Disease at the Cellular Level

THE NEXTDDS

Abstract

Cellular and molecular biologists have been uncovering the mechanisms by which plants and animals attempt to maintain their function at a cellular level. As cells age they need to be replaced or the organism would eventually die. The process of cellular death and rebirth is a tightly regulated process seen in the simplest of multicellular organisms, and dysfunction of that process can quickly lead to death. Programmed cell death is a genetically-controlled, locally mediated process to remove injured or redundant cells in a way that preserves nutrients and minimizes inflammation. Necrosis is an abnormal, uncontrolled process that results in loss of nutrients and localized or systemic inflammation. Cells can be damaged by a variety of extrinsic factors causing injuries that can be reversible or irreversible.

Key Points

• Billions of cells are created and destroyed every day
• Programmed cell death is a tightly controlled process to remove senescent, damaged, and nonfunctional cells
• Two types of programmed cell death, apoptosis and autophagy
• Necrosis results in death of cells that is not controlled and does not preserve cellular nutrients
• Cells can be injured by a variety of factors, sometimes resulting in reversible cell injuries and other times producing irreversible injuries
• Programmed cell death is part of an overall process of adaptation and plasticity of the organ and the organism

Introduction

Cellular and molecular biologists have been uncovering the mechanisms by which plants and animals attempt to maintain their function at a cellular level. As cells age they need to be replaced or the organism would quickly die. The process of cellular death and rebirth is a tightly regulated process seen in the simplest of multicellular organisms, and dysfunction of that process can quickly lead to death. An understanding of the processes involved and abnormalities of those systems can help the dental student better understand pathological processes in the oral cavity.

Normal Cellular Life Cycle

Approximately 50-70 billion cells die each day in adults.¹ Human cells are constantly dividing, creating new diploid cells with the same or similar function. Cellular senescence, meaning that cells can no longer divide, occurs after about 50 divisions, eliminating the cumulative effects of errors in copying. These senescent cells cease to divide but continue to function, adopting senescent phenotypes including flattened cell morphology and altered gene expression and secretion profiles.² The accumulation of senescent cells contributes to the typical age-related phenotypes of the organism, and senescent cells are more susceptible to effects of starvation, dehydration, oxidants, and toxins. Of note, the experimental removal of senescent cells results in removal of the typical age-related phenotype of the organism and reduces age-related changes seen in older animals.³

Cellular Death

Cells can die in normal or abnormal ways. Programmed cell death is cellular suicide that is tightly regulated by mitochondria and intracellular molecular signaling systems. This process is genetically encoded and allows the body to remove nonfunctional, injured, or redundant cells in an orderly fashion.⁴ Hypofunction of this system leads to tumors and metastases⁵; hyperfunctioning leads to premature aging. There are two types of programmed cell death: apoptosis and autophagy. Subtypes and variants of these categories have been named as well.

Apoptosis is the controlled self-destruction of a damaged cell. It is an orderly genetically-scripted process that preserves the nutrients in the cell for later reuse. (See Figure 1.) Apoptosis is regulated by the mitochondria and is triggered in response to stress such as the binding of nuclear receptors by glucocorticoids, excessive heat, radiation exposure, nutrient deprivation, viral infection, hypoxia, and increased intracellular calcium concentration. In fact increased intracellular calcium concentration appears to be one of the primary triggers of apoptosis. As has been noted, the inhibition of apoptosis can result in a number of cancers, autoimmune diseases, inflammatory diseases, and viral infections.⁶ In contrast, hyperactive apoptosis has been linked to certain neurodegenerative diseases, hematologic diseases, and tissue damage.

Autophagy is a “housekeeping” process used by cells to clean up intracellular debris. This is seen as an attempt to repair damaged cells and is important to repair of DNA fragmentation. In autophagy, a double-walled vacuole called an autophagosome forms around the debris and fuses with a lysosome, allowing lysosomal enzymes to digest the vacuolar contents. (See Figure 2.) Under more severe cellular stress, autophagy removes organelles and protein more rapidly than they can be replaced and the cell dies. This process allows the recovery of amino acids, electrolytes, and phospholipids for reuse by new cells.

Necrosis is another form of cellular turnover that is not part of the programmed cell death system. Necrosis is an abnormal process that occurs in response to injury, loss of nutrients, trauma, infection, or exposure to various toxins. (See Figure 3.) In contrast to programmed cell death, necrosis is not a controlled process and is seen as being generally detrimental to the organism. In necrosis the cell wall is disrupted, releasing intracellular contents including digesting lysozymes into the extracellular fluid resulting in an inflammatory reaction. Because of the uncontrolled nature of necrosis, the contents of cell are not made available for recycling.

Repair or Replace

Programmed cell death is seen as an attempt to either repair damaged cells or replace them with new ones. Organs are in a constant state of differentiation and plasticity. As new functionality is needed or older functionality becomes obsolete, cells are destroyed and replaced by either new cells or stromal cells, the fibrotic scaffolding used by the body to support other cells. Apoptosis and autophagy are efficient, regulated, locally-triggered processes that retain amino acids and lipids for use by other cells. Uncontrolled cellular suicide ultimately leads to the death of the organism. Impaired apoptosis leads to unchecked cell growth, hyperplasia, malignancy, and metastases.⁷ Impairment of autophagy leads to the accumulation of dysfunctional cells that contain damaged organelles, organ dysfunction, and premature ageing.⁸

Cellular Injury

Cells are vulnerable to a variety of injurious factors. Injury of cells can result in the death of cells, tissue, organ, or the entire organism. The body is constantly bombarded by toxic molecules causing damage to the proteins, fats, and DNA of the cell. When cells (and in fact the entire organism) are young, they are able to repair most cellular damage through a process of autophagy and self-repair. As the cell ages, the repair process becomes less efficient, less accurate, and less effective.

Cellular injury can be reversible or irreversible. Reversible cell injury usually involves injury to the cell wall. This is manifested as cellular swelling which results in disruption of the sodium-potassium transport pump and loss of calcium homeostasis. This may be seen in response to hypoxia, starvation, and hyper- or hypothermia. Cellular swelling is the initial response to almost every injury and can usually be repaired by removal of the cause of the insult. As it progresses, cell wall swelling results in an elevated intracellular calcium which stimulates apoptosis.

Another potentially reversible cell injury is injury to the DNA. Typically an oxidative stress results in fragmentation of DNA, and the DNA becomes non-functional or functions abnormally. Glycation is a process of the deposition of glucose onto DNA, and glycated DNA becomes non-functional or functions abnormally. This is commonly seen in diabetes mellitus and explains some of the forms of end-organ damage seen in diabetes including nephropathy, neuropathy, and microangiopathy. Chemical damage can occur where extrinsic toxins result in DNA breakage. In general cells try to repair DNA damage and if they are unsuccessful, apoptosis is triggered.

Irreversible cellular injury includes necrosis. This is a progressive failure of the essential metabolic and structural cell components, usually resulting in the death of cells and tissue. Necrotic cells are disrupted and nonviable, and the only effective treatment requires removal of the necrotic cells to prevent release of cytotoxins into the organism. An example of necrosis is gangrene where cells and tissues have died because of lack of vascular supply. The only effective treatment is excision or debridement back to viable tissue.

Apoptosis is also considered an irreversible process. This is the normal turnover of cells that is controlled and results in recovery and reuse of cellular components. It has been shown that apoptosis can be aborted locally should conditions change such that the cell no longer needs to die.

References

1.            Karam JA. Apoptosis in Carcinogenesis and Chemotherapy. Netherlands: Springer; 2009.

2.            Campisi J. Aging, cellular senescence, and cancer. Annu Rev Physiol. 2013;75:685-705.

3.            Baker DJ, Wijshake T, Tchkonia T, et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. Nov 10 2011;479(7372):232-236.

4.            Lockshin RA, Beaulaton J. Programmed cell death. Life sciences. 1974;15(9):1549-1565.

5.            Srivastava R. Apoptosis, Cell Signaling, and Human Diseases: Molecular Mechanisms. Humana Press, Inc.; 2007.

6.            Scatena R. Mitochondria and Cancer: A Growing Role in Apoptosis, Cancer Cell Metabolism and Dedifferentiation. In: Scatena R, Bottoni P, Giardina B, eds. Advances in Mitochondrial Medicine. Vol 942: Springer Netherlands; 2012:287-308.

7.            Wong RS. Apoptosis in cancer: from pathogenesis to treatment. J Exp Clin Cancer Res. 2011;30(1):87.