anatomy
Cellular Pathophysiology
Srujana Rayalam DVM, PhD
Dept. of Pharmaceutical Sciences
PCOM-GA Campus
PHAR 113G Anatomy, Physiology & Pathophysiology I
Learning Objectives
Review the following concepts before class:
Explain the concept of homeostasis & its relevance to physiology
Describe the major constituents of extracellular fluid & their normal ranges
Explain the role of negative feedback mechanisms in homeostasis
Describe the differences between hypertrophy, hyperplasia, atrophy, metaplasia and dysplasia
Must know concepts after the end of the lecture:
Explain the nature & primary mechanisms for cellular injury
Describe the mechanisms of apoptosis & explain how it differs from necrosis
Describe how intracellular accumulation of a substance can cause disease
Describe the components of cellular aging
Extracellular fluid: the internal environment
About 60 percent of the adult human body is fluid
most of this fluid is intracellular fluid
about one third is extracellular fluid – also called “internal environment”
Cells in body are bathed by extracellular tissue fluid which supports cell functions
Cells are capable of performing their special functions as long as the internal environment is conducive
Chemical compositions of extracellular and intracellular fluids
Negative feedback mechanisms
Most homeostatic control mechanisms are negative feedback mechanisms.
A negative feedback mechanism causes the variable to change in a way that opposes the initial change.
Both the nervous system and the endocrine system are important to the maintenance of homeostasis.
The goal of negative feedback mechanisms is to prevent sudden, severe changes in the body.
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Robbins & Cotran Pathologic Basis of Disease (8th edition)
Cellular responses to stress and injurious stimuli
Robbins & Cotran Pathologic Basis of Disease (8th edition)
Robbins & Cotran Pathologic Basis of Disease (8th edition)
Non-dividing cells adapt to stress by increase in size
Cell number unaltered, but organ increases in size
Characteristic response of cardiac & skeletal muscle to increased load
Hypertrophy
Robbins & Cotran Pathologic Basis of Disease (8th edition)
Increase in the size of cells, resulting in an increase in the size of the organ – physiologic hypertrophy
Hypertrophy
Hyperplasia
Dividing cells adapt to stress by increase in number
Results in increase in size of organ
Often accompanied by hypertrophy
Typically triggered by growth factors (as hypertrophy)
Physiologic
hormonal hyperplasia
compensatory hyperplasia
Pathologic
caused by excesses of hormones or growth factors acting on target cells
Benign prostatic hyperplasia; skin warts caused by HPV
hyperplasia is distinct from cancer, but pathologic hyperplasia constitutes a fertile soil in which cancerous proliferation may eventually arise
Decrease in cell size and function with concurrent decrease in organ size and/or function.
Renal atrophy
Testicular atrophy
Normal Brain
Atrophic Brain
Atrophy
Alteration in cell differentiation with concurrent alteration of tissue/organ function.
Reversible replacement of one differentiated cell type by another adult cell type as an adaptation to withstand adverse environment
Characteristic of epithelial & mesenchymal cells
Columnar to squamous epithelial metaplasia
most common
respiratory tract of heavy smoker
stones in excretory ducts
Squamous to columnar
in esophagus – Barrett’s esophagus
Metaplasia
Dysplasia
Characterized by deranged cell growth of a specific tissue that results in cells that vary in size, shape, and organization
The pattern is most frequently encountered in areas of metaplastic squamous epithelium of the respiratory tract and uterine cervix.
Strongly implicated as a precursor of cancer.
Example: Cancer of the uterine cervix develops in a series of incremental epithelial changes ranging from severe dysplasia to invasive cancer
Mechanisms of intracellular accumulations
Robbins & Cotran Pathologic Basis of Disease
Buildup of substances that cells cannot immediately use or eliminate
Accumulations can be due to metabolic alterations, genetic conditions or chronic injury
Triglyceride Accumulation Steatosis (Fatty Liver)
Normal Liver
Fatty Liver
Oil Red O Stain
Causes of Cellular Injury
Hypoxia (e.g., due to ischemia)
Physical agents (e.g., trauma, extreme temperature, electric shock)
Chemical agents (e.g., drugs, pesticides)
Infectious agents (e.g., bacteria, viruses)
Immune response (e.g., autoimmune disease)
Genetic defects or variations
Nutritional imbalance (deficiency or excess)
Robbins & Cotran Pathologic Basis of Disease (8th edition)
Mechanisms of cell injury
Robbins & Cotran Pathologic Basis of Disease (8th edition)
Depletion of ATP Hypoxia – Ischemia Model
Blood Clot
O2
Oxidative
Phosphorylation
ATP
Impaired function of the
plasma membrane
ATP-dependent
Na+ pump
Glycolysis
Detachment of
ribosomes
Mitochondrial Damage
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Calcium induced cell injury
Ca2+ usually kept at very low concentration in cells
100 nmol/L or lower (compared to 1 mmol/L outside); about 10,000-fold concentration gradient
Maintained by active transport
Ca2+ rise in cell activates many enzymes
Phospholipases & proteases (membrane damage)
Endonuclease (DNA damage)
Also triggers mitochondrial dysfunction
Robbins & Cotran Pathologic Basis of Disease (8th edition)
Oxidative Stress: Accumulation of Oxygen-Derived Free Radicals
Free radicals - chemical species that have a single unpaired electron in an outer orbit
ROS – a type of oxygen-derived free radicals
Energy created by free radicals is unstable and is released through reactions with adjacent molecules – autocatalytic
When ROS levels increase or when the scavenging systems are ineffective, a condition called oxidative stress develops
implicated in a variety of pathologic processes like cell injury, cancer, aging etc.
Role of ROS in Cell Injury
Robbins & Cotran Pathologic Basis of Disease (8th edition)
Removal of free radicals
Antioxidants: lipid soluble vitamins
Free radical scavenging enzymes: Superoxide dismutase, catalase, glutathione peroxidase
Loss of Membrane Permeability
Mechanisms of membrane damage: ROS, ↓ phospholipid synthesis, ↑ phospholipid breakdown, cytoskeletal abnormalities
Robbins & Cotran Pathologic Basis of Disease (8th edition)
Consequences of membrane damage:
Damage to mitochondrial membrane
Failure of ATP generation
Damage to cell membrane
Loss of osmotic balance
Damage to lysosomal membrane
Release of hydrolytic
enzymes into cytoplasm
Damage to DNA and Proteins
Cells have capability to repair modest DNA damage
Extensive DNA damage usually triggers apoptosis
(“programmed cell death”)
Reduces risk that mutant cell will survive & divide
Reduces risk of neoplasia (cancer)
Improper protein folding also triggers apoptosis
Also reduces risk that mutant cell will survive
Cell Death
Irreversible injury
Two principle types of cell death
Necrosis
“accidental” and unregulated form of cell death
cell death in many commonly encountered injuries
ischemia, exposure to toxins, various infections, and trauma
Apoptosis
highly regulated process
when the cell’s DNA or proteins are damaged beyond repair, the cell kills itself by apoptosis
Robbins & Cotran Pathologic Basis of Disease (8th edition)
Necrosis
Progressive injury beyond the point of no return
loss of integrity of cell & organelle membranes
Leakage of cellular contents
triggers inflammatory response
Morphology
↑ eosinophilic staining
myelin figures
calcification
Nucleus – karyolysis, pyknosis, karyorrhexis
Apoptosis
Apoptosis (“programmed cell death”) occurs in embryogenesis when cell is no longer needed
Also triggered by some forms of irreparable injury to cell
Distinct process from necrosis
Characterized by cell shrinkage (not swelling)
Cell membrane remains intact
Chromatin condenses in nucleus
Characteristic DNA fragmentation
Formation of “apoptotic bodies”
Negligible inflammatory response
Robbins & Cotran Pathologic Basis of Disease (8th edition)
Causes of Apoptosis
Physiological conditions
Programmed destruction of cells during embryogenesis
Involution of hormone-dependent tissues upon hormone withdrawal
Elimination of potentially harmful self-reactive lymphocytes
Cell loss in proliferating cell populations
Pathological conditions
Cell death in certain infections
DNA damage
Accumulation of misfolded proteins
Morphology of Apoptosis
Chromatin condensation
Progressive cell shrinkage
Plasma membrane blebbing
Apoptotic bodies
Phagocytosis - no inflammation
Mechanisms of Apoptosis: Intrinsic or Mitochondrial Pathway
increased mitochondrial permeability due to activation of pro-apoptotic proteins like Bax and inhibition of anti-apoptotic proteins like Bcl2
release of cytochrome c into the cytoplasm
activation of caspase cascade
Caspases – cysteine proteases “executioner” proteins
Robbins & Cotran Pathologic Basis of Disease (8th edition)
Mechanisms of Apoptosis: Extrinsic or Death Receptor Pathway
Death receptors are members of the TNF (tumor necrosis factor) receptor family (Fas receptor and Fas ligand)
Activation of caspases
Characteristic mechanism for apoptosis in lymphocytes
Robbins & Cotran Pathologic Basis of Disease (8th edition)
Summary of Intrinsic and Extrinsic Pathways
Robbins & Cotran Pathologic Basis of Disease (8th edition)
Necrosis vs. Apoptosis
Robbins & Cotran Pathologic Basis of Disease (8th edition)
Cellular Aging
Robbins & Cotran Pathologic Basis of Disease (8th edition)
Sirtuin activators present in red wine???
Progressive decline in cellular function and viability caused by genetic abnormalities and the accumulation of cellular and molecular damage
Role of telomeres and telomerase in replicative senescence of cells
Robbins & Cotran Pathologic Basis of Disease (8th edition)
Telomerase activity is expressed in germ cells and is present at low levels in stem cells, but it is absent in most somatic tissues.
In immortalized cancer cells, telomerase is usually reactivated and telomere length is stabilized, allowing the cells to proliferate indefinitely.
Summary
Concept of homeostasis & its relevance to physiology
Major constituents of ECF and ICF; their normal ranges
Explain the role of negative feedback mechanisms in homeostasis
Outline the differences between hypertrophy, hyperplasia, atrophy & metaplasia
Explain the nature & primary mechanisms for cellular injury
Outline the mechanisms of apoptosis & explain how it differs from necrosis
Outline how intracellular accumulation of a substance can cause disease
Understand the components of cellular aging