Cell Injury, Adaptation, Inflammation and Repair — Comprehensive Study Notes

Cell Injury, Adaptation and Death

Core idea: Damage to cells is the basis of most abnormalities or disease; pathologic processes are linked to morphological changes.
Focus areas: alterations in injured cells/tissues, cell and tissue responses to injury (adaptation, damage, death), physiologic and pathologic death, with emphasis on injury due to infection and inflammatory responses.

Overview: Normal Cell, Injury Continuum

Normal cell (homeostasis) operates within a narrow functional and structural range.
Injurious stimuli can arise from many sources but cells may respond in predictable ways.
Reversible injury: cellular changes that can return to normal if the stress is removed.
Irreversible injury: progresses to cell death.
Death forms include necrosis and apoptosis; necroptosis is a regulated form of necrosis.
Key conceptual pathway: Homeostasis → Reversible Injury → Irreversible Injury → Cell Death (necrosis or apoptosis) with possible intermediate forms like necroptosis.
Visual cue (concept): reversible injury involves sublethal organelle and membrane disturbances; irreversible injury involves loss of mitochondrial function, DNA/chromatin integrity, and plasma membrane disruption.

Cellular Injury and Death: Reversible vs Irreversible

Reversible injury (to a point): energy failure leads to failure of energy-dependent ion pumps, cellular swelling, vacuolar degeneration; cells may accumulate lipids (fatty change) in stressed organs (e.g., liver).
Irreversible injury: when mitochondrial function cannot be restored, DNA/chromatin integrity is lost, and plasma/intracellular membranes disintegrate leading to necrosis.
Inflammation often accompanies dying cells and can be part of the adaptive response.
Common reversible injuries shown: vacuolar degeneration in keratinocytes; fatty change in liver; general cellular swelling.
Irreversible injury examples: extensive membrane damage, nuclear changes (pyknosis, karyorrhexis, karyolysis), and cell rupture.

Morphology of Reversible Injury

Organelles take up water due to failure of energy-dependent ion pumps in the plasma membrane (vacuolar degeneration).
Lipid accumulation occurs in cells that metabolize lipids (e.g., hepatocytes) leading to “fatty change.”
Reversible injuries are often detectable microscopically.
Epithelial cells may react to injurious stimuli without dying (metabolic changes).
Dying cells often elicit an inflammatory response and may involve adaptive changes.

Irreversible Injury and Necrosis

Irreversible injury leads to cell death; morphological patterns depend on tissue type and cause.
Types of necrosis (morphology): coagulative, liquefactive, caseous, fat necrosis, fibrinoid necrosis, and gangrenous forms.
Common causes: ischemia/hypoxia, ischemia-reperfusion injury, chemical/toxic injury, and certain viral infections causing lytic cell death.
Ulcer formation is a form of surface necrosis with inflammation.
Necrosis triggers inflammation due to release of cellular contents; necroptosis and pyroptosis can also trigger inflammation.
Necrosis may present with characteristic features such as loss of cell outline, eosinophilia, nuclear changes, and tissue disruption depending on the tissue.

Necrosis vs. Apoptosis: Key Differences

Necrosis: cell swelling, disruption of plasma membrane, enzymatic digestion of cellular components, robust inflammation.
Apoptosis: programmed cell death; cell shrinkage, chromatin condensation, membrane blebbing, apoptotic bodies; typically minimal inflammation; can be physiologic or pathologic.
Necroptosis and pyroptosis are regulated forms of programmed necrosis that also trigger inflammation.

Apoptosis: Mechanisms and Pathways

Physiologic triggers: homeostasis (elimination of unwanted cells), removal of leukocytes post-infection, clonal deletion during development, involution of hormone-dependent organs, exercise-induced remodeling.
Pathologic triggers: DNA damage, accumulation of misfolded proteins; infection-related cell death; immune-mediated killing (T cells, NK cells).
Morphology: chromatin condensation, membrane blebs, fragmentation into apoptotic bodies, phagocytosis by macrophages.
Pathways:
- Extrinsic (Death Receptor) pathway: Receptor-ligand interactions (e.g., Fas-FasL, TNFR-TNFα) -> caspase-8 activation -> downstream execution by caspases.
- Intrinsic (Mitochondrial) pathway: Cellular stress → mitochondrial outer membrane permeabilization → release of cytochrome c -> caspase-9 activation -> executioner caspases.
Sequence (abbreviated): stress → cytochrome c release → caspase activation → DNA/protein degradation → membrane changes → apoptotic bodies → phagocytosis.
Distinguishing features: apoptosis is generally non-inflammatory or anti-inflammatory due to orderly clearance; necrosis is inflammatory.
Practical note: necrosis can be accompanied by necroptosis or pyroptosis under certain conditions; these can provoke inflammation similar to necrosis.

Interplay with Inflammation

Necrosis and necroptosis typically provoke inflammation due to release of cellular contents.
Apoptosis may be non-inflammatory or less inflammatory; however, necrosis may drive more robust inflammatory responses.
Inflammation itself can contribute to tissue injury or help in resolution depending on context.

Inflammation: Overview and Components

Inflammation is a vascularized tissue response to infections and tissue damage, recruiting host defense elements to the site of injury to eliminate offending agents.
Involves innate and adaptive immune components; the extent depends on trigger type (agent, cell death type, lesion size/loc.
Major components:
- Vascular changes to facilitate leukocyte and protein recruitment.
- Cellular response with infiltration by leukocytes (neutrophils, monocytes/macrophages, lymphocytes, plasma cells).
- Activation and coordination by endothelial cells, mast cells, dendritic cells, and macrophages.
Key steps: recognition of injury, recruitment of leukocytes, removal of offending agent, regulation/shut down, and resolution/repair.
Acute vs Chronic: acute inflammation is fast; chronic inflammation persists longer with different cellular infiltrates and tissue remodeling.

Acute Inflammation: Features and Morphology

Onset: rapid (minutes to hours); infiltrate mainly neutrophils (PMNs).
Exudates/types:
- Serous inflammation: watery, protein-poor fluid; few leukocytes.
- Fibrinous inflammation: fibrin-rich exudate; more severe; can affect body cavities.
- Purulent (suppurative) inflammation: pus; abscesses and phlegmon due to pyogenic bacteria.
- Ulcers: surface necrosis with inflammation and granulation tissue underneath.
Outcomes: resolution (recovery), healing with fibrosis (scar), or progression to chronic inflammation if persistent.
Examples in oral/oral mucosa: ulcers, gingivitis, abscesses, and leukocytic responses.
Important to recognize clinical signs of inflammation: redness (erythema), swelling (edema), heat (calor), pain (dolor), and sometimes systemic signs (fever).

Chronic Inflammation and Granulomatous Inflammation

Chronic inflammation: prolonged duration (weeks to years) with ongoing inflammation, tissue injury, and healing by fibrosis; angiogenesis and mononuclear infiltrates are common.
Key cellular infiltrates: monocytes/macrophages, lymphocytes, plasma cells; eosinophils and mast cells may also participate in certain contexts.
Fibrosis and scarring result from ongoing repair; normal tissue function can be compromised.
Chronic granulomatous inflammation: a special form occurring with persistent organisms (e.g., Mycobacterium tuberculosis, certain fungi), immune-mediated diseases (e.g., Crohn disease), and foreign materials.
- Caseating granulomas: caseous necrosis with epithelioid macrophages and multinucleated giant cells (TB-like).
- Non-caseating granulomas: histology without central necrosis (e.g., histoplasmosis, sarcoidosis).
Clinical examples in the oral cavity include Crohn disease-related granulomatous lesions and sarcoidosis.

Specific Concepts in Inflammation and Repair

Angiogenesis and granulation tissue: new capillaries and proliferating endothelial cells are central to healing tissue; granulation tissue forms the scaffold for repair.
Resolution vs repair: resolution aims to restore normal tissue architecture; repair may involve fibrosis and scar tissue formation which can reduce organ function.
Abscess formation and phlegmon: localized collections of purulent exudate with tissue destruction; can spread along fascial planes.
Ulcers: surface defects with inflammation and underlying granulation tissue; may result from persistent injury or infection.
Healing of surfaces: skin and mucosal healing share common principles; primary intention (well-approximated wounds) vs secondary intention (larger wounds, contamination) differ in time to heal and scar formation.
Wound complications: large or contaminated wounds may require suturing or more extensive repair strategies; scars can become hypertrophic or form keloids.
Keloids vs hypertrophic scars: hypertrophic scars are raised but within the wound boundary; keloids extend beyond the original wound and may have autosomal-dominant tendencies.

Metaplasia and Adaptive Changes

Metaplasia: reversible change where one adult cell type is replaced by another (reprogramming of stem cells within the lineage) to withstand chronic irritants; may predispose to malignancy in some contexts.
Metaplasia can be a precursor to malignant transformation in some epithelia.
Examples:
- Squamous metaplasia of bronchial epithelium in response to chronic irritation; can progress to squamous cell carcinoma.
- Goblet cell hyperplasia and reserve cell hyperplasia in adaptive responses.
- Epithelial dysplasia may progress to squamous cell carcinoma in the bronchial or oral mucosa.
Clinical relevance: chronic irritation and metaplastic change emphasize the link between chronic injury, adaptation, and cancer risk.

Adaptive Changes: Common Forms and Examples

Hyperplasia: increase in cell number due to cell proliferation.
- Examples: epithelial hyperplasia in response to irritants; hairy tongue from dermatologic/microbial changes; inflammatory papillary hyperplasia of the palate.
- Can be physiologic (hormonal stimuli) or pathologic (irritants).
Hypertrophy: increase in size of cells; often accompanies hyperplasia or occurs alone (e.g., cardiac muscle in hypertension).
Atrophy: reduction in cell/tissue size due to loss of cell substance; mechanisms include ubiquitin-proteasome degradation and autophagy; occurs with diminished blood supply or trophic stimulation.
- Autophagy: nutrient-recovery mechanism that forms autophagic vacuoles to recycle cytoplasmic components in times of deprivation; can contribute to atrophy.
- Brain atrophy and other organ atrophies are illustrated in various disease states.
Metaplasia (repeat): adaptive transformation of one adult cell type to another; can be a risk factor for malignancy when chronic stress persists.
Summary of adaptive changes: hyperplasia, hypertrophy, atrophy, metaplasia; each can be physiologic or pathologic and can occur alone or together.

Examples and Visual Cues Mentioned in Transcript

Epithelial hyperplasia in response to irritants; hairy tongue (fili form papillae hyperplasia related to microorganisms).
Fibrous hyperplasia as a reaction to chronic irritation; lymphoid hyperplasia in secondary lymphoid organs.
Cardiac hypertrophy as a response to increased workload (physiologic hypertrophy of cardiac muscle).
Atrophic kidney and brain examples shown with vascular occlusion or atherosclerotic disease.
Autophagy as a mechanism of atrophy with autophagic vacuole formation.
Metaplasia examples in oral/oral mucosa and bronchial epithelium with progression to dysplasia and cancer.

Clinical Relevance and Take-Home Points

Inflammation is a central driver of tissue injury and repair; understanding the balance between injury, inflammation, and healing helps explain many oral and systemic diseases.
Acute inflammation is characterized by neutrophil-dominated infiltrates and various exudates; chronic inflammation features mononuclear cells and fibrosis.
Granulomatous inflammation represents a specialized chronic response to persistent pathogens or foreign material, often with granulomas containing macrophages, lymphocytes, and sometimes caseation.
Repair processes include regeneration of parenchymal cells where possible and fibrosis where regeneration is limited; the latter can lead to functional impairment depending on the tissue.
Metaplastic changes indicate adaptation but require surveillance due to potential progression to malignancy in some contexts.
The relationship between necrosis and inflammation is bidirectional: necrosis can trigger inflammation, while inflammatory mediators can influence cell fate and tissue remodeling.

Key Terms to Remember (Glossary)

Reversible injury: cellular changes that can revert to normal after removal of stress.
Irreversible injury: progresses to cell death (necrosis) due to loss of mitochondrial function, DNA/chromatin integrity, or plasma membrane integrity.
Necrosis: uncontrolled cell death with cellular swelling, membrane disruption, enzymatic digestion, and inflammation.
Apoptosis: programmed cell death with cell shrinkage, chromatin condensation, blebbing, apoptotic bodies, and phagocytosis; usually non-inflammatory.
Necroptosis: regulated necrosis that triggers inflammation.
Autophagy: cellular self-digestion pathway that recycles cytoplasmic components for survival during nutrient deprivation; can contribute to atrophy.
Hyperplasia: increased cell number.
Hypertrophy: increased cell size.
Atrophy: decreased cell/tissue size.
Metaplasia: replacement of one mature cell type by another.
Ulcer: surface necrosis with inflammation.
Granulation tissue: vascularized tissue form during repair, rich in new capillaries and inflammatory cells.
Fibrosis: deposition of collagen-rich scar tissue during healing.
Keloid: excessive scar tissue that extends beyond the original wound.
Serous, fibrinous, purulent (suppurative) inflammation: different exudates indicating severity and type of injury.
Caseating vs non-caseating granulomas: TB-like versus other granulomatous diseases.

Formulas and Notations (LaTeX)

Reversible injury features can include organelle swelling and vacuolar degeneration: ext{Vacuolar degeneration: energy-dependent ion pump failure}
Fatty change in liver: ext{Fatty change}
ightarrow ext{lipid accumulation in hepatocytes}
Mitochondrial pathway of apoptosis: ext{Cytochrome c release}
ightarrow ext{caspase-9 activation}
ightarrow ext{caspase-3 activation}
ightarrow ext{apoptosis}
Extrinsic pathway: ext{Fas-FasL/TNFR-TNF}
ightarrow ext{caspase-8 activation}
ightarrow ext{executioner caspases}
Inflammation outcomes: ext{Resolution} ext{ vs. } ext{Fibrosis (scarring)} ext{ vs. Chronic inflammation}
Types of necrosis (morphology) example: ext{Coagulative necrosis}, ext{Liquefactive necrosis}, ext{Caseous necrosis}, ext{Fat necrosis}, ext{Fibrinoid necrosis}

Clinical Vignette-Style Connections (Framing Ideas)

Ischemia in tissues tends to cause coagulative necrosis in solid organs like heart and kidney; ischemia-reperfusion injury adds inflammatory damage.
Chronic irritation can drive metaplasia, with potential progression to dysplasia and cancer in susceptible epithelia (e.g., bronchial or oral mucosa).
Inflammation can heal by regeneration when cells can re-enter the cell cycle, or by fibrosis when regeneration is limited (example: large tissue loss, or fibrotic repair in lungs or liver).

End of Notes

This set of notes consolidates content from the presented slides on cell injury, adaptation, inflammation, and repair, including definitions, mechanisms, morphologic features, pathways, and clinical implications.