Regeneration healing (repair)-General Pathology Lecture note

Objectives of this Post

• Review the normal physiology and concepts of cell proliferation, cell growth, cell “cycle”, and cell differentiation
• Understand the basic factors of tissue regeneration
• Understand the relationships between cells and their extracellular matrix (eECM)
• Understand the roles of the major players of healing---angiogenesis, growth factors (GFS), and fibrosis
• Differentiate 1st & 2nd intention healing

Definitions:

Regeneration: growth of cells to replace lost tissues

Healing: a reparative tissue response to a wound, inflammation or necrosis, often leads to fibrosis 

Granulation tissue 

“Organizing” inflamation

Regeneration

• Replacement of lost structures
• Is dependent on the type of normal turnover the original tissue has
• Can be differentiated from “compensatory” growth

Healing (repair)

• Needs a wound, inflammatory process, or necrosis
• Many disease appearances anatomically are the result of “healing” such as atherosclerosis
• Often ends with a scar
• Fibrosis, as one of the 3 possible outcomes of inflammation, follows “healing”
• Requires a connective tissue “scaffold”
• Fibrosis occurs in proportion to the damage of the ECM

 

Cell population fates

Proliferation

• Hormonal, especially steroid hormones
• Eg., EPO, CSF

Differentiation*

• Unidirectional, gain and loss

Apoptosis

*One of the most key concepts in neoplasia

• Ectoderm
• Mesoderm
• Entoderm

Cell cycle

G0

Quiescent (not a very long or dominent phase)

G1

Pre-synthetic, but cell growth taking place

S

• Cells which have continuous “turnover” have longer, or larger s-phases, i.e., dna synthesis
• S-phase of tumor cells can be prognostic

G2

Pre-mitotic

M (mitotic:, P,M,A,T cytokinesis)

Cell types

Labile: eg. marrow, GI

Quiescent: liver, kidney

Non-mitotic: neuron, striated muscle

Stem cells (totipotential*)

1. Embryonic
2. Adult

Embryonic stem cells

• Differentiation
• Knockout mice (mice raised with specific gene defects)
• Repopulation of damaged tissues, in research

Adult Stem cells

Marrow (hemocytoblast)

(hematopoetic stem cells)

Non-marrow (reserve)

Marrow stromal cell

Adult tissue differentiation and regeneration parallels embryonic development

Growth factors (GFS)

Polypeptides

Cytokines

• Locomotion
• Contractility
• Differentiation
• Angiogenesis

Growth factors (GFS)

Epidermal

Transforming (alpha, beta)

Hepatocyte

Vascular endothelial

Platelet derived

Fibroblast

Keratinocyte

Cytokines (TNF, IL-1, interferons)

Cell players (source and targets)

• Lymphocytes, especially t-cells
• Macrophages
• Platelets
• Endothelial cells
• Fibroblasts
• Keratinocytes
• “mesenchymal” cells
• Smooth muscle cells

E(epidermal) GF

• Made in platelets, macrophages
• Present in saliva, milk, urine, plasma
• Acts on keratinocytes to migrate, divide
• Acts on fibroblasts to produce “granulation” tissue

T(transforming) GF-alpha

• Made in macrophages, t-cells, keratinocytes
• Similar to egf, also effect on hepatocytes

H(hepatocyte) GF

• Made in “mesenchymal” cells
• Proliferation of epithelium, endothelium, hepatocytes
• Effect on cell “motility”

Ve(vascular endothelial) GF

• Made in mesenchymal cells
• Triggered by hypoxia
• Increases vascular permeability
• Mitogenic for endothelial cells
• Key substance in promoting “granulation” tissue

Pd(platelet derived) GF

• Made in platelets, but also many other cell types
• Chemotactic for many cells
• Mitogen for fibroblasts
• Angiogenesis
• Another key player in granulation tissue

F(fibroblast) GF

• Made in many cells
• Chemotactic and mitogenic, for fibroblasts and keratinocytes
• Re-epithelialization
• Angiogenesis, wound contraction
• Hematopoesis
• Cardiac/skeletal (striated) muscle

T(transforming) GF-beta

• Made in many cells
• Chemotactic for PMNS and many other types of cells
• Inhibits epithelial cells
• Fibrogenic
• Anti-inflammatory

K(keratinocyte) GF

• Made in fibroblasts
• Stimulates keratinocytes:
• Migration
• Proliferation
• Differentiation

I (insulin-like) GF-1

• Made in macrophages, fibroblasts
• Stimulates:
• Sulfated proteoglycans
• Collagen
• Keratinocyte migration
• Fibroblast proliferation
• Action similar to gh (pituitary growth hormone)

TNF (tumor necrosis factor)

• Made in macrophages, mast cells, t-cells
• Activates macrophages
• Key influence on other cytokines

Interleukins

• Made in macrophages, mast cells, t-cells, but also many other cells
• Many functions:
• Chemotaxis
• Angiogenesis
• Regulation of other cytokines

Interferons

• Made by lymphocytes, fibroblasts
• Activates macrophages
• Inhibits fibroblasts
• Regulates other cytokines

Signaling

• Autocrine (same cell)
• Paracrine (next door neighbor) (many gfs)
• Endocrine (far away, delivered by blood, steroid hormones)

Transcription factors

Hepatic

Regeneration

• TNF
• IL-6
• HGF

Extracellular matrix (ECM)

• Collagen(s) I-xviii
• Elastin
• Fibrillin
• Cams (cell adhesion molecules)
• Immunoglobulins, cadherins, integrins, selectins
• Proteoglycans
• Hyaluronic acid

ECM

• Maintain cell differentiation
• “scaffolding”
• Establish microenvironment
• Storage of GF’s

1. Collagen one - bone (main component of bone)
2. Collagen two - cartwolage (main component of cartilage)
3. Collagen three - rethreeculate (main component of reticular fibers)
4. Collagen four - floor - forms the basement membrane

Genetic collagen disorders

• I                               osteogenesis imperfecta, e-d
• Ii                              achondrogenesis type ii               
• Iii                             vascular ehlers-danlos
• V                             classical  e-d
• Ix                            stickler syndrome
• Iv                            alport syndrome
• Vi                            bethlem myopathy
• Vii                           dystrophic epidermolysis bullos.
• Ix                            epiphyseal dysplasias
• Xvii         gen. Epidermolysys bullosa
• Xv, xviii knobloch syndrome

Definitions:

Regeneration: growth of cells to replace lost tissues

Healing: a reparative tissue response to a wound, inflammation or necrosis

Healing

• Follows inflammation
• Proliferation and migration of connective tissue cells
• Angiogenesis (neovascularization)
• Collagen, other ecm protein synthesis
• Tissue remodeling
• Wound contraction
• Increase in wound strength (scar = fibrosis)

Angiogenesis (neovascularization)

• From endothelial precursor cells
• From pre-existing vessels
• Stimulated/regulated by gf’s, especially VEGF
• Also regulated by ECM proteins
• AKA, “granulation”, “granulation tissue”, “organization”, “organizing inflammation”

Wound healing

1 intention

Edges lined up

 

2 intention

Edges not lined up

Ergo….

More granulation

More epithelialization

More fibrosis

“Healthy” granulation tissue

Fibrosis/scarring

• Deposition of collagen by fibroblasts
• With time (weeks, months, years?) The collagen becomes more dense, ergo, the tissue becomes “stronger”

Wound retarding factors (local)

• Decreased blood supply
• Denervation
• Local infection
• FB
• Hematoma
• Mechanical stress
• Necrotic tissue

Wound retarding factors (systemic)

• Decreased blood supply
• Age
• Anemia
• Malignancy
• Malnutrition
• Obesity
• Infection
• Organ failure

Cellular Adaptations PowerPoint Presentation Free Download

Cellular Adaptations PowerPoint Presentation includes

• Hyperplasia
• Hypertrophy
• Atrophy
• Cellular adaptation to abnormal stimuli
• Metaplasia

Cellular Adaptations

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Skin Pigmentations and Calcifications PowerPoint Presentation free Download

This "Skin Pigmentations and Calcifications" PowerPoint Presentation Includes

• Skin Pigments
• Hyper pigmentation
• Hypo pigmentation
• Addison’s disease
• Café Au Leit Pigmentation
• Neurofibromatosis
• Hyper-pigmented skin nodules
• Lack of pigmentation
• Vitiligo
• Ochronosis
• Haemosiderosis
• Haemachromatosis/Bronze diabetes
• Wilson’s disease
• Lipofuscins
• Exogenous pigments
• Heterotrophic calcification
• Dystrophic calcification
• Metastatic calcification
• Mechanism of calcification
• Chondrocalcinosis

Skin Pigmentations and Calcifications
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Chronic Inflammation,Granulomatous Dieases,Tuberculosis Pathology Lecture Note

Chronic inflammation

•Chronic Suppurative on acute:

•Chronic granulomatus: (Initiates without an acute phase)

Suppurative in type:

•Abscesses

Inadequate or delayed drain leads to thick fibrous wall formation.

The residual bacteria get reactivated

Pus formation.

•Presence of foreign material or indigestible dead tissue.

Eg: Osteomyelitis, damaged Collagen

Chronic inflammation

•Follow acute inflammation

Persistence of the stimulus

Disturbance to the healing process

•Repeated bouts of acute inflammation and healing in between.

•Low grade persistent infection.

Definition

Prolong process in which destruction and acute inflammation proceeds together with the healing process.

Causes

•Sequelae of an acute inflammation

•Foreign bodies

•Microorganisms where body can mount limited immune reactions

•Impaired body defense

•Immune reactions

Chronic inflammation without an acute phase

•Infection: TB, Leprosy, Syphilis

•Immunological: Rheumatiod arthritis Ulcerative colitis Crohn’s disease

•Poor bloodsupply (leg ulcer)

Chronic inflammatory lesions

•May vary histologically according to causative agent

•However there is a set of morphological features in common.

Histologically

•Infiltration by mononuclear cells

Macrophages

lymphocytes

plasma cells

•Proliferation of blood vessels/fibrosis (angiogenesis)

•Fibrosis

•Tissue destruction (induce by inflammatory cells)

Mononuclear phagocytic system

•Blood monocyte:

•Macrophages (at extra vascular tissue)

•Tissue macrophages (Scattered in connective tissue or concentrated in organs)

Eg: Kupffer cells in Liver

Sinus histiocytes in lymph nodes

Alveolar macrophages in lung

Osteoclasts in bones

Microglia (CNS)

Monocytes

•Migration

•Morphological transformation (macrophages and giant cells)

•Activation

•Secretion of biologically active products

Cells types present

•Macrophages

•Lymphocytes

•Eiosenophils

•Mast cells

Existence of CI, AI and repair

•Macrophages persist at the site (Due to the influence of chemical mediators)

•Destruction of invading microorganisms /normal tissues

•Secretion of chemical mediators by macrophages

Functions of them,

Proliferation of fibroblasts, Laying down of collagen

Angiogenesis, Activation of lympho macrophages

· Dead and dieing leukocytes/necrotic tissues helps in developing acute inflammation

Granulomas /Granulomatus infection

•Chronic inflammatory lesion in the form of mass.

•Collection of macrophages or modified macrophages (epitheliod / giant cells)

Granulomas /Granulomatus infection

•A granuloma is a focal area of granulomatus inflammation.

•Consist of macrophage aggregation

•Epithelial cell transformation

•Collar of lymphocytes

•Appearance giant cells and of fibrosis can see with the time

Eg:

•TB

•Sarcoidosis

•Cat scratch disease

•Leprosy

•Syphilis

•Mycotic infections

Two types of granulomas: Base on pathogenesis

•Foreign body type:

Form around foreign bodies

•Immune type: When the foreign practical are capable of induce cell mediate immune responses

(but not always granulomas will develop)

Definition

Granulomas is a result of chronic inflammatory reaction containing a collection of cells of monocytic series arrange in a compact mass.

Cells

•Macrophages

•Epithelioid cells

•Giant cells: Langhans giant cells

Foreign body type giant cells

Accumulation of macrophages

· Under the influence of chemotaxis

C5a, fibrinopeptides, cationic proteins

Lymphokines :

PDGF, TGF(beta)

products of collagen brake down

· By mitotic division

· Immobilization and prolong survival (if the irritants are low virulent )

Tuberculosis

· Chronic disease common worldwide.

· Causes a characteristic granulomatous inflammation

· Inability of the neutrophils to kill the micro organisms due to lipoprotein coating.

· Mycobacterium tuberculosis.

Hominis (lungs)

Bovis (Tonsils, Intestine)

Spread

•Droplet from patients (weeks or months)

•Conjunctiva

•Punctures

•However need sustain contact than casual contact.

Tissue damage

•MT has no Endotoxins

Exotoxins

Histiolitic enzymes

Development of immune response against outer coat of the organism.

Tuberculin test

•2 to 4 weeks after infection : + Tuberculin test

•PPD (purified protein derivative)

(Culture in which TB is grown)

•Induration More that 5.mm within 48 hours.

•Positivity indicates infection but not the disease.

Primary Tuberculosis

•Occurs in individuals who have never previously been infected with M. tuberculosis (childhood infection if TB is common, adult life if uncommon)

•Usually caused by inhalation of the organisms or rarely by ingestion of the organism.

Primary infection

•Lungs Hilum

•Tonsils neck nodes

•Intestine mesentery

Primary Tuberculosis

•In respiratory system, inhalation of the organisms cause a subpleural lesion usually in the lower part of the upper lobe or upper part of the lower lobe. This is called Ghon focus.

•Location is in these sites is because bacterium is a strict aerobe and prefers these well oxygenated regions

Ghon’s focus

· When the tissue is invaded by the mycobacteria there is no hypersensitivity reaction. Instead there is acute, non specific inflammatory response with predominant neutrophils.

· This is followed by macrophages which ingest the bacilli and present Ags to to T lymphocytes leading to proliferation of a clone of T cells .

· The emergence of specific hypersensitivity lead to release of lymphokines,that attract more macrophages.

· These accumulate to form the characteristic granuloma.

Ghon focus

•Usually single

•1 to 2 cm

•Location –Beneath pleura- mid zone of the lung

Primary complex

•Tubercle bacilli, either free or contained in macrophages, may drain to the regional lymph nodes and set up granulomatous inflammation, causing massive lymph node enlargement.

•The combination of the Ghon focus, draining lymphatics and the regional lymph nodes is called the primary complex.

Calcification of the lymph nodes

Microscopic appearance

Sequelae of primary complex

•Healing with small fibrous scar replacing caseous necrosis. Lesion will be walled off.

•Calcification

•Reactivation of infection later when host defences become lowered.

•plural effusion

•Enlarged caseous nodes can obstruct bronchi, leading to collapse, retention of secretion and inflammatory consolidation

•Caseous node erodes into a bronchi with satellite lesions in lungs (TB bronchopneumonia).

•Eroding into a pulmonary vein causing generalised milliary TB.

•Erosion into pulmonary artery leads to miliary TB of lungs

TB bronchopneumonia

· Opening of the caseous node to a bronchus.

· Air bone infection

· TB bronchopneumonia

· (Multiple pneumonic patches arrangeed in and around terminal bronchi)

· The lesions spread rapidly and accumulate macrophages and lymphocytes followed by necrosis

TB bronchopneumonia

•Necrotic patches get enlarged and discharged which will lead to dissemination and cavitations. (no fibrous walls)

•Pneumothorax

•TB bronchopneumonia can happen after both 1ry and 2ry TB.

•Rapidly spreading tuberculous bronchopneumonia: debilitated by intercurrent disease, diabetes, malnutrition etc.

•Acute miliary tuberculosis of the lungs due to blood stream spread to lungs. Grey tubercles visible to naked eye 3mm in diameter. More numerous and larger in upper lobes than lower lobes. Microscopically these are ill formed and often giant cells are absent. Usually these lesions do not cavitate

Effects on the other organs of the body

•Miliary tuberculosis due to systemic spread to kineys, spleen, brain, liver etc.

•Tuberculous ulcers in the intestine due swallowed sputum.

•Tuberculosis of larynx due to direct spread from sputum.

•Secondary amyloidosis.

Miliary TB

•Common with 1ry TB

•Due to involvement of veins

•Multiple scatted tubercles

•Not well developed/uniform in size

•1-2 mm

•Some times without giant cells (necrosis)

•

Secondary Tuberculosis (Post primary)

•Infection may me exogenous or endogenous

•After active primary infection

•Reactivation asymptomatic primary lesions:

Malnutrition,

Severe illness,

Intercurrent lung infection,

Systemic immunosuppression

•Exogenous: caused by inhaled organisms

Immunity

•During primary tuberculosis or during BCG immunisation, the patient develops cell mediated immunity to antigens of tubercle bacillus.

•This is demonstrated by skin test (Mantoux) test

•Immunity is associated with increased resistance to subsequent infection.

Re infected lesions:

•Apex of the lungs

•Endogenous infections (swallowing sputum)

•Metastatic lesions are similar to re-infected

Lesions

•Large in size (spread locally) no lymph node involvement

Cavity formation

•Caseous material discharge gradually leaving a small cavity.

•Cavities can become very large with overgrowth of fibrous tissue.

•Cavity walls are irregular with raised bands representing obliterated blood vessels.

•The surface is lined by caseous material or by pus and debris mixed with blood.

•If the disease is inactive the wall becomes very smooth

· In early cases the lesions are often in the apices of the lungs

· In advanced cases there may be more than one cavitatory lesion.

· All the lesions are distributed in the upper part of the lungs

· Caseation may involve the wall of a bronchus leading to obstruction of the lumen.

Sequelae of tuberculous cavities
Local effects

· Due to fibrosis lung tissue shrinks causing bronchiectasis (upper lobe bronchiectasis)

· Blood vessels can become weaken and rupture leading to haemoptysis

· Aneurysm formation- called Rasmoussen’s aneurism leading to fatal haemorhage.

· Fungal infections can be localized in these cavities.