, kinins, prostaglandins and cytokines, especially interleukin 1 (IL-1). The list of these chemical mediators is long and is growing rapidly (Zuccarelli, 2000). The cytokines (lymphokines, monokines) are released at the site of injury and enhance the activity of the body's immune and non-specific responses.


One of the monokines, IL-1, is released from activated macrophages and damaged endothelium. IL-1 is the initial signal for activation of T-cells, neutrophils (in local inflammation). IL-1 stimulates bone marrow, acute-phase protein synthesis and is responsible for the induction of a fever (Staines et al, 1994).


IL-1 may play a role in linking the immune response to the neuroendocrine system (Huddleston, 1992), as it stimulates the sympathetic nervous system, hypothalamus, pituitary and adrenal glands (Tan, 1997).


However, a lack of regulation of the IR can lead to an uncontrolled intravascular inflammation that ultimately harms the body (Edwards, 2002) (Table 3). This process leads to a severe and prolonged increase in vascular permeability. The mediators may become toxic to other cells, damaging tissues, vessels and organs far away from the initial injury site (Huddleston, 1992). As overfilling the 'third space' (interstitial space) becomes critical, oxygen diffusion from capillary to cell is impaired, producing hypoxic damage to organs. If the pathophysiologic changes cannot be reversed or slowed, organ dysfunction and failure follow.


Endothelial damage The endothelium plays a major contribution in the activation of the IR. It is not simply an inert barrier between the flowing blood and the substructure of the blood vessels and tissue. The endothelium is an active metabolic organ, responsible for anticoagulation; it is closely linked to the IR, since haemostatic mechanisms always accompany injury, to prevent excessive blood loss and isolate the injured site (Huddleston, 1992). In someone who has suffered acute myocardial infarction, multisystem trauma or pneumonia, the release of inflammatory mediators that circulate in the blood stream could result in changes to that individual's endothelial integrity (Bell, 1992). This may result in coagulation abnormalities, whereby there is a concomitant activation of coagulation or alterations in the haemostatic balance which could cause systemic thrombosis or gross haemorrhage known as disseminated intravascular coagulation (Table 3).


- The second paper will examine the physiological responses to hypoxic injury and the implications for practice.

Bell, T.N. (1992) Coagulation and disseminated intravascular coagulation. In: Huddleston, V. (ed.). Multisystem Organ Failure: Pathophysiology and clinical implications. St Louis, Mo: Mosby Year Books.

Carelock, J., Clark, A.P. (2001) Heart failure: pathophysiologic mechanisms. American Journal of Nursing 101: 12, 26-33.

Edwards, S.L. (2002)Physiological insult/injury: pathophysiology and consequences. British Journal of Nursing 11: 4, 263-274.

Huddleston, V. (1992) The inflammatory/immune response: implications for the critically ill. In: Huddleston, V. (ed.). Multisystem Organ Failure: Pathophysiology and clinical implications. St. Louis, Mo: Mosby Year Books.

Hunter, J.J., Chien, K.R. (1999) Signalling pathways for cardiac hypertrophy and failure. New England Journal of Medicine 341: 17, 1276-1283.

Piano, M.R., Bondmass, M., Schwertz, D.W. (1998) The molecular and cellular pathophysiology of heart failure. Heart and Lung 27: 1, 3-19.

Staines, N., Brostoff, J., James, K. (1994) Introducing Immunology. St Louis, Mo: Mosby.

Tan, I., (1997) Metabolic response to illness, injury and infection. In: Oh, T.E. (ed.). Intensive Care Manual. Oxford: Butterworth Heinemann.

Zuccarelli, L.A. (2000) Altered cellular anatomy and physiology of acute brain injury and spinal cord injury Critical Care Nursing Clinics of North America 12: 4, 403-411.

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