Histology, Cell Death


Article Author:
Katherine Brown
Neelofer Awan
Patrick Le


Article Editor:
Allecia Wilson


Editors In Chief:
Sherri Murrell


Managing Editors:
Avais Raja
Orawan Chaigasame
Khalid Alsayouri
Kyle Blair
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Abbey Smiley
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beenish Sohail
Hajira Basit
Phillip Hynes
Sandeep Sekhon


Updated:
9/20/2019 1:40:05 PM

Introduction

Essential to any organism’s survival is its ability to sustain a stable internal environment. In medicine, this balance is referred to as homeostasis, a relatively stable state that the body attempts to maintain for a smoothly functioning system.[1] Cell growth, division, and death are all important parts of this regulation, and each is highly regulated. Loss of this balance is seen in tumor cells where mechanisms of cell death are avoided, resulting in uncontrolled cell growth. Conversely, conditions where extensive cell death is seen also result in loss of homeostasis, such as in the case of neuronal loss in Alzheimer disease.

Issues of Concern

When a cell is exposed to an insult, external or internal, it can react to this injury differently depending on the circumstance. Cell response can lead to adaptation, apoptosis, or necrosis. Adaptation successfully maintains homeostasis by reversible responses that can alter cell function and structure. A physiological example of adaptation is seen in pregnancy, where uterine cells increase in size (hypertrophy) and number (hyperplasia). Adaptations may also result in atrophy, a decrease in cell size and activity that is classically seen in disuse of certain muscle groups. Metaplasia is an adaptation that results in a change of the cell type. Pathologically, this is seen in diseases such as Barrett esophagus, where increased exposure of acid to esophageal cells from the stomach results in a phenotypical change in cells from columnar to squamous.

Function

If a cell is unable to adapt to increased stress, injury results. Cell injury is reversible until a certain threshold where it progresses to cell death. Historically, cell death has been designated into two classes: necrosis and apoptosis. Necrosis is often coined as accidental death as it is generally seen as not controlled by the cell. Apoptosis, on the other hand, is typically viewed as programmed cell death, regulated and controlled. The two differ in presentation, morphology, and mechanism though there has been recognized overlap which will be discussed at the end of this review.

Necrosis typically occurs when there is extensive damage to the cell membrane and internal structures that push the cell past reversible injury. It is usually the result of acute external factors, such as trauma, ischemia, toxins, or some other non-physiologic mechanism. Necrotic cell death results in a specific presentation such as damage to the plasma membrane, cellular swelling, and unregulated nuclear degradation. 

Ischemia, for example, typically ends in necrotic cell death. With the decreased delivery of oxygen to the cell, oxidative phosphorylation performed by the mitochondria becomes compromised. This results in a decreased amount of ATP available in the cytoplasm. In cells with a Na+/K+ (sodium-potassium) pump, lack of sufficient ATP disables the transporter. Sodium begins to increase within the cell as it can no longer be pumped out. This results in cellular swelling as the increase in intracellular sodium pulls water in. Cellular swelling, blebbing, and loss of microvilli are typical presentations of necrotic cell death. If ATP is restored in time, these presentations are reversible. If ATP is not restored before further cell damage, the loss of ATP progresses to have extensive effects on the cell.

Without restoration of ATP, the Ca+ pump ceases to function, causing an influx of calcium ions. Free calcium levels are usually kept low inside the cytoplasm as calcium is an activator of many cellular processes. With the increased free calcium now in the cell, it begins to interact with cellular enzymes that cause further membrane and nuclear damage.[2] Phospholipase, protease, endonuclease, and ATPase are all activated by increased cytoplasmic calcium. Phospholipase damages the plasma membrane by hydrolyzing phospholipids, resulting in whorled patterns called myelin figures. Protease results in proteolysis, breaking down proteins inside the cell and disrupting regular cellular activity. Endonuclease cleaves the phosphodiester bond in a polynucleotide chain, collapsing nuclear chromatin into clumps. ATPase breaks down any remaining ATP, quickening the loss of energy and leading to further damage.

Free cytoplasmic calcium increases mitochondrial permeability by opening a transitional pore. Exposure of mitochondrial contents artificially releases cytochrome c (Cyt c), an important factor in the electron transport chain as well as in apoptosis and cell death. Cyt c begins a cascade of cell injury by direct activation of caspases. This would be one of the ways that necrosis and apoptosis begin to overlap, as caspase activation is a primary mechanism of apoptotic death. In necrotic cell death, the release of caspases is coincidental to cellular injury. In apoptosis, caspase activation is purposeful and initiated through a series of regulating factors.

The cellular characteristics of necrotic cell death do not always follow the pattern seen in ischemic injury, but it serves as a good example. Necrosis results in cell lysis and exposure of cytoplasmic contents in an uncontrolled setting as the plasma membrane is damaged, regardless of the type of damage that led it to this stage. A release of cellular content into the surrounding area generally elicits an inflammatory response not seen in apoptosis.

Clinically, cell lysis and enzymatic leakage are used to assess a potential pathology in patients. When a cardiac cell is damaged and then results in cell lysis, cell-specific enzymes are leaked into the extracellular space. The presence of these cell-specific enzymes, troponin and CK-MB (creatine kinase-muscle/brain), can be used to diagnose myocardial infarctions.

If necrotic cell death is considered accidental cell death, then apoptosis would be referred to as a type of programmed cell death. Recently, a type of controlled necrosis called necroptosis was identified.[3],[4] Apoptosis may be viewed as self-sacrifice by the cell to prevent collateral damage to the surrounding area. Although the mechanisms that lead to necrosis are always pathological, apoptosis does not share the same distinction. Apoptotic mechanisms are used during embryology to shape fingers, selectively resorbing the webbing between digits.[5] Immunologically, apoptotic mechanisms are used during T-cell development to destroy cells that attack self-antigen. Apoptosis is an essential topic in cancer research and DNA damage. When cell cycle regulators detect unrepairable DNA, signals are released to call for cell death. Cancer cells usually employ mechanisms that evade these signals, resulting in immortal cell lines full of mutated DNA that is no longer constrained by cell cycle checkpoints.

Characteristics of apoptosis are cell shrinkage, an intact membrane, chromatin condensation (pyknosis), apoptotic bodies, and lack of inflammatory response. Potentially dangerous cytoplasmic enzymes are carefully packaged and blebbed off the membrane in vacuoles called apoptotic bodies. These bodies are later phagocytosed by lymphocytes without causing local damage. The key to controlled apoptosis is caspases.

Caspase is a portmanteau for cysteine-aspartic proteases, named for the active site cysteine and its cleaving after aspartic acid residues. Caspases exist as inactive enzymes (zymogens) until appropriate activation by apoptotic signals.[6] These pro-caspases are the targets of Cyt C and FADD.

If a cell recognizes it is infected, it may signal for its destruction by altering its membrane, flipping the inner leaflet membrane out to expose phospholipids (specifically, phosphatidylserine) to the outer leaflet, and ultimately, triggering a response from patrolling lymphocytes. The lymphocytes, upon noticing the altered membrane, will initiate the extrinsic apoptosis pathway for that cell.

The extrinsic pathway is initiated by an outside signal via death receptors (DRs). In the case of T-cell mediated death, the plasma membrane-associated death receptor (FasR) is engaged by the T-cell death ligand (FasL). The FasR/FasL interaction, also known as the death receptor pathway, fuses inner membrane Fas-associated death domain proteins (FADD).  FADD (or the death effector domain) newly formed is now able to combine with pro-caspase 8 (zymogen of caspase 8).[7] This fusion creates the death-inducing signaling complex (DISC). DISC can then self-cleave and release the active caspase 8 from its zymogen form.

Caspases are broken into two groups: activators and executioners. Appropriately named, activator caspases 2, 8, 9, and 10 switch on the executioners, caspases 3, 6, and 7. The executioner caspases control DNA fragmentation, membrane alterations, chromatin condensation, and many other factors manipulating the cell content for apoptosis. Caspase 9 released from the extrinsic pathway will extinguish the cell unless inhibited by the survival factor XIAP (X-linked inhibitor of apoptosis protein). Because of its ability to escape the death cycle of a cell, XIAP has been connected to several types of cancer. [8]

The intrinsic apoptotic pathway (also referred to as the mitochondrial pathway) responds to triggers from inside the cell, like irreparable DNA damage.[9] MOMP (mitochondrial outer membrane permeabilization) is the climactic deciding factor in the intrinsic pathway.[10],[11] Like in ischemic cell death, this is where mitochondrial contents like Cyt c initiate terminal effects by caspase activation. Upstream from MOMP is the controller (and often main target of cancer mutations) of the intrinsic pathway, BCL-2 (b-cell lymphoma 2).

BCL-2 is part of the BCL family with anti-apoptotic properties (along with BCL-X and MCL-1).[12] It is located on the outer mitochondrial membrane (OMM) and blocks pro-apoptotic, channel-forming proteins, Bax (bcl-2 associated X protein) and Bak (BCL-2 antagonist or killer) from causing MOMP and releasing inner mitochondrial membrane (IMM) content. Bax/Bak are transmembrane proteins that can oligomerize and create a pore allowing proapoptotic intermembrane space (IMS) proteins to leak out in the cytoplasm. One of these IMS proteins known as Cyt C initiates the caspase cascade when lost from the IMM. Loss of Cyt C from the IMM destroys the energy-creating capacity of the cell via the electron transport chain. For these two reasons, MOMP is often seen as an “all or nothing” step since, without functioning mitochondria, the cell is unlikely to survive.

BCL-2 is inactivated by pro-apoptotic BH3 proteins Bim, Bad, or Bid (subsets of the BCL-2 family that contains only a single BH3 domain). Inactivation of BCL-2 allows Bax/Bak to combine and form a pore, letting IMS proteins leak into the cytoplasm. Newly released Cyt C begins the formation of apoptosomes by combining with adaptor proteins (Apaf-1) in the cytoplasm. Apoptosomes activate the zymogen pro-caspase 9, similar to how DISC activated pro-caspase 8.

Clinical Significance

Cells that harbor a mutation in BCL-2 where it increases quantity or remains to inhibit of Bak/Bax despite death signals can become cancerous. Follicular lymphoma, for example, has a quantity mutation that leads to excessively high levels of BCL-2, decreasing the propensity of these cells to release Bak/Bax and enter apoptosis. If there is a lot of BCL-2 protecting the cell, then there would need to be a greater increase in Bim/Bad/Bid to counter, which does not happen in this cancerous state.

P53 is a tumor suppressor gene that can work in this same Bax/Bak pathway. P53 functions as a regulator within the cell cycle at the G1/S checkpoint. It can arrest the cell cycle at this stage to allow time for DNA repair if P53 senses any mutation. P53 is upregulated when the cell experiences DNA damage or cell cycle abnormalities. The apoptotic pathway of P53 is turned on when the mutations are beyond repair, leading to activation of Bax.[13] As a prominent tumor suppressor, mutations with P53 are related to a multitude of cancers. Endometrial carcinoma commonly has a P53 mutation that turns off the protein’s ability to pause growth or terminate the cell. Pathology reports may show heavy staining of P53 in these biopsies suggesting upregulation due to mutations, but the increased P53 is nonfunctional.

The understanding of cell death and the players involved is a subject of constant research. The better one understands the mechanism of cell death, the more likely that understanding can be integrated into clinical medicine. It is possible to use these pathways to one's advantage, simulating the actions of apoptosis by inhibiting BCL-2 in tumor cells like the chemotherapy drug oblimersen used for chronic lymphocytic leukemia. Chemotherapy treatments with radiation can manipulate these pathways more directly by causing DNA damage that drives the cell to apoptosis.[14] Understanding the basics of cell death allows for better understanding of how tumor cells may evade death and how to counter-evade clinically.


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Histology, Cell Death - Questions

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A 52-year-old male arrives at the emergency department with substernal chest pain. He describes the pain as sharp with radiation to the left arm. Troponin levels are 0.52 microg/L (normal less than 0.04 micorg/L). Which characteristic of cell injury would be most specific to the irreversible cell death seen in affected cardiac cells?



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A 30-year-old, G1P1, woman recently gave birth to a healthy boy at 40 weeks of gestation. He was delivered via cesarean section. After 2 hours, the clinician reports the complete fusion of the middle and ring fingers of the right hand of the baby while the fingers of the left hand are normal. The mother's vitals are stable and she is recovering in the unit. What is the underlying cause of fused fingers of the baby?



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A 65-year-old previously healthy woman comes to her healthcare provider for a follow-up evaluation of retrosternal pain for two months. The pain worsens after heavy meals and upon lying down on the bed at night. She has taken oral omeprazole for several months without any relief of her symptoms. She is a chronic smoker for 15 years. Esophagogastroduodenoscopy shows distal esophageal ulcerations. A biopsy of the distal esophagus shows the presence of columnar epithelium with goblet cells. What is the most likely etiology of this change?



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A 65-year-old male is brought to his healthcare provider by his daughter after getting lost while coming back home this morning. This was the third time that he has gotten lost. The patient states that he feels perfectly well. The daughter reports that she noticed him having trouble with memory for the past year. He is unable to safely take care of himself. On examination, his vitals are normal and there is no focal neurological deficit. After extensive evaluation, he is diagnosed with Alzheimer disease. Which pathological process is most likely the underlying cause of this patient’s condition?

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A 38-year-old, G3P3, woman comes to the clinician for a follow-up evaluation of postcoital bleeding for three months. She is a chronic smoker for 15 years and has a history of 3 sexual partners last year. Her vitals are within the normal range. During an annual exam, her routine cervical Pap smear was done. The cytological evaluation showed squamous cell carcinoma of the cervix. The mutation of tumor suppressor gene p53 is found to be responsible for the patient's condition. This tumor suppressor gene p53 prevents tumor formation by blocking which of the following cellular process?



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A 65-year-old man is diagnosed with malignant lymphoma involving the hilar lymph nodes bilaterally. Chemotherapy is started that causes fragmentation of individual neoplastic cell nuclei and cytoplasm resulting in the loss of neoplastic cells. Over the next 3 months, abdominal CT scans show a significant reduction in the size of the malignant lymphoma. Which of the following mechanisms is responsible for the reduction in lymphoma size?



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A 65-year-old woman presents to the emergency department with severe chest pain for the past 3 hours. She is afebrile but has hypotension and tachycardia. Laboratory studies show increased levels of troponin I in blood. An emergent coronary angiogram reveals more than 90% occlusion of the left anterior descending (anterior interventricular) artery. Which of the following cellular changes would be seen in the myocardial cells assuming irreversible cellular injury has taken place?



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A 65-year-old hypertensive male was taken to his healthcare provider after suddenly losing consciousness. When he regained consciousness after two hours, he was unable to speak or move his left arm and left leg. A cerebral angiogram showed occlusion of his right anterior and right middle cerebral artery. After 2 months, a computed tomographic (CT) scan revealed a large 4 cm cystic area in the cortex of his right parietal lobe. Resolution of which of the following cellular events is responsible for this patient’s CT scan finding?

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A 65-year-old woman presents to the emergency department with severe abdominal pain for the past 4 hours. Physical examination reveals diffuse abdominal tenderness with guarding and muscular rigidity. Her laboratory findings reveal elevated levels of serum AST, ALT, and lipase. An emergent abdominal computed tomographic (CT) scan reveals an enlarged pancreas with a significant peritoneal fluid collection. Which of the following cellular changes is responsible for this patient’s condition?



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A 35-year-old woman presents to the emergency department with significant bleeding from traumatic injury of her left arm. She is afebrile but her blood pressure is 65/30 mmHg and heart rate is 115/min. Which of the following cellular events represent irreversible cellular injury in this patient?



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Histology, Cell Death - References

References

Fuchs Y,Steller H, Live to die another way: modes of programmed cell death and the signals emanating from dying cells. Nature reviews. Molecular cell biology. 2015 Jun     [PubMed]
Beresewicz M,Kowalczyk JE,Zabłocka B, Cytochrome c binds to inositol (1,4,5) trisphosphate and ryanodine receptors in vivo after transient brain ischemia in gerbils. Neurochemistry international. 2006 May-Jun     [PubMed]
Tait SW,Ichim G,Green DR, Die another way--non-apoptotic mechanisms of cell death. Journal of cell science. 2014 May 15     [PubMed]
Linkermann A,Green DR, Necroptosis. The New England journal of medicine. 2014 Jan 30     [PubMed]
Pérez-Garijo A,Steller H, Spreading the word: non-autonomous effects of apoptosis during development, regeneration and disease. Development (Cambridge, England). 2015 Oct 1     [PubMed]
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Günther C,Martini E,Wittkopf N,Amann K,Weigmann B,Neumann H,Waldner MJ,Hedrick SM,Tenzer S,Neurath MF,Becker C, Caspase-8 regulates TNF-α-induced epithelial necroptosis and terminal ileitis. Nature. 2011 Sep 14     [PubMed]
Yang W,Cooke M,Duckett CS,Yang X,Dorsey JF, Distinctive effects of the cellular inhibitor of apoptosis protein c-IAP2 through stabilization by XIAP in glioblastoma multiforme cells. Cell cycle (Georgetown, Tex.). 2014     [PubMed]
Parsons MJ,Green DR, Mitochondria and apoptosis: a quick take on a long view. F1000 biology reports. 2009 Feb 24     [PubMed]
Parsons MJ,Green DR, Mitochondria in cell death. Essays in biochemistry. 2010     [PubMed]
Kalkavan H,Green DR, MOMP, cell suicide as a BCL-2 family business. Cell death and differentiation. 2018 Jan     [PubMed]
Chipuk JE,Moldoveanu T,Llambi F,Parsons MJ,Green DR, The BCL-2 family reunion. Molecular cell. 2010 Feb 12     [PubMed]
Jin S, p53, Autophagy and tumor suppression. Autophagy. 2005 Oct-Dec     [PubMed]
Shimizu S, [Development of anti-cancer drugs mediated by apoptosis and autophagy]. Nihon rinsho. Japanese journal of clinical medicine. 2015 Aug     [PubMed]

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