Mednotes

L1 Pathology Introduction to Pathology Cell adaption and injury

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tagspathology, lecture
aliasesL1 Pathology Introduction to Pathology Cell adaption and injury

36 min read

Overview

This deck covers three linked introductory pathology lectures built around one question: what happens to stressed, abnormal or dead tissue, and what does the body do about it. L1 covers cell injury and death (causes, molecular mechanisms, adaptation, reversible versus irreversible injury, necrosis and apoptosis). L2 covers how the body eliminates that damaged tissue through acute and chronic inflammation. L3 covers healing, either by regeneration of the same cell type or by fibrosis and scarring, worked through skin wounds, myocardial infarction and fracture. Recommended textbook is Robbins Basic Pathology; the lecture material relates directly to case histories and tutorials, and previous years’ notes are needed.

Causes of cell injury

Categories of injury:

  • Hypoxia (oxygen deprivation), emphasised as a common cause of cell injury and necrosis
  • Chemical agents
  • Infectious agents
  • Physical agents
  • Immunologic reactions
  • Genetic
  • Nutritional imbalance: diabetes, atherosclerosis, starvation/deficiency, excess

Mechanisms by which hypoxia arises:

  • Ischaemia: loss of blood supply to a tissue due to impeded arterial supply, from blockage of a vessel by thrombus or embolism. Atherosclerotic narrowing of an artery reduces flow compared with a normal open lumen.
  • Thrombosis: formation of a clotted mass of blood (a thrombus) in the cardiovascular system, the basis of myocardial ischaemia and infarction.
  • Cardio-respiratory failure: inadequate oxygenation, for example pneumonia, where normal alveolar spaces are obliterated by inflammatory cells.
  • Reduced oxygen carrying capacity of blood: severe anaemia (reduced haemoglobin, clinically pale) and carbon monoxide poisoning (blocked haemoglobin, cherry-pink skin discolouration).

Histology baseline for the course: on H&E (haematoxylin and eosin), nuclei stain purple and collagen stains pink. In dense connective tissue, mature fibroblasts show condensed elongated purple nuclei embedded in pink collagen fibres, and capillaries are lined by endothelial cells and contain red cells.

Molecular mechanisms and the timing of injury

An injurious stimulus acts through four converging pathways:

  1. Decreased ATP leading to loss of energy-dependent cellular functions
  2. Membrane damage, affecting mitochondria (cell death), lysosomes (enzymatic digestion of cellular components) and the plasma membrane (loss of cellular contents)
  3. Increased intracellular Ca2+, causing protein breakdown and DNA damage
  4. Reactive oxygen species (O2-, H2O2, OH.), also causing protein breakdown and DNA damage

Cell function is lost before morphological signs of injury are apparent. Plotted against duration of injury, cell function falls rapidly while injury is still reversible; cell death, then ultrastructural changes, then light microscopic changes, then gross morphological changes appear sequentially later, in the irreversible zone.

Overall scheme: a normal cell in homeostasis meets stress and either adapts, or, if unable to adapt, is injured. An injurious stimulus can cause injury directly. Mild transient injury is reversible and the cell returns to normal; severe progressive injury is irreversible and leads to cell death, by necrosis or apoptosis.

What determines the outcome of cell stress:

  • Vulnerability of the cell type to that stress
  • Dose intensity of the stress (and its duration)
  • The cell’s ability to respond

The sequence runs adaptation, or injury that is first reversible, then passes a “point of no return” to irreversible injury and death.

Morphology of reversible injury and adaptation

From a normal cell, the possible non-lethal changes are:

  • Reversible cell swelling and blebbing, and cell accumulations
  • Change in cell size or number: hyperplasia, hypertrophy, atrophy
  • Change in cell type: metaplasia, dysplasia

Morphological examples:

  • Mitochondrial swelling on electron microscopy: markedly swollen mitochondria compared with normal.
  • Cell swelling in renal tubules: tubular cells with pale, swollen, vacuolated cytoplasm.
  • Fatty change (steatosis) in injured liver cells: accumulation of triglycerides as small lipid droplets in the cytoplasm. It may occur in other organs but is most noticeable in the liver because of the liver’s major involvement in fat metabolism. Alcohol abuse is the most common cause. The liver becomes larger, paler and greasy while maintaining its normal overall structure, and cells are stuffed with lipid-containing vacuoles.

Atrophy

The organ diminishes in size. Cells may be alive but with diminished function, or may have undergone apoptosis. Causes:

  • Decreased workload: muscle in an immobilised limb
  • Reduced endocrine stimulation: breast and endometrium after menopause
  • Diminished blood supply: elderly brain
  • Loss of innervation: muscle after nerve damage (skeletal muscle atrophy secondary to nerve fibre damage)
  • Inadequate nutrition: protein-calorie malnutrition leading to muscle wasting

Gross examples: unilateral renal atrophy due to impaired blood supply (a small kidney beside a normal one), and atrophy of the cerebral cortex in Alzheimer’s disease (widened sulci and shrunken gyri).

Hypertrophy

Increase in cell size and consequently organ size. It may be physiologic or pathologic, driven by increased functional demand or hormonal stimulation. The cells concerned cannot divide, so they increase cellular components in response to demand. There is a limit to hypertrophy: continued demand leads to necrosis.

  • Physiologic: hypertrophy of the uterus during pregnancy
  • Pathologic: left ventricular hypertrophy from increased blood pressure (hypertension); normal LV wall thickness is 10-15 mm, and hypertrophic myocardium shows larger fibres and nuclei

Hyperplasia

Increase in the number of cells and hence organ size; cells respond to demand by dividing. It can occur in conjunction with hypertrophy.

  • Physiological, hormonal: glandular epithelium in the female breast at puberty and during lactation
  • Physiological, compensatory: partial resection of liver stimulates mitosis in the remaining cells
  • Pathologic: gynaecomastia in alcoholics with liver cirrhosis, from lack of oestrogen inactivation in the liver; hyperplasia of the prostate, driven by dihydrotestosterone (increased estradiol with age increases androgen receptors)

Metaplasia and dysplasia

Metaplasia is a reversible change in adult cell type, by reprogramming of stem cells present in epithelium or mesenchyme. Cells sensitive to a particular stress are replaced by a “tougher” type. The epithelial example is replacement of the pseudostratified ciliated columnar epithelium of the respiratory tract by squamous epithelium in cigarette smokers. While this may confer survival advantages to the epithelium, important functions are often lost, specifically mucus secretion and ciliary action. Metaplasia follows chronic injury or irritation and reverses if the stimulus is removed.

Dysplasia is disordered cellular morphology, organisation and function, manifesting as abnormal variation in cell shape and size, and is a pre-malignant change. It follows persistent severe injury or irritation. If the stimulus persists, metaplastic epithelium may become dysplastic and even progress to malignancy, for example squamous cell carcinomas of cervix and lung.

Adaptation versus injury, side by side: a normal myocyte can adapt to increased load and become a hypertrophied myocyte (thickened ventricular wall), or be injured, pass through reversible injury and die (pale necrotic myocardium).

Cell death: necrosis versus apoptosis

Two major types:

  • Necrosis, “cell homicide”
  • Apoptosis, “cell suicide”

Contrasting sequences from a normal cell:

  • Necrosis: cell and organelle swelling and disruption, then enzymatic digestion and leakage of cellular contents
  • Apoptosis: chromatin condensation and cell shrinkage, formation of apoptotic bodies, then phagocytosis of the apoptotic cell and its fragments by a phagocyte

Apoptosis settings:

  • Physiological: cell removal during embryogenesis (implantation, organogenesis, development, for example separation of the digits by resolution of interdigital webbing); hormone-dependent involution (endometrium in the menstrual cycle, lactating breast after weaning); cell death induced by cytotoxic T cells
  • Pathological: cytotoxic T cells acting against a self antigen

Necrosis: determinants and nuclear changes

The cellular response to injury depends on:

  • Cell type: neurons and cardiac muscle are sensitive to oxygen deprivation
  • Severity of the injury

Healing depends on whether cells are labile, stable or permanent, that is whether they can enter the cell cycle to regenerate. If no replacement is possible, scarring results.

Nuclear changes of necrosis:

  • Pyknosis: nuclear shrinkage and condensation
  • Karyorrhexis: nuclear fragmentation
  • Karyolysis: nuclear dissolution or fading

Patterns of necrosis

Distinct morphological patterns are seen after the initial phases, which are a balance between protein denaturation and enzyme action:

  1. Coagulative necrosis: preservation of the basic structural outline for several days although cellular detail is lost, with predominance of protein denaturation and cross-linking. Myocardial infarction is a good example, and is replaced by scar tissue. In a tissue with labile cells such as liver, kidney or lung, if the basic connective tissue framework is maintained, the tissue can regenerate. Often pale (loss of colour) at the gross level; necrotic material is ultimately removed by phagocytosis. Gross example: pallor of necrotic myocardium in a myocardial infarct.
  2. Liquefactive necrosis: transformation of necrotic tissue into a liquid viscous mass. If triggered by infection the liquid contains large numbers of dead inflammatory cells (neutrophils), which is pus. Eventually removed by phagocytosis. In the CNS there is no healing by scar formation, so a cavity is left: brain abscess, and healed brain infarct (stroke).
  3. Caseous necrosis: associated with chronic, not acute, inflammation. Caseous means “cheesy”. Observed in tuberculosis. Gross appearance is white cheesy material; microscopically it is structureless granular debris, eosinophilic, seen centrally within a granuloma with surrounding inflammatory cells and multinucleated giant cells.
  4. Gangrenous necrosis: ischaemic coagulative necrosis, frequently of a limb or digit, frequently dark or black grossly. “Wet gangrene” is the term when there is superimposed infection and thus a liquefactive component.

L1 key terms

The lecture lists the vocabulary to carry forward: cell injury and organ injury; susceptibility, and injury having dose intensity and duration; adaptations and reversibility; oedema (swelling) and cellular accumulations; proliferation and regeneration (mitosis, daughter cells) depending on the cell cycle; hyperplasia, hypertrophy, atrophy, metaplasia, dysplasia; disturbance of function and irreversible injury; cell death, organ death and death; homicide, suicide, or a mixture; necrosis, pyknosis, karyorrhexis, karyolysis, cellular release of contents, infarction; apoptosis, nuclear disintegration, membrane-bound cellular contents; coagulative, liquefactive, caseous. For L2 and L3, the body’s response: removal of dead tissue and organisms, collateral damage, sequential damage, damage repair (healing), damage control, acute inflammation, chronic inflammation, healing.

What inflammation is

From the Latin inflammare, to set on fire. It is a protective response intended to detect and eliminate the cause of cell injury and then clean up after the injury.

  • Acute: lasts minutes to days, innate immune system
  • Chronic: lasts days to weeks or longer, adaptive immune system

It involves circulating cells, plasma proteins, the vascular wall, and supporting tissue cells and matrix.

Acute inflammation is the immediate and early response of living vascularised tissue to injury. It is relatively stereotyped, delivers white blood cells to the site of damage, and leads to healing. It has two components, vascular (vasodilation, increased vascular permeability) and cellular (emigration of leucocytes), integrated by chemical mediators.

Clinical and laboratory features of acute inflammation

The five cardinal local signs: heat, redness, swelling, pain, loss of function.

Systemic signs: fatigue, loss of appetite, weight loss, fever, night sweats, chills, aches and pains.

Assessment of the acute inflammatory response comes from history and examination (local and systemic signs), blood differential (neutrophils and new neutrophils, that is metamyelocytes), blood film, biochemistry (CRP, ESR) and microbiology.

Worked full blood count in acute inflammation, with reference ranges:

TestUnitsRef rangeResult
Haemoglobing/L140-180152
Plateletsx10^9/L150-400400
Metamyelocytesx10^9/L02.3
Neutrophilsx10^9/L2.0-7.517.3
Lymphocytesx10^9/L1.5-4.02.3
Monocytesx10^9/L0.2-0.80.6
Eosinophilsx10^9/L0.1-0.40.3
ESR (erythrocyte sedimentation rate)mm/hr1-8130
CRP (C reactive protein)mg/L<1060

Film comment: neutrophils show marked toxic changes.

White blood cell types identified on the blood diagram: band cell, basophil, neutrophil, lymphocyte, eosinophil, monocyte.

Gross and clinical examples of acute inflammation: acute appendicitis (a swollen, congested appendix beside a normal slender one), meningitis (congested, thickened surface vessels with haemorrhagic discolouration), pneumonia (patchy pale-tan consolidation of the cut lung surface versus uniformly aerated normal lung), acute cellulitis (erythema and swelling of the skin), and an abscess with liquefactive necrosis containing pus.

The participants and the plasma systems

The elements involved in acute inflammation are the vascular wall (smooth muscle, endothelium, basement membrane), the cellular components of the blood (polymorphonuclear leukocytes, lymphocytes, platelets), chemical mediators, and four plasma protein systems: the clotting (coagulation) system, the “un-clotting” (fibrinolysis) system, the complement system and the kinin system.

Chemical mediator pathway given in detail: arachidonic acid is converted by prostaglandin H synthase, which is blocked by aspirin, to prostaglandin H2, which branches to:

  • Thromboxane A2: increases platelet aggregation, increases vasoconstriction
  • Prostaglandins I2, E2, D2 and F2a: inhibit gastric acid production, increase vasodilation, increase renal blood flow

The vascular response

Alterations in the microcirculation are among the earliest responses to tissue injury:

  1. Vasodilation
  2. Increased permeability
  3. Congestion and stasis

Normally, across an arteriole-capillary-venule bed there is net flow out at the arteriole end, no net flow in the capillary bed, and net flow in at the venule end. In acute inflammation there is net flow out at all three points, driven by increased hydrostatic pressure and decreased colloid osmotic pressure.

Consequences of increased vascular permeability (leakiness):

  • Transudate gives way to exudate, a protein-rich fluid
  • This increases interstitial osmotic pressure and decreases intravascular osmotic pressure, contributing to oedema (water and ions) and accounting for swelling
  • Increased intravascular fluid produces vascular congestion
  • There are many ways for vessel walls to become leaky

The amount of fluid lost from the circulation may be fatal, especially in severe burns. Histologically, oedema shows as widened alveolar septa with inflammatory cells in airspaces, against thin normal septa.

Congestion and stasis: increased concentration of red cells in the blood and increased viscosity, so white blood cells slow down and migrate.

The cellular response

Leukocytes leave the vasculature through the following sequence:

  1. Margination and rolling
  2. Adhesion and transmigration
  3. Chemotaxis and activation

They are then free to participate in phagocytosis and degranulation, and in leukocyte-induced tissue injury.

The adhesion cascade in molecular detail, in four stages:

  1. Rolling: the leukocyte’s Sialyl-Lewis X-modified glycoprotein binds P-selectin and E-selectin on endothelium; its integrin is still low-affinity
  2. Integrin activation by chemokines: proteoglycan-bound chemokines are released in response to cytokines (TNF, IL-1) from a macrophage that has encountered microbes, converting the integrin to high affinity
  3. Stable adhesion: high-affinity integrin binds its integrin ligand (ICAM-1)
  4. Migration through endothelium via PECAM-1 (CD31) into the fibrin and fibronectin of the extracellular matrix

Margination is visible histologically as neutrophils lined up along the vessel wall while red cells fill the centre of the lumen.

Chemotaxis: once in the extravascular space, leukocytes follow a chemical gradient to the site of injury. Chemotactic agents are soluble bacterial products, complement components (C5a), cytokines of the chemokine family (for example IL-8), and leukotriene B4 (LTB4). These bind surface receptors, causing calcium mobilization and assembly of cytoskeletal contractile elements.

Chemotaxis and activation: leukocytes extend pseudopods with overlying surface adhesion molecules (integrins) that bind extracellular matrix and pull the cell along the chemotactic gradient. Chemotactic factors also activate the leukocytes, regulating leukocyte adhesion molecule affinity and preparing them for degranulation and release of lysosomal enzymes (oxidative burst).

Phagocytosis and degranulation: once at the site of injury, leukocytes recognize and attach to the target, engulf it forming a phagocytic vacuole, and kill or degrade it.

Time course of acute inflammation over roughly three days: oedema rises and peaks earliest (before day 1), neutrophils peak around day 1, and monocytes/macrophages peak later and more broadly around day 2, declining slowly thereafter.

Outcomes of acute inflammation

Three outcomes:

  1. Abscess, via liquefactive necrosis
  2. Persistent inflammation (chronic inflammation), due to a failure to completely eliminate the pathological insult
  3. Healing

Flow of outcomes: the acute inflammatory response leads to resolution, to abscess, or to chronic inflammation and demolition. An abscess can itself progress to chronic inflammation. Chronic inflammation is also fed by adaptive immunity and hypersensitivity reactions. Demolition leads on to healing, either by regeneration or by scarring.

Chronic inflammation

Characteristics:

  • Defined by duration/time
  • Accompanied by active inflammation that is mostly lymphocytic and macrophage, by tissue destruction, and by attempts at repair (healing) occurring simultaneously
  • May follow acute inflammation, or may not follow it, arising as insidious low-grade inflammation

Clinical scenarios:

  • Prolonged exposure to toxins: silicosis (particulate silica is non-biodegradable when inhaled into lung); atherosclerosis (associated with lipid deposition)
  • Autoimmunity, where autoantigens evoke a self-perpetuating immune reaction: rheumatoid arthritis, lupus erythematosus (SLE), scleroderma
  • Persistent infections: TB (Mycobacterium tuberculosis), a delayed type hypersensitivity giving granulomatous inflammation with caseous necrosis; Treponema pallidum (syphilis), with lots of plasma cells; fungal infection, viruses, parasites

Systemically, chronic inflammation can produce severe wasting and cachexia.

Granulomatous inflammation forms a granuloma, an aggregate of epithelioid histiocytes and multinucleated giant cells. Note that a granuloma is not the same thing as granulation tissue.

Organ example: chronic pancreatitis, with dense fibrous stroma replacing parenchyma, residual islands of glandular tissue and dilated ducts.

Lecture objectives for chronic inflammation: understand the differences between acute and chronic inflammation and the circumstances in which chronic inflammation may occur; describe the pathogenesis of some of the complications of chronic inflammation in various organs and tissues; understand how some forms of chronic inflammation are characterised by granuloma formation, and describe how this differs from the more classic form of chronic inflammation.

Tissue repair and proliferative potential

Repair begins early after a necrosis-inducing injury and overlaps with inflammation. There are two distinct processes:

  • Regeneration by cells of the same type
  • Replacement by connective tissue: fibrosis or scarring

Which occurs depends on the proliferative potential of the tissue, defined by position in the cell cycle (G1 growth phase 1, S DNA synthesis, G2 growth phase 2, M mitosis, with G0 as the resting state outside the cycle):

  • Labile cells: continuously dividing (and dying). Epithelial cells, haematopoietic cells. Illustrated by intestinal villous epithelium and bone marrow.
  • Stable cells: quiescent normally but able to divide rapidly in response to stimuli, that is usually in G0 but able to enter G1 and proliferate. Liver, kidney, pancreas, endothelium, fibroblasts, smooth muscle.
  • Permanent cells: no capacity for cell division, fixed in G0. Neurons, myocardium. These essentially cannot regenerate.

The liver: when regeneration happens and when it does not

The liver is the worked example of the principle that regeneration requires an intact supporting framework.

  • Normal liver architecture shows lobules with a central vein and portal tracts containing bile ducts and vessels. Regeneration is visible histologically as binucleate hepatocytes and mitotic figures.
  • Hepatic centrilobular necrosis: pale necrotic centrilobular zones grossly and loss of hepatocyte cellular detail microscopically, but a reticulin stain shows the supporting reticulin framework remains intact despite extensive hepatocyte necrosis. The hepatocytes will therefore be able to regenerate and the liver will return to normal.
  • Liver cirrhosis: a diffusely nodular liver, with reticulin staining showing thick disorganised bands of fibrous tissue subdividing the parenchyma into irregular nodules, in contrast to the intact fine network of the regenerating liver.
  • Hepatic abscess: a localised area of hepatic necrosis, with inflammatory exudate replacing necrotic hepatocytes and viable hepatocytes remaining at the margin. The reticulin framework within the abscess is disrupted, meaning hepatocytes will not be able to regenerate in a normal fashion.

Important

The determinant of whether an injured liver regenerates or scars is whether the reticulin scaffold survives: intact in centrilobular necrosis (regeneration), destroyed in an abscess (no normal regeneration).

Tissue repair by scarring

Scar tissue formation, or fibrosis, is the replacement of non-regenerated cells by connective tissue, with loss of parenchyma and extracellular matrix (ECM). Four stages:

  1. Formation of new blood vessels (angiogenesis)
  2. Fibroblast migration and proliferation
  3. Deposition of ECM
  4. Maturation and organization (remodeling) of fibrous tissue

Granulation tissue is the hallmark of repair by connective tissue:

  • Pink, soft and granular grossly
  • Appears by 3-5 days after damage
  • Consists of new thin-walled delicate vessels and proliferating fibroblasts in loose ECM
  • There is gradual accumulation of ECM including collagen
  • It results in dense fibrosis, or scar, which is remodeled over time

Angiogenesis occurs by two routes:

  • From pre-existing vessels: capillary sprouting from the vessel wall, then a branching capillary network, maturing into a dense mature vascular network
  • By mobilization of endothelial progenitor cells (EPCs) from the bone marrow: EPCs home into the bloodstream, incorporate into a vessel wall, and form a capillary plexus that develops into a mature vascular network

Fibrosis (stages 2 and 3) occurs within the granulation tissue framework: emigration and proliferation of fibroblasts at the site of injury, driven by growth factors TGF-beta, PDGF, EGF, FGF sourced from activated endothelium and macrophages, and by cytokines (IL-1, TNF-alpha); then deposition of ECM, collagen in particular, from fibroblasts, which adds strength.

Scar remodeling (stage 4) strengthens the repair. Metalloproteinases (collagenases, gelatinases, stromelysins) turn over interstitial proteins. They are produced by macrophages, neutrophils and fibroblasts as inactive precursors, in response to growth factors, cytokines and mechanical stress. The scar achieves 70-80% of the strength of normal tissue by 3 months, and there is gradual contraction of the scar.

Host factors that influence inflammation and repair

  • Nutrition: protein, vitamin C
  • Metabolic status: healing is slower in diabetics
  • Steroids: anti-inflammatory and slow collagen synthesis
  • Infection: the most important cause of delayed healing
  • Mechanical factors: excessive movement slows healing
  • Blood supply: impaired in diabetics and other disorders

Healing of skin wounds

Baseline skin histology: epidermis and dermis containing hair follicles and adnexal glands, with mitotic figures in the basal epithelium.

Two patterns:

  • Primary union: a clean incision; the line of closure fills with clotted blood; dehydration of tissue fluid and blood at the surface creates a scab. Clinically, a sutured wound with closely apposed edges.
  • Secondary union: a large tissue defect, with more inflammation, more granulation tissue, and wound contraction mediated by myofibroblasts. Clinically, a punched-out ulcer with a large gap between the edges, healing through a thin layer of re-epithelialization over extensive dermal granulation tissue, then continuing re-epithelialization with wound contraction.

Timeline of primary union:

  • 24 hours: neutrophils; mitoses of basal epithelium
  • 1-2 days: epithelial basal cells grow along the cut dermis
  • 3 days: neutrophils gone, macrophages enter, granulation tissue forms
  • 5 days: space filled with granulation tissue, collagen fibrils bridge the wound, epidermis at pre-incision thickness
  • Week 2: accumulation of collagen and fibroblasts, and “blanching” begins as granulation tissue becomes less prominent
  • End of first month: connective tissue devoid of inflammation, epidermis intact
  • 3 months: tensile strength increased to 70-80% of unwounded skin

Sequence in the four-panel diagram of primary intention: a fresh wound gap filled with blood clot containing red cells and inflammatory cells; then neutrophils and macrophages in the clot with epidermal cells migrating along the cut edges and early dermal fibroblast activity; then a continuous thin epidermal layer with fibroblasts and new vessels proliferating beneath; then a fully continuous epidermis over a thinner scar of organizing fibrous tissue with few inflammatory cells.

Relative timing of the phases of wound healing, plotted on a log time axis (days 1 to 100): inflammation peaks first (about days 1-3), granulation tissue next (about days 3-7), wound contraction around days 10-20, and collagen accumulation and remodeling rises progressively and continues latest, out beyond day 100.

Aberrations of inflammation and repair

  • Inadequate scar formation
  • Wound dehiscence: rupture. External evidence of wound sepsis appears on the third post-operative day, as reactive, brown, murky wound drainage. If the wound is not opened, the septic process is confined to the subcutaneous space, making the fascia vulnerable to infection and dehiscence (splitting open), with herniation through the fascial layer.
  • Ulceration: due to inadequate vascularisation
  • Hypertrophic scar: keloid, a raised nodular scar with thick densely packed collagen bundles in the dermis, that is excess collagen deposition in the skin
  • Wound contracture, for example the limb deformity following extensive burn scarring

Healing of a myocardial infarct

Myocardial ischaemia and infarction arise from atherosclerosis with a narrowed artery and thrombus, producing an area of pale infarcted myocardium. The wave of healing by repair over time:

  • 24 hours: early myocardial fibre necrosis and the beginnings of the acute inflammatory response, with early neutrophilic infiltrate between fibres
  • 3 days: necrotic fibres with a predominantly mononuclear (macrophage) infiltrate replacing the neutrophils
  • 5 days: immature granulation tissue, with thin-walled new vessels and plump fibroblasts, and little collagen as yet
  • Later: maturing granulation tissue, with less obvious new vessels and fibroblasts laying down intercellular collagen
  • Old infarct: repaired by dense collagenous scar replacing myocardium, interspersed among surviving myocardial fibre bundles

Healing of a bone fracture

Bone structure for reference: a long bone has proximal and distal epiphyses, articular cartilage, cancellous bone, compact bone, periosteum, medullary cavity and diaphysis. Compact bone consists of concentric bony layers containing lacunae that hold osteocytes, fed by blood vessels in Haversian and Volkmann’s canals, with lamellae, an interstitial system, cortical bone and periosteum. Osteoblasts line the bone surface beneath the periosteum.

Cell roles: osteoblasts lay down uncalcified bone matrix, osteoid. Osteoclasts are multinucleate cells that resorb bone.

Three phases: inflammatory, reparative, remodeling.

Inflammatory phase

  • 1-2 days: tearing of periosteum and adjacent soft tissues leads to extensive haemorrhage and clot formation; necrosis of bone fragments, shown by absence of osteocytes in lacunae (blood being supplied via Volkmann and Haversian canals), with or without soft tissue necrosis
  • 2-5 days: acute inflammatory response with fluid and cellular exudate, and the beginnings of granulation tissue

Reparative phase

  • 7 days: osteoblasts grow from stem cells in granulation tissue; the ECM synthesised by osteoblasts encourages mineralisation; cartilage often also forms initially and is gradually replaced by bone; the bone that appears is woven, that is disorganised in structure. Granulation tissue containing bone or cartilage is callus, seen spanning cortex and medulla across the fracture site, with trabeculae of woven bone rimmed by active osteoblasts sitting in granulation tissue of thin-walled vessels and fibroblasts.
  • Next few weeks: progress depends on movement and fixation, where rigid fixation slows healing but excessive movement also delays healing; blood clot and bone fragments are cleared by phagocytosis; callus is built and organised by the action of osteoclasts and osteoblasts; the fractured bone ends are joined by callus.

Remodelling phase

  • Long term: reorganisation of woven bone to lamellar bone, again by balanced action of osteoclasts and osteoblasts, in response to mechanical stress.
  • Problems: non-union or fibrous union resulting from delayed healing, caused by infection, excessive movement or poor blood supply.

Warning

The “next few weeks” slide is headed “Fracture Healing: Inflammatory Phase” but its content describes later reparative-phase events (callus organisation). The transcript records the heading exactly as it appears on the slide.

Healing key points

  • Healing by scarring involves replacement of damaged cells by connective tissue
  • Granulation tissue is composed of new, proliferating thin-walled vessels, loose ECM and plump fibroblasts that are synthesizing collagen
  • The initially loose and fragile granulation tissue gradually gains strength as the collagen content increases
  • Scar remodelling occurs over months, but original strength is not regained

Lecture objectives for healing: describe healing of skin wounds and fractures and list common causes for impaired healing of both; describe the conditions under which the liver heals by regeneration and when it heals by repair; describe healing of myocardial infarcts and recognise and describe infarcts that are days, weeks and months old; describe and recognise the “wave of healing by repair” in a healing myocardial infarct; describe healing of cerebral infarcts and recognise cerebral infarcts that are days, weeks and years old.

For these topics, for now: know the basics, and know the overall sequence of events.

Self-test

  1. List the categories of causes of cell injury given in the lecture, with an example for the nutritional category.
  2. Distinguish ischaemia from the other mechanisms by which hypoxia can arise, and give one example of each mechanism.
  3. Describe the four molecular pathways through which an injurious stimulus damages a cell, naming the consequence of each.
  4. Explain why cell function is lost before morphological signs of injury appear, in terms of the order in which changes become detectable.
  5. List the three factors that determine whether a stressed cell adapts, is reversibly injured, or dies.
  6. Distinguish reversible from irreversible cell injury in terms of outcome.
  7. Describe the morphological features of fatty change in the liver, both gross and microscopic, and name its most common cause.
  8. List the causes of atrophy given in the lecture, with an example of each.
  9. Distinguish hypertrophy from hyperplasia, and explain why some tissues can only undergo hypertrophy.
  10. What is the normal left ventricular wall thickness?
  11. Explain what limits hypertrophy when demand continues.
  12. Give one physiological hormonal, one physiological compensatory and two pathological examples of hyperplasia.
  13. Define metaplasia, and explain what is gained and what is lost in the respiratory example.
  14. Define dysplasia and explain its clinical significance.
  15. Distinguish necrosis from apoptosis in terms of cell morphology, membrane integrity and fate of the cell contents.
  16. List two physiological and one pathological setting for apoptosis.
  17. Distinguish pyknosis, karyorrhexis and karyolysis.
  18. List the four patterns of necrosis and give one distinguishing feature and one example of each.
  19. A patient develops a black toe following arterial occlusion, which then becomes infected. Name the necrosis pattern and the specific term for the infected form, and explain what the infection adds.
  20. Explain why liquefactive necrosis in the CNS leaves a cavity.
  21. Define acute inflammation and name its two components and what integrates them.
  22. List the five cardinal local signs of acute inflammation and the systemic signs.
  23. A full blood count shows neutrophils 17.3 x10^9/L, metamyelocytes 2.3 x10^9/L, ESR 130 mm/hr and CRP 60 mg/L. Explain which of these are abnormal and what the pattern indicates.
  24. Describe the arachidonic acid pathway from arachidonic acid to its two branches, name the enzyme aspirin blocks, and give the actions of each branch.
  25. Describe the three changes of the vascular response, and explain how fluid movement across the microcirculation differs from normal in acute inflammation.
  26. Distinguish a transudate from an exudate, and explain how the change produces oedema.
  27. Describe the four stages of the leukocyte adhesion cascade, naming a key molecule at each stage.
  28. List four chemotactic agents and describe what happens inside the leukocyte once they bind their receptors.
  29. Describe the relative time course of oedema, neutrophils and macrophages over the first three days of acute inflammation.
  30. List the three outcomes of acute inflammation, and predict which outcome follows failure to eliminate the insult.
  31. List the characteristics that define chronic inflammation, and distinguish a granuloma from granulation tissue.
  32. Give one example each of chronic inflammation caused by prolonged toxin exposure, by autoimmunity and by persistent infection.
  33. Distinguish labile, stable and permanent cells by cell cycle status, and give tissue examples of each.
  34. Explain why a liver with centrilobular necrosis can return to normal while a liver with an abscess cannot.
  35. List the four stages of tissue repair by scarring.
  36. Describe granulation tissue: its gross appearance, when it appears, and its microscopic components.
  37. Distinguish the two mechanisms of angiogenesis described in the lecture.
  38. Name the growth factors and cytokines driving fibrosis and their cellular sources.
  39. Describe what happens during scar remodeling, and state the strength the scar reaches and by when.
  40. List the host factors that influence inflammation and repair, and name the most important cause of delayed healing.
  41. Distinguish healing by primary union from healing by secondary union.
  42. Describe the timeline of primary union from 24 hours to 3 months.
  43. List the aberrations of inflammation and repair, and state on which post-operative day external evidence of wound sepsis appears.
  44. Describe the appearances of a myocardial infarct at 24 hours, 3 days, 5 days and after months.
  45. Describe the three phases of fracture healing and what occurs in each.
  46. Explain what callus is and how fixation and movement affect fracture healing.
  47. Predict what happens to a fracture with infection, excessive movement or poor blood supply.
  48. Integrative: a myocardial infarct and a partial hepatectomy both remove functioning parenchyma, yet only one is restored to normal tissue. Explain the difference using cell proliferative potential and the supporting framework.

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