General Pathology – Cell Injury, Death & Aging

A set of vocabulary flashcards covering essential terms related to cellular injury, necrosis, apoptosis, oxidative stress, aging, and pigment disorders, distilled from the lecture notes.

Describe the fundamental characteristics distinguishing pathological cell death, including its key features like membrane integrity loss and inflammatory response.

• Uncontrolled, pathological process.

• Characterized by loss of cell membrane integrity.

• Involves enzymatic digestion of cellular components.

• Typically elicits an inflammatory response in surrounding tissue.

Elaborate on the type of necrosis where basic tissue architecture is preserved due to protein denaturation, noting its classical occurrences and exceptions.

• Form of necrosis where protein denaturation predominates.
• Preserves the basic tissue architecture for a period.
• Classically observed in hypoxic injury.
• Commonly affects solid organs, with the notable exception of the brain.

Detail the necrotic pattern resulting from enzymatic digestion that leads to a viscous liquid mass, providing examples of its typical presentation.

• Characterized by enzymatic digestion of dead cells.
• Leads to the formation of a viscous liquid mass or pus.
• Most typical in the central nervous system (e.g., brain infarcts).
• Also characteristic of suppurative (pus-forming) infections.

Describe the distinct, 'cheese-like' necrotic appearance often associated with granulomatous inflammation, particularly in specific infectious diseases.

• Distinctive 'cheese-like' or 'crumbly' appearance.
• Characterized by fragmented, amorphous granular debris.
• Often surrounded by a granulomatous inflammatory reaction.
• Highly characteristic feature of tuberculosis.

Explain the process of adipose tissue destruction involving lipase activity, and how it results in specific chalky deposits, citing common clinical scenarios.

• Involves the enzymatic destruction of adipose (fat) tissue.
• Mediated by lipases, which break down triglycerides.
• Results in the formation of chalky white, soap-like deposits.
• This process is known as saponification.
• Classically observed in contexts such as acute pancreatitis and traumatic injury to fatty tissues like the breast.

Identify the specific type of vascular injury characterized by bright eosinophilic deposits resembling fibrin in vessel walls, and list conditions where it is typically seen.

• A form of necrosis affecting blood vessel walls.
• Characterized by the deposition of bright eosinophilic, fibrin-like material.
• Often indicative of immune-mediated vascular damage.
• Commonly seen in conditions like vasculitides and malignant (severe) hypertension.

Differentiate between 'dry' and 'wet' forms of this clinical term referring to ischemic tissue necrosis, primarily affecting extremities.

• A clinical-pathological term, not a specific morphological pattern of cell death.

• Refers to ischemic necrosis, most commonly affecting the extremities.

• Dry Gangrene: - Primarily a form of coagulative necrosis.

  • Occurs due to insufficient blood supply (ischemia).
  • Appears dry, shrunken, and dark (often black).

• Wet Gangrene: - Occurs when bacterial infection is superimposed on ischemic necrosis.

  • Involves liquefactive necrosis due to bacterial enzymes and leukocytes.
  • Appears moist, swollen, putrid, and has a foul odor.

At what critical juncture does cellular damage become permanent, inevitably leading to cell death, encompassing key organelle systems?

• Represents the 'point of no return' for a cell.

• Damage to critical cellular components becomes permanent.

• Key affected organelles include:- Mitochondria (irreversible dysfunction).

  • Cell membranes (irreversible rupture / permeability changes).
  • Nucleus (irreversible changes like pyknosis, karyorrhexis, karyolysis).

Describe the process of programmed cell death, highlighting its key morphological and biochemical features, and its distinction from necrosis regarding inflammation.

• A genetically programmed and highly regulated form of cell death.

• Often referred to as 'cellular suicide'.

• Key characteristics include:- Cell shrinkage.

  • Chromatin condensation and fragmentation.
  • Formation of membrane blebs and apoptotic bodies.

• Mediated by a family of proteolytic enzymes called caspases.

• Does not typically induce an inflammatory response in surrounding tissues.

Trace the sequence of events in the intrinsic pathway of apoptosis, emphasizing the role of the Bcl-2 family, cytochrome-c, and specific caspase activation.

• Also known as the mitochondrial pathway.
• Initiated by various intracellular stresses (e.g., DNA damage, growth factor withdrawal).
• Involves a delicate balance of pro-apoptotic (e.g., Bax, Bak) and anti-apoptotic (e.g., Bcl-2, Bcl-xL) proteins of the Bcl-2 family.
• Leads to mitochondrial outer membrane permeabilization (MOMP).
• Triggers the release of cytochrome c and other pro-apoptotic factors from mitochondria into the cytoplasm.
• Cytochrome c then activates Apaf-1, forming the apoptosome, which recruits and activates initiator caspase-9.

Outline the apoptotic cascade initiated by specific cell surface receptors, detailing the ligands involved and the resultant caspase activation.

• Also known as the death receptor pathway.

• Initiated by the binding of specific ligands to cell surface 'death receptors' (transmembrane proteins).

• Key death receptors include:- Fas (CD95) binding to Fas ligand (FasL).

  • TNF receptor 1 (TNFR1) binding to TNF-alpha.

• Activation leads to a signaling complex (DISC) formation.

• This complex recruits and activates initiator caspase-8.

• Granzyme B, released by cytotoxic T lymphocytes, can also directly activate caspases or cleave Bid, linking to the intrinsic pathway.

Explain the paradox of tissue damage that can occur upon restoration of blood flow following an ischemic insult, identifying key contributing factors like free radicals and immune responses.

• Refers to the paradoxical exacerbation of cellular injury.

• Occurs when blood flow (reperfusion) is restored to tissues.

• This damage follows a period of ischemia (lack of blood supply).

• Key mechanisms contributing to reperfusion injury include:- Generation of excessive reactive oxygen species (ROS).

  • Activation of the complement system.
  • Inflammation, involving neutrophils and cytokines.
  • Intracellular calcium overload.

Define reactive oxygen species and provide examples of these highly reactive free radicals, elaborating on their detrimental effects on cellular components.

• Highly reactive, oxygen-containing molecules.

• Possess unpaired electrons in their outer shell (free radicals).

• Examples include:- Superoxide anion (O_2^{\cdot-}).

  • Hydrogen peroxide (H2O2).
  • Hydroxyl radical (OH^{\cdot}).

• Their reactivity leads to significant cellular damage by:- Lipid peroxidation of membranes.

  • Oxidation and fragmentation of proteins.
  • DNA damage, including single and double-strand breaks.

Describe the role of antioxidants in cellular defense, providing examples of both endogenous and exogenous molecules that mitigate oxidative injury.

• Molecules that can neutralize or scavenge reactive oxygen species (ROS).

• Protect cells from oxidative damage.

• Can be:- Endogenous (produced by the body):

  • Glutathione.
  • Uric acid.
  • Coenzyme Q10.
  • Exogenous (obtained from diet):
  • Vitamin E (tocopherol).
  • Vitamin C (ascorbic acid).
  • Carotenoids.

Explain the concept of the Hayflick Limit in the context of cellular aging, linking it to the finite replicative capacity of somatic cells and a specific chromosomal structure.

• Refers to the finite number of times a normal human somatic cell population can divide.
• Typically ranges from approximately 40 to 60 cell divisions in vitro.
• Reaching this limit triggers cellular senescence (irreversible growth arrest).
• Directly linked to the progressive shortening of telomeres with each cell division.

Detail the structure and critical protective function of telomeres, explaining how their dynamics contribute to cellular aging and division limits.

• Specialized protective caps located at the ends of eukaryotic chromosomes.
• Consist of repetitive non-coding DNA sequences, specifically TTAGGG repeats in humans.
• Act as buffers, protecting the vital coding DNA sequences from degradation and fusion during DNA replication.
• They progressively shorten with each successive cell division due to the 'end-replication problem' of DNA polymerase.

Describe the enzymatic activity and physiological distribution of telomerase, explaining its role in maintaining telomere length and its implications in cell proliferation, particularly in cancer.

• A specialized ribonucleoprotein reverse transcriptase enzyme.

• Contains an RNA template (TERC) and a catalytic protein subunit (TERT).

• Its function is to synthesize and add new telomeric DNA repeats to the ends of chromosomes.

• Activity is typically high in:- Germline cells.

  • Embryonic stem cells.
  • Certain adult stem cells.

• Crucially, its expression is reactivated in over 85\% of human cancers, contributing to their unlimited proliferative potential.

Discuss the genetic basis and clinical manifestations of Werner Syndrome, characterizing it as an adult-onset progeroid disorder.

• An autosomal recessive genetic disorder.

• Characterized as an adult-onset progeroid syndrome, meaning it causes premature aging.

• Caused by mutations in the WRN gene.

• The WRN gene encodes a DNA helicase, an enzyme crucial for DNA replication, repair, and telomere maintenance.

• Clinical features include:- Premature graying and thinning of hair.

  • Bilateral cataracts.
  • Skin atrophy and ulceration.
  • Type 2 diabetes mellitus.
  • Osteoporosis.
  • Increased risk of certain cancers.

Explain the molecular defect underlying Hutchinson-Gilford Progeria Syndrome and its impact on cellular structure, leading to a severe childhood progeroid presentation.

• A rare, severe, and rapid-onset progeroid syndrome.

• Symptoms appear in early childhood (e.g., within the first two years of life).

• Caused by a de novo point mutation in the LMNA gene.

• The LMNA gene encodes Lamin A, a protein essential for maintaining the structural integrity of the nuclear lamina.

• The mutation leads to the production of an abnormal, truncated Lamin A protein called 'progerin'.

• Progerin causes nuclear instability, leading to widespread cellular dysfunction and premature aging phenotypes.

• Clinical features include:- Alopecia.

  • Failure to thrive.
  • Characteristic facial features (e.g., prominent eyes, small jaw).
  • Severe cardiovascular disease, leading to early death, often by teenage years.

Elaborate on the significance of ERCC genes in DNA repair and their association with specific premature aging syndromes.

• Stands for Excision-Repair Cross-Complementing genes.

• Encode proteins involved in nucleotide excision repair (NER), a crucial DNA repair pathway.

• NER is responsible for repairing bulk-distorting DNA lesions, such as those caused by UV radiation.

• Mutations in specific ERCC genes are associated with several premature aging syndromes, including:- Cockayne Syndrome (CS): Mutations in ERCC6 (also known as CSB) or ERCC8 (also known as CSA). Leads to neurodegeneration, photosensitivity, and growth retardation.

  • Xeroderma Pigmentosum (XP): Mutations in other ERCC genes (e.g., ERCC2/XPD, ERCC3/XPC). Characterized by extreme photosensitivity and high cancer risk.

Discuss the general function of DNA repair enzymes and the broad implications of their defects on cellular integrity, particularly in relation to cancer and accelerated aging.

• A diverse group of cellular proteins.

• Crucial for detecting and correcting various types of damage to DNA.

• They maintain the genomic integrity of cells.

• Defects or mutations in these enzymes can have severe consequences, leading to:- Increased rates of somatic mutations.

  • Genomic instability.
  • A significantly elevated predisposition to cancer development.
  • Contribution to premature aging syndromes (progeroid states).

Identify the specific intracytoplasmic inclusion found in plasma cells, explaining its composition and its clinical significance as an indicator of cellular activity.

• An eosinophilic, homogeneous, spherical inclusion.
• Found within the cytoplasm of plasma cells.
• Represents an excessive accumulation of newly synthesized immunoglobulins (antibodies) within the rough endoplasmic reticulum (RER).
• Their presence often indicates chronic antigen stimulation, suggesting sustained immune activation or chronic inflammation.

Define Xanthoma in terms of its cellular composition and location, linking its appearance to underlying metabolic disorders.

• A focal accumulation of lipid-laden macrophages (foam cells).
• Appears as yellowish plaques or nodules.
• Commonly found in the skin and/or tendons.
• Their presence is a clinical sign highly suggestive of underlying hyperlipidemia (elevated levels of fats/lipids in the blood).

Describe the pathological condition known as 'strawberry gallbladder,' detailing its cellular basis and typical location.

• A condition of the gallbladder, often referred to as 'strawberry gallbladder' due to its appearance.
• Characterized by the accumulation of cholesterol-loaded macrophages (foam cells).
• These cells are found predominantly within the lamina propria of the gallbladder wall.
• The yellowish flecks against the red mucosal background resemble strawberry seeds, hence the descriptive name.

Explain the reversible cellular accumulation of triglycerides, identify the most common organ affected, and discuss its reversibility.

• Refers to the reversible intracellular accumulation of triglycerides (fats).
• Occurs within the cytoplasm of parenchymal cells.
• Most commonly observed in the liver, leading to 'fatty liver' changes.
• It is typically a reversible change, meaning that if the causative stress is removed, the fat accumulation can resolve.

Characterize Lipofuscin, describing its appearance, composition, and its significance as a 'wear-and-tear' pigment indicative of cellular aging or atrophy.

• A yellow-brown, finely granular intracellular pigment.
• Often referred to as 'wear-and-tear' or 'aging pigment'.
• Composed of lipid-protein complexes.
• Represents the indigestible residues of lipid peroxidation and other cellular damage.
• Accumulates progressively within senescent cells, particularly in stable, long-lived cells (e.g., heart muscle, liver, neurons).
• Its presence is a common indicator of past free radical injury and cellular atrophy or aging processes.

Define Hemosiderin, explaining its origin from hemoglobin breakdown, its characteristic color, and the special stain used for its identification.

• A yellow-brown, granular or crystalline pigment.
• Chiefly composed of aggregates of ferritin micelles.
• Represents a form of stored iron.
• Derived from the breakdown of hemoglobin, primarily after hemorrhage or red blood cell lysis.
• Readily identified histologically by its positive reaction to the Prussian blue stain specific for iron.

Characterize Bilirubin, explaining its derivation from heme and its role in clinical conditions characterized by yellow discoloration.

• A yellow-orange bile pigment.

• Formed as a byproduct of heme catabolism, primarily from the breakdown of aged red blood cells.

• In its unconjugated form, it is insoluble in water and transported by albumin.

• Elevated levels (hyperbilirubinemia) lead to:- Jaundice: Yellow discoloration of the skin and mucous membranes.

  • Icterus: Yellow discoloration of the sclera (whites of the eyes).

Distinguish dystrophic calcification by its occurrence in damaged tissues, emphasizing that it happens despite normal systemic calcium levels.

• Involves the abnormal deposition of calcium salts.

• Occurs specifically in dead, dying, or degenerated tissues.

• A crucial diagnostic feature is that it occurs in the presence of normal serum calcium levels.

• Common examples include:- Necrotic areas (e.g., caseous necrosis in tuberculosis).

  • Atherosclerotic plaques.
  • Damaged heart valves.

Contrast metastatic calcification from dystrophic, focusing on its occurrence in healthy tissues and its direct association with systemic hypercalcemia, providing specific examples of causative conditions.

• Involves the abnormal deposition of calcium salts.

• Occurs in otherwise healthy, normal tissues.

• Directly results from systemic hypercalcemia (elevated serum calcium levels).

• Conditions causing hypercalcemia include:- Hyperparathyroidism (primary or secondary).

  • Bone destruction due to metastasis.
  • Vitamin D intoxication.
  • Sarcoidosis.

Describe the complement system as a crucial plasma protein cascade, highlighting its activation mechanisms and its multifaceted roles in inflammation and immune defense.

• A complex system composed of over 30 plasma proteins.

• Acts as a crucial part of the innate immune system.

• Functions as a biochemical cascade, meaning activation of one component leads to activation of the next.

• Plays a central role in:- Enhancing inflammation.

  • Directly killing pathogens (via membrane attack complex).
  • Opsonization (tagging pathogens for phagocytosis).

• Can be activated by:- Pathogen surfaces (alternative pathway).

  • Antibody-antigen complexes (classical pathway).
  • Lectin binding (lectin pathway).

• Is particularly active during reperfusion injury and various immune reactions.

Define caspases, specifying their enzymatic nature and their pivotal role as executioners in the cascade of apoptotic processes.

• A family of cysteine-dependent aspartate-directed proteases.
• They are the primary executioners of apoptosis.
• Exist as inactive pro-enzymes (pro-caspases) in healthy cells.
• Upon activation, they cleave specific target proteins at aspartate residues.
• Their proteolytic activity dismantles the cell in a controlled manner, leading to the characteristic features of apoptosis (e.g., chromatin condensation, DNA fragmentation, cell shrinkage).

Discuss the diverse roles of the Bcl-2 protein family in regulating apoptosis, distinguishing between its anti-apoptotic and pro-apoptotic members and their impact on mitochondrial membrane permeability.

• A critical family of proteins serving as key regulators of the intrinsic apoptotic pathway.

• Their function is primarily to control the permeability of the mitochondrial outer membrane.

• Divided into two main groups:- Anti-apoptotic members:

  • Examples: Bcl-2, Bcl-xL, Mcl-1.
  • Act to preserve mitochondrial membrane integrity, preventing cytochrome c release.
  • Pro-apoptotic members:
  • Examples: Bax, Bak (effector proteins).
  • BH3-only proteins (e.g., Bid, Bad, Puma, Noxa) which activate Bax/Bak.
  • Induce mitochondrial outer membrane permeabilization, leading to the release of pro-apoptotic factors like cytochrome c.

Characterize cytokines as signaling molecules, describing their origin, general properties, and their broad modulatory roles in inflammation and immune responses.

• Small, soluble proteins or glycoproteins.

• Act as intercellular messengers (cell signaling molecules).

• Secreted by various cell types, including immune cells (e.g., macrophages, lymphocytes) and injured cells.

• They bind to specific receptors on target cells, activating intracellular signaling pathways.

• Play crucial roles in modulating:- Inflammation (pro-inflammatory like IL-1, TNF-alpha; anti-inflammatory like IL-10).

  • Immune cell growth, differentiation, and activation.
  • Wound healing and tissue repair.

Explain the cellular process of phagocytosis, identifying the primary cell types involved and the purpose of engulfing extraneous materials.

• A specialized form of endocytosis ('cell eating').

• A fundamental process performed by professional phagocytes.

• Primary cell types involved are:- Neutrophils.

  • Macrophages.

• Involves the engulfment and internalization of:- Microbes (bacteria, fungi).

  • Dead cells.
  • Cellular debris.
  • Foreign particles.

• The internalized materials are then sequestered into intracellular vesicles called phagosomes for destruction.

Describe the formation and functional significance of a phagolysosome in the intracellular degradation of engulfed materials.

• An intracellular organelle formed within phagocytic cells.
• It is created by the fusion of a phagosome (a vesicle containing engulfed material) with one or more lysosomes.
• Lysosomes are organelles rich in hydrolytic enzymes.
• The fusion enables the enzymatic degradation and destruction of the internalized microbes, dead cells, or debris within this acidic compartment.

Detail the mechanism of free radical injury, explaining how uncontrolled reactive oxygen species induce damage to critical cellular macromolecules.

• Refers to cellular damage caused by an imbalance between the production of free radicals and the cell's ability to detoxify or repair the resulting damage.

• Uncontrolled accumulation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) leads to:- Lipid peroxidation: Damage to cell membranes and organelles.

  • Protein fragmentation: Oxidation and cross-linking, impairing enzyme function.
  • DNA strand breaks: Leading to mutations and impaired cell division.

• This oxidative stress can overwhelm cellular antioxidant defenses, leading to irreversible injury and cell death.

List and briefly describe the function of key endogenous antioxidant enzymes that constitute a cell's primary defense against oxidative stress.

• A group of endogenous enzymes produced by the cell.

• They serve as a crucial part of the cell's defense system against oxidative stress.

• Key examples include:- Superoxide Dismutase (SOD): Converts superoxide radicals (O2^{\cdot-}) into hydrogen peroxide (H2O_2) and oxygen.

  • Catalase: Decomposes hydrogen peroxide (H2O2) into water and oxygen.
  • Glutathione Peroxidase (GPx): Reduces hydrogen peroxide and organic hydroperoxides to less harmful molecules, using glutathione as a cofactor.

Characterize reversible cell injury, describing its key morphological hallmarks and the condition under which a cell can return to normal function.

• An early stage of cellular damage where the cell can recover and return to normal function.

• This recovery is possible if the injurious stimulus is removed.

• Key morphological changes observed during reversible injury include:- Cellular swelling: Due to influx of water consequent to ion pump failure.

  • Fatty change (steatosis): Accumulation of triglycerides, particularly in organs like the liver and heart.

• Other changes may include detachment of ribosomes from ER and mitochondrial swelling.

Define cellular senescence, explaining its underlying mechanisms related to cell division limits and DNA damage, and its implications for tissue homeostasis.

• A state of irreversible growth arrest in which cells stop dividing but remain metabolically active.

• It is a stable, non-proliferative state.

• Triggered by various cellular stressors, including:- Telomere shortening: Reaching the Hayflick limit.

  • Accumulation of DNA damage.
  • Oncogene activation.

• Serves as an important tumor-suppressive mechanism.

• Senescent cells exhibit distinct phenotypes, including altered gene expression and secretion of pro-inflammatory factors (SASP - Senescence-Associated Secretory Phenotype).