Level 4

4 ways a cell may die

For ninety five out of hundred wounds, discovering and removing the cause is sufficient to solve the problem. If that approach fails, the wound may become a chronic wound. For adequate interventions, (in this case super-) simplified knowledge of processes at cellular level may help. At least, in presentations it is appreciated.

Understanding how cells cope with stress, injury and damage is central in understanding the development and healing of wounds. There is no abrupt transition from normal tissue to necrotic tissue, in most wounds the conditions for cells are gradually getting worse towards the lesion, This is divided into a healthy part, a part in stress, a part with repairable damage and a part with non-repairable damage. This zone classification is different for each tissue type involved which may on of the explanations of tissue undermining, this happens when the underlying tissue is more susceptible to stress and damage comparted to the tissue above.

Cell stress and damage are often caused by the action of forces on tissue (1), lack of oxygen (2) and/or lack of nutrients (3). Stress and damage may lead to cell death, however, the most common cause of cell death is apoptosis, programmed cell death(4).

The action of forces on cells leads to pressure, tensile- and shear-forces. Increased pressure may cause membrane leakage, tensile forces can lead to cell rupture and shear forces can do both. Casual observance may suggest that pressures are the main cause of problems, but that is probably not the case. Cells and tissues are often anisotropic, which means they are not equally strong in all directions. Many tissues have a special construction to handle forces in a certain direction. If force is applied from a “wrong” direction to a cell or tissue it may deform or lose its tensegrity and tear. In addition, instead of popping and rupturing, deformation may most of the time be causing damage of the cell membrane resulting in calcium ions leaking into the cell which is a direct cause for problems.[1,2].

The cell nucleus senses the properties of force applied to the cell [3], this allows her to assess the situation and respond appropriately at the cellular level. Signalling and tensegrity systems augment and translate these signals to the higher organisational levels of tissue, organs and the body.

The availability of oxygen may also cause problems; human cells depend on haemoglobin for their oxygen supply. If a human cell has no access to oxygen produced by red blood cells it will die. Oxygen related issues usually cause mitochondrial problems. Under hypoxia. Mitochondrion will adapt its processes to keep producing energy, this process also produces reactive oxygen species and nitric oxides. These reactive substances signal the cell and its surroundings about the (oxidative) stress. Too many reactive parts are damaging so if the amount of reactive oxygen surpasses a threshold the immune system will be activated to remove damaged cells. This system allows tissue to function under hypoxic circumstances[4].

Lack of nutrients will disturb the cell metabolism, which will endanger its survival. Focal in these processes is the endoplasmic reticulum, which is sensitive to intracellular circumstances. Since the endoplasmic reticulum functions as the main chemical factory of cell producing most proteins any disturbance of the necrotic reticulum will have a dramatic effect. This is called endoplasmic reticulum stress (ER-stress)[5].

Circumstances such as exerted forces, hypoxia or a lack of nutrients are noted by the cell and it will respond to counter these problems(stress responses). However, these responses influence the internal cooperation between the nucleus, mitochondrion and the endoplasmic reticulum in positive or negative manner[2]. It is important for cells to not only adapt the internal processes but also to inform its surrounding about its problems. Therefore it will start sending out signals which quite specific inform surrounding cells and tissues and the rest of the body on the nature of its problems[6,7].

Cells are part of tissue, to maintain the quality of these tissues cells which are not functioning properly have to be removed or replaced. Removing non-functional or obsolete cells by the body itself is the commonest reason for cells to die. The body prefers to remove cells in a controlled manner where cells are properly recycled. This process is called apoptosis. The opposite process necrosis were cells structural fall apart and their contents are spread in the tissue. The remains of cells in tissue are the result of an uncontrolled situation and therefore have a strong signalling function, these are the so-called damps en pamps (damage-associated molecular patterns en pathogen-associated molecular patterns)[8].

Both apoptosis and necrosis exist in several varieties[9].

Cells do not immediately fall apart or die if exposed to forces, hypoxia or lack of nutrients. For practical reasons, we may classify the level of stress in stress (no damage, fully reversible), injury (reversible damage) and damage (irreversible damage). Stress does not require regeneration, injured tissue can regenerate fully, but damaged tissue cannot be regenerated fully and the body will try to restore the main functions of the tissue. This means that the affected area is much larger than the wound itself, this implies that visually vital tissue does not have to be vital that all.

Cells and tissues can adapt to survive difficult circumstances. Continuous monitoring the circumstances and the signals cells and tissues send out allow the body to respond. This can be a short-term responses where a blood vessel is opened up or an immune response is started. Long-term responses can be by changing the composition of tissues, for example making extra blood vessels to composite for lack of perfusion or changing collagen composition in support of tissue due to forces from different angles.

Regardless of the cause of the wound, the wound bed will, due to lack of perfusion, always, always suffer from odd forces and a lack of oxygen and nutrients. Due to the damage the structures the body uses to monitor the situation in the body like sensors, vessels and nerves are also dysfunctioning. This is a perfectly normal situation and most of the disturbance is actually used to guide the wound healing process. That is in a young patient, if the wound is larger, complex and or the patient has more issues related to tissue regeneration, this perfect process is impaired.[10,11].

This impairment be qualitative, wrong signals are send or misinterpreted. It can also be qualitative, more damage leads to more signals, more signals are harder to interpret and the signal to noise ratio is also reduced. Noise and miscommunication in the body, may lead to misinterpretation of signals or the generation of wrong signals. This may seem far-fetched, in practice it is called a chronic, wound.

An out-of-control inflammation response may cause havoc in a wound bed. This may produce additional damps which only increase the (sterile) inflammation[12]. And impaired endothelial hypoxia and capillary refill a cause reperfusion injury[13,14]. Reperfusion injury is a cause of problems in other parts of the body, like the lungs[15]. A cacophony of signals in the wound bed may disable guidance for cells which may cause impaired cell movements and proliferation. These are just a few of the many causes of chronic.

Despite the difference in causes, chronic wound pathology has surprising similarities at the level (4) of the cell and the tissue. And this opens up treatment possibilities. Not only are the issues often similar, there are several possibilities to intervene and restore impaired processes. Goal will be to either guide communication or delay the stress-injury-damage cascade. Available knowledge is not always available in the wound care practice. An example is the use of pentoxifylline, which is well documented for years [16–20] yet rarely used. There are dozens of other interventions like pentoxifylline available. Not only on this level, but also on the other four levels in wound knowledge a smorgasbord of interventions is available. So the real problem is not even new knowledge but to make current knowledge available for the clinical practice.



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9         Nikoletopoulou V, Markaki M, Palikaras K, et al. Crosstalk between apoptosis, necrosis and autophagy. Biochim Biophys Acta – Mol Cell Res 2013;1833:3448–59. doi:10.1016/j.bbamcr.2013.06.001

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11       Yin F, Sancheti H, Liu Z, et al. Mitochondrial function in ageing: coordination with signalling and transcriptional pathways. J Physiol 2015;0:n/a-n/a. doi:10.1113/JP270541

12       Feldman N, Rotter-Maskowitz A, Okun E. DAMPs as mediators of sterile inflammation in aging-related pathologies. Ageing Res Rev 2015;24:29–39. doi:10.1016/j.arr.2015.01.003

13       Manson PN, Anthenelli RM, Im MJ, et al. The role of oxygen-free radicals in ischemic tissue injury in island skin flaps. Ann Surg 1983;198:87–90. doi:10.1097/00000658-198307000-00017

14       Lejay A, Meyer A, Schlagowski AI, et al. Mitochondria: Mitochondrial participation in ischemia-reperfusion injury in skeletal muscle. Int J Biochem Cell Biol 2014;50:101–5. doi:10.1016/j.biocel.2014.02.013

15       Mansour Z, Charles AL, Kindo M, et al. Remote effects of lower limb ischemia-reperfusion: Impaired lung, unchanged liver, and stimulated kidney oxidative capacities. Biomed Res Int 2014;2014. doi:10.1155/2014/392390

16       Sharma K, Ishaq M, Sharma G, et al. Pentoxifylline triggers autophagy via ER stress response that interferes with Pentoxifylline induced apoptosis in human melanoma cells. Biochem Pharmacol 2016;103:17–28. doi:10.1016/j.bcp.2015.12.018

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20       Falanga V, Fujitani RM, Diaz C, et al. Systemic treatment of venous leg ulcers with high doses of pentoxifylline: efficacy in a randomized, placebo-controlled trial. Wound Repair Regen 1999;7:208–13.

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