Chapter 1 - Cell Injury, Adaptation & Death Flashcards
4 Aspects of a Disease Process
- Etiology or cause
- Pathogenesis: sequence of cellular, biochemical, and molecular events
- Morphological changes: structural alterations
- Functional derangements and clinical manifestations
Mechanism of Cell Injury
Cellular response to injurious stimuli depends on the nature of the injury, duration, and severity
Consequence depends on type, state, and adaptability of the injured cell
Injury results from different biochemical mechanisms
Depletion of ATP
Reduction of ATP levels - necrotic cell death
ATP is produced via oxidative phosphorylation of adenosine diphosphate or Glycolytic pathway (absence of oxygen)
Major causes of ATP depletion - reduced supply of oxygen and nutrients, mitochondrial damage, action of some toxins
Mitochondrial damage
Supply life-sustaining energy by producing ATP
Damaged by: inc of cytosolic calcium, ROS, oxygen deprivation, mutations in mitochondrial genes
Influx of Calcium and Loss of Calcium Homeostasis
Calcium normally maintained @ v. low [ ] compared to extracellular calcium, sequestered in mitochondria and ER
Ischemic and certain toxins cause an increase in the cytosolic calcium concentrations
Accumulation of Oxygen-Derived Free Radicals
Cell injury induced by free radicals, particularly reactive oxygen species, is an important mechanism of cell damage
Unpaired e- are highly reactive and “attack” and modify adjacent molecules
Reactive oxygen species are produced normally in cells during mitochondrial respiration and energy generation
Defects in Membrane Permeability
Loss of selective membrane permeability, leading ultimately to overt membrane damage
ischemic - membrane defects may be a result of ATP depletion and calcium-mediated activation of phospholipases
membrane damaged by: various toxins, viral proteins, lytic complement components, variety of physical and chemical agents
Damage to DNA and Proteins
DNA damage too severe, suicide program - apoptosis
similar rxn triggered by improper folded proteins
Cellular metabolism, UV exposure, ionizing radiation, chemical exposure, replication errors -> Cell cycle checkpoint activation, transcriptional program activation, DNA repair, Apoptosis
Ischemic and Hypoxic Injury
Most common type of cell injury leading to cell death, due to diminished blood flow
Reduced O2 leads to reduced oxidative phosphorylation and dec ATP generation -> reduction of Na+ pump function -> efflux of K+, influx of Ca2+, Na+ and H2O = cell swelling and progressive loss of glycogen and dec protein synthesis
Irreversible = accumulation of Ca2+ rich densities in mitochondrial matrix, lack of oxidative phosphorylation and ATP generation, cell membrane damage
Ischemia/ Reperfusion Injury
Restoration of blood flow can promote recovery or exacerbate injury and cell death
Contributes to tissue damage during myocardial and cerebral infarction
Oxidative stress: reoxygenation inc generation of ROS and nitrogen species
Intracellular Calcium Overload: beings during ischemia and exacerbated during reperfusion due to calcium influx
Inflammation: ischemic injury associated w/ inflammation
Activation of complement system: IgM antibodies deposit for unknown reasons, blood flow resumed & proteins bind antibodies and activate = injury
Chemical Injury
limitation to drug therapy
liver -> frequent target to drug toxicity
direct toxicity, conversion to toxic metabolites
Hypertrophy
Inc in size of cells
No new cells
Due to synthesis & assembly of additional structural components
Striated muscle in the heart and skeletal muscles have limited capacity to divide
Hyperplasia
Inc in # of cells
Only take place in tissue containing cells capable of dividing
Physiologic: action of hormones when there is a need for inc capacity; action of growth factors when need for compensatory inc after damage
Pathologic: excessive or inappropriate action of hormones or growth factors acting on target cells
Atrophy
Decrease in cell size and number
Physiologic: common during normal development
Pathologic: dec workload, loss of innervation, diminished blood supply
Metaplasia
Reversible change in which one differentiated cell type (epithelial or mesenchymal) is replaced by another cell type [columnar to squamous]
results form reprogramming of stem cells
Dysplasia
Atypical changes in nuclei, “premalignant” condition
Intracellular Accumulations
One of the manifestations of metabolic derangements in cells
harmless or associated w/ varying degrees of injury
Lipid Accumulations
Accumulate in cells - triglycerides, cholesterol, phospholipids
Steatosis (fatty changes)
abnormal accumulations of triglycerides
Often seen in liver, heart, muscle, and kidney
Causes: toxins, protein malnutrition, diabetes mellitus, obesity, and anoxia
Alcohol abuse and fatty liver disease
Cholesterol and Esters
cellular metabolism is tightly regulated
Most cells use cholesterol for synthesis of cell membrane w/out intracellular accumulations
accumulations seen in atherosclerosis, xanthomas, Niemann-Pick disease type C
Protein accumulations
rounded, eosinophilic droplets, vacuoles, or aggregates in the cytoplasm
causes: renal diseases, defective intracellular transport and secretion of proteins, accumulation of cytoskeleton proteins (alzheimer’s)
“Mallory bodies” - hepatocytes in alcoholic liver disease representing aggregated intermediate filaments of the cytoskeleton
Glycogen Accumulations
readily available energy, abnormality in glucose or glycogen metabolism - diabetes mellitus
Pigment accumulations
colored substances
Coal dust: most common, macrophages in alveoli of lungs
Tattooing: localized exogenous pigmentation of skin
Endogenous: lipofuscin - lipochrome or wear-and-tear pigment. melanin- black/brown pigment. hemosiderin - hemoglobin-derived, golden yellow to brown
Pathologic Calcification
abnormal tissue deposition of calcium salts, together w/ smaller amounts of iron, magnesium, and other mineral salts
Dystrophic calcification
when deposit occurs locally in dying tissues
areas of necrosis, atheroma and damaged heart valves, tuberculous lymph node
cause of organ dysfunction
serum calcium is normal
Metastatic calcification
normal tissues wherever there is hypercalcemia
1. inc secretion of PTH, 2. resorption of bone tissue, 3. Vit D related disorders, 4. renal failure
Extracellular deposits of amyloid
Amyloid: abnormal, fibrillar protein deposited in intercellular matrix of blood vessel walls
AL- immunoglobulin light chains
AA- non-immunoglobulin protein associated w/ chronic inflammatory states
Deposition in kidney may produce nephrotic syndrome
may affect gastrointestinal tract
small vessels of brain
Reversible injury
- cellular swelling: appears whenever cells are unable to maintain ionic and fluid homeostasis
- fatty changes: occur in hypoxic injury and various forms of toxic or metabolic injuries
Irreversible Injury
Denaturation of intracellular proteins
Enzymatic digestion of the lethally injured cells
Elicit inflammation in surrounding tissues
Necrosis
Microscopic appearance in H&E stain: pale, eosinophilic cells due to binding of eosin dye to denatured proteins
Pyknosis
nuclei shrink
Karyorrhexis
nuclei fragment
karyolysis
nuclei disintegrate
Coagulative necrosis
Architecture of the dead tissue is preserved for a span of @ least some days
ischemic leads to it
A localized area of coagulative necrosis is called an infarct
Liquefactive Necrosis
digestion of the dead cells
Seen in focal bacterial, or occasionally, fungal infections
Necrotic material is frequently creamy yellow b/c of presence of dead leukocytes and is called pus
Also occurs in ischemic necrosis of brain for unclear reasons (no inflammatory cells)
Caseous (Caseation) Necrosis
Associated with tuberculosis
Cheesy appearance
architecture is completely obliterated
Appearance is characteristic of a focus of inflammation known as granuloma
Fat Necrosis
focal area of fat destruction
typically results from release of activated pancreatic lipases into the substance of pancreas and peritoneal cavity
“Gangrenous” Necrosis
limb, lower leg, lost blood supply
ischemic coagulative necrosis
“Wet” gangrene has superimposed bacterial petrification leading to slimy appearance
Apoptosis
tightly regulated suicide program -> intrinsic enzymes activated and degrade DNA and cytoplasmic proteins
normal but can be pathologic
50-70 billion cells die each day
An active, intracellular, energy-dependent process as opposed to necrosis
Doe NOT elicit an inflammatory response or damage adjacent cells
Inducers of Apoptosis
growth factor reduction Corticosteroids Viruses Free Radicals Ionizing radiation Cytotoxic Drugs Immune-mediated cytolysis (T-cell induced)
Inhibitors of apoptosis
sex steroids
certain viral proteins
chromosomal abnormalities in malignant cellular transformation which activate the bcI-2 gene
Diseases w/ Increased Apoptosis
cell loss in neurodegenerative disease, may contribute to dec. CD4 lymph in HIV, exposure to ionizing radiation
Diseases w/ Decreased Apoptosis
Leads to cell accumulation, failure to inhibit may follow loss of p53 protein
inc expression of bc1-2 protein (lymphomas) -> inhibits apoptosis enabling tumor to grow, autoimmune disease (autoreactive T-cells), cell accumulation, loss of p53 proteins (switch defective cells to apoptosis before enter mitosis)
