TISSUE RESPONSE TO INJURY/STRESS

Prof. Khoo SP
IMU
LESSON OUTCOME

 Describe the various types of responses of the

tissue to stress/injury
 Describe the pathophysiological processes that are
involved in these tissue responses
 Illustrate these tissue responses with examples in
the oro-facial region
CELL INJURY

 Stressed so severely, can’t adapt further

 Exposed to inherently damaging agents
 REVERSIBLE OR IRREVERSIBLE
 Outcome depends on:-
- Type, duration and severity of injury
- Type, state, and adaptability of cell
Normal Adapted
cell cell

Injury

Reversibly
injured cell

Irreversibly
Injured cell
AGENTS OF CELL INJURY

• Oxygen (++ or --)

• Physical agents (trauma, temp, pressure, electric shock)
-
• Chemical agents (CN , Hg, O3, CO, EtOH, drugs, ROS)
• Infectous agents (viruses, bacteria, fungi)
• Immunologic reactions (anaphylaxis, autoimmune diseases)
• Genetic defects (Sickle cell disease, Down synd, Tay-Sachs)
• Dietary (vitamins ++/--; malnutrition, ++ calories)
 Mechanisms of cellular injury
• ATP depletion
• Mitochondrial damage
• Membrane damage
• Altered ion concentrations (Na, K, Ca)
• Activation of proteases, phospholipases
• Inactivation of enzymes
• Proteolysis of cytoskeleton
• Detachment of ribosomes
• Increased ROS production
• DNA damage
 Important targets of injury

• Mitochondria (aerobic respiration; apoptotic

signals)
• Membranes (cell and subcellular organelles)
• Protein synthesis machinery
• Cytoskeleton
• Genetic apparatus (DNA)
 Agents of cell injury :
1. TOO MUCH VIA ROS**
Major ROS eg. Free radicals
Sources of ROS :-
 UV light, ionixing radiation
 Enzymes (P450, XO, NADPH
oxidase)
 Reduced metals (Fe, Cu, etc)
**Reactive Oxygen Species (ROS)
Oxygen
2. TOO LITTLE VIA
hypoxia…..decreased O2
content of blood
ischemia….inadequate blood
flow (compromises
delivery of nutrients and
removal of wastes)
NB: ischemia worse than
hypoxia
 + Stress
Normal Adapted
cell Cell
- Stress

Injury

Reversibly
injured cell

Apoptosis
Irreversibly
Dead cell
Injured cell
Necrosis
MORPHOLOGY OF REVERSIBLE CELL INJURY

 Hydropic changes – to bacterial toxins,

chemicals
 Hyaline changes

 Mucoid change
INTRACELLULAR ACCUMULATIONS

 Fatty change (fatty liver – DM, obesity,

starvation)
 Intracellular accumulation of proteins

 Intracellular accuulation of glycogen

MORPHOLOGY OF IRREVERSIBLE CELL INJURY

 Autolysis
 Necrosis – coagulative, liquefaction, caseous,
fat
 Apoptosis – programmed cell death

 Gangrene – dry, wet

 Pathologic calcification
TISSUE RESPONSE TO INJURY
PRIMARY RESPONSE: SECONDARY RESPONSE:

 tissue destruction directly  occurs from cell death

associated with traumatic
force; can’t change amount
of initial damage
caused by a blockage of O2
supply; can assist to keep
minimum damage to other
tissues

Injury Response Cycle = pain-spasm-pain cycle.

(Chemicals stimulate free nerve endings  pain 
muscle spasm & triggers body’s protective
mechanism.)
PERIODONTAL SURGERY
WOUNDS
FRACTURES
Acute Inflammatory Phase

Proliferation/Fibroblastic/
Repair/Regeneration Phase

Remodeling/ Maturation Phase

PHASE I: ACUTE INFLAMMATORY PHASE

 Begins immediately, lasts approx. 2-4 days

 Goal
 Protect,
 Localize,
 Decrease injurious agents,
 Prepare for healing and repair
 Important- If this phase does not accomplish what it is
supposed to or if it does not subside, normal healing
cannot take place.
 Lasts until damaged tissue has been removed & new
capillary network has been formed
 ACUTE INFLAMMATORY RESPONSE

 INJURY OCCURS
 VASCULAR CHANGES
 Vasoconstriction – immediately; decreased blood flow to area
(approx. 5-10 mins.); platelet plug formed; blood coagulation;
produces local anemia
 Vasodilation – increased blood flow; increased hydrostatic
pressure in blood vessels (↑ capillary permeability, plasma
proteins leak out; proteins attract H2O - edema)
 CELLULAR CHANGES – chemical reactions start immediately
 PROTEIN PRESENCE - changes osmotic relationship between
blood & adjacent tissues (Plasma protein  while interstitial fluid
protein ↑. H2O follows plasma proteins out of vessel resulting in
edema!)
 Neutralizes/destroys offending agents, restricts tissue damage
to the smallest possible tissue & prepares area for healing
 PHASE II: PROLIFERATION/FIBROBLASTIC PHASE

 “Repair/Regeneration or Fibroblastic phase”

 Phase will extend from 48 hours to 3-6 weeks

 Phase removes debris & temporary repair – SCAR

FORMATION

 Adenosine triphosphate (ATP) is a critical factor that

regulates the rate & quality of healing
- cell’s primary source of energy
- provides metabolism needed to restore cell’s membrane
properties by moving Na2+ & K+ into & out of cell, to build new
proteins & synthesize proteins
PROLIFERATION PHASE
 4 processes of soft tissue repair
- fibroblast formation - tissue remodeling
- synthesis of collagen - tissue alignment

Dependent on levels of: debris removal, endothelial

production, production of fibroblasts

 Repaired through 3 phases

 Resolution - dead cells & cellular debris are removed by
phagocytosis (tissue left with original structure & function in
tact)
 Regeneration – damaged tissue is replaced by cells of the
same type (structure retains some or all of its original
structure & function)
 Repair – original tissue is replaced with scar tissue (original
structure & function is lost)
 PHASE III: REMODELING/REGENERATION/
MATURATION PHASE

 Begins in Week 3
 Aim : increase strength of repaired/replaced tissues
 First 3-6 weeks involves laying down of collagen and strengthening of
fibers
 3 months to 2 years allowed for enhanced scar tissue strength
 Balance must be maintained between synthesis & lysis
 # of fibroblasts, myofibroblasts, & macrophages reduced to pre-
injury state
 # of capillaries decrease, H2O content decreases
 Take into consideration forces applied, immobilization
time frames relative to tissue and healing time
 Scars fade & eventually return to near normal color
 Type I collagen continues to replace Type III collagen
WOUND HEALING - PROCESSES
Acute Inflammatory Phase

Proliferation/Fibroblastic/
Repair/Regeneration Phase

Remodeling/ Maturation Phase

 REPAIR OF TISSUE DAMAGE – TYPES
 Regeneration = Restitution of lost tissue
Tissue with high proliferative capacity = labile
tissue
(e.g hematopoietic cells, epithelial cells of skin
and gastrointestinal tract regenerate from stem
cells)
Quiescent tissues = stable tissue
which normally have low levels of replication,
however can undergo rapid cell division when
stimulated
(e.g parenchymal cells of liver, kidney, pancreas;
mesenchymal cells as lymphocytes, fibroblasts,
smooth muscle cells, endothelial cells…)
 Healing may restore original structures but
results in

I. collagen deposition and scar formation in tissue

where scaffold is disrupted
II. or damage occurs in non dividing = permanent
tissue (e.g central nervous system, skeletal and
cardiac muscle)
 REGENERATION REQUIRES

 Presence of stem cells for renewal

 or tissue cells that are capable to divide in

response to growth factors

 Intact tissue scaffold

Most of the processes that are referred to as “regeneration “ in mammalian

organs are actually
compensatory growth processes involving cell hypertrophy and hyperplasia
(e.g liver regeneration, gingival hyperplasia)
 STEM CELLS

 Undifferentiated cells that do not yet have a specific

function.

 Can replicate for a long period of time and give rise to

differentiated cells.

 In every cell division one cell retains its self renewing

capacity while the other cell can undergo differentiation
(“asymmetric replication”)
 Two types of stem cells

 EMBRYONIC STEM CELLS

 derived from the inner cell

mass of a blastocyst from in
vitro fertilized eggs
 are pluripotent and can
generate all tissues
 ADULT (SOMATIC) STEM CELLS

 present in small numbers in various tissues of the adult body

 are typically programmed to form different cell types of their
own tissue and are therefore multipotent
 in tissues with high turn over (hematopoietc system, epithelial
lining of the gut and skin) they are instrumental in renewal
 although present in a variety of permanent non-dividing
tissues they are not very active
 Bone marrow contains 2 different types of adult stem cells:
the hematopoietic stem cell and the bone marrow stromal cell
Potential plasticity of hematopoietic stem cells
 REPAIR BY HEALING  (SCARRING)
 Induction of an inflammatory response to
remove dead and damaged tissue
 Proliferation of parenchymal and
connective tissue cells
 Angiogenesis (blood vessel formation) and
formation of granulation tissue
 Synthesis of ECM proteins and collagen
deposition
 Tissue remodeling
 Wound contraction
 Acquisition of wound strength

 It usually leads to scar formation and does not

lead to complete restitution of the injured
tissue
 CUTANEOUS WOUND HEALING

Generally divided into 3 overlapping phases

 Inflammation

 Granulation tissue formation and re-

epithelialization

 Wound contraction, extracellular matrix

deposition and remodeling
CELLULAR ADAPTATIONS
+ Stress
Normal Adapted
cell Cell
- Stress

Injury

Reversibly
injured cell

Apoptosis
Irreversibly
Dead cell
Injured cell
Necrosis
 Stress =?
 Increased/decreased workload
* skeletal muscle and body building
* cardiac muscle and hypertension
* skeletal muscle disuse (limb immobilization)

 Increased/decreased stimulation
* estrogenic stimulation of uterus in pregnancy
* estrogen/prolactin stimulation of breast (lactation)
* denervation of muscle
 Adapted
Cell

Cellular adaptations to stress

1. Hyperplasia (more cells)
2. Hypertrophy (bigger cells)
3. Atrophy (smaller cells)
4. Metaplasia (different type of cells)
5. Chronic inflammation
1. HYPERPLASIA (MORE CELLS)

 1. Physiologic
* Hormonal (breast/uterus in pregnancy)
* Compensatory (liver after partial hepatectomy)

 2. Pathologic
 Excessive hormone/GF stimulation of target tissue
* Endometrial hyperplasia (x’s estrogen)
* Benign prostatic hyperplasia (x’s androgens)
* Connective tissue cells in wound healing
*Gingival hyperplasia
THYROID HYPERPLASIA
 HYPERPLASIA
(Mechanism)
Cell proliferation via increased production of
TRANSCRIPTION FACTORS due to :-
• Increased production of Growth factors
• Increased levels of Growth factor receptors
• Activation of intracellular signaling
 Results in larger organ
GINGIVAL HYPERPLASIA
 Adapted
Cell

2. Hypertrophy (larger cells)

 Not due to swelling
 Increased synthesis of structural components
 Results in larger organ
 May occur with hyperplasia
 Hypertrophy
Comments
* Often involves switch from adult to fetal/neonatal forms
i.e. α-myosin heavy chain  β-myosin heavy chain
* Limited (can only increase so much)
HYPERTROPHY (HEART)
HYPERTROPHY OF UTERUS
Normal Hypertrophied
Cardiac smooth muscle hypertrophy
HYPERTROPHY
(MECHANISMS)

•Increased synthesis of structural proteins via

•Transcription factors (i. e. c-fos and c-jun)
•Growth factors (TGF-β, IGF-1, FGF)
•Vasoactive agents (endothelien-1, AII)
Changes in the expression of selected genes and proteins during
myocardial hypertrophy.
MASSETER HYPERTROPHY
 3. ATROPHY
(SMALLER CELLS)

1. Physiologic
During development: i.e. notochord; thyroglossal duct

2. Pathologic (local or generalized) via

* disuse * Loss of endocrine stimulation
* denervation * Aging
* ischemia * Pressure
* Nutrition
 Atrophy
(Mechanism)

Reduction in structural components

Decreased number of mito, myofilaments, ER via
proteolysis (lysosomal proteases; ubiquitin-proteosome system)
Increase in number of autophagic vacuoles
Residual bodies (i.e. lipofuscin  brown atrophy)

 diminished function but not dead

Normal Artophied

Brain atrophy
MUSCLE FIBER ATROPHY.

Nos. of cells is the same; size of some fibers is reduced.

This is a response to injury by "downsizing" to conserve the cell.
In this case, innervation of the small fibers in the center was lost.
ALVEOLAR RIDGE ATROPHY
HEMIFACIAL ATROPHY – ROMBERG DISEASE

 Progressive atrophy of skin,

subcutaneous fat, muscle, and
bone
 The contralateral face may be
involved but uncommon.
 The skin and adnexa atrophy,
fat becomes inflamed, and
muscle atrophies. Nerves are
unaffected.
 4. Metaplasia
**One adult cell type replaces another**

Reversible
Columnar to squamous epithelium (most common epithelial type of
metaplasia)

Chronic irritation i.e. (in trachea and bronchi of smokers)

Vit A deficiency squamous metaplasia in respirastory epithelium

May be some loss of function

May predispose to maligancy

Photomicrograph of the trachea from a smoker. Note that the columnar
ciliated epithelium has been replaced by squamous epithelium.
Photomicrograph of the junction of normal epithelium (1) with hyperplastic
transitional epithelium (2).
 METAPLASIA
(MECHANISM)

Reprogramming
1. of stem cells present in normal tissues
2. of undifferentiated mesenchymal cells in connective tissue
Mediated by signals fromcytokines, GF or ECM
Leading to induction of specific transcription factors
5. CHRONIC INFLAMMATION - OUTCOME OF
ACUTE INFLAMMATION
 Complete resolution
 due to elimination of the offending agent and regeneration of
injured tissue with normal function
 Healing by connective tissue replacement
(fibrosis/scar formation)
 Occurs after large tissue destruction,
 fibrinous exudation into serous cavities
 tissue without regeneration capabilities
 Progression to chronic inflammation
 Resulting in granuloma formation to wall off injurious agent and
tissue fibrosis (scar formation)
CHRONIC INFLAMMATION

Inflammatory response of prolonged duration (weeks

– months - years)

Provoked by the persistence of the causative stimulus

Simultaneous presence of acute inflammation, tissue

destruction and repair
EG. FOREIGN BODY GRANULOMA
 Infectious organisms that resist clearance and form a
persistent infection in tissue or undrained abscess cavities
 e.g mycobacterium tuberculosis, actinomycetes, treponema palidum
and Staph aureus (in bone and pleural cavities).
 Chronic osteomyelities of mandible
 Exposure to irritant non-living foreign material that can not be
removed
 implanted materials into wounds (wood splinters), inhaled materials
(silica, asbestos), deliberately introduced material (surgical suture
material or prosthesis)
 Potentially normal tissue components as seen in auto-immune
diseases
 Beta islet cell in diabetes mellitus type I, Acetyl cholin receptor in
Myastenia gravis
CHARACTERISTICS OF CHRONIC
INFLAMMATION

 Infiltration of mononuclear cells

 Tissue destruction

 Healing with scar formation and fibrosis

Role of macrophages - eliminate injurious agents and initiate repair-
however.
Also responsible for much of the tissue injury that occurs
Tissue macrophage

Activated T cell or NK cell

Non Immune activation: IFN-g

Endotoxins,
fibronectin,
chemical mediators
Activated macrophage

Fibrosis (Scaring)
Growth factors involved
in fibroblast proliferation
Tissue injury (PDGF,TGFb,FGF)
Toxic oxygen metabolites Angiogenesis factors
Metallo-proteases (FGF,VEGF)
Coagulation factors Collagen deposition
AA metabolites and NO (IL-13 and TGFb)
OUTCOME OF CHRONIC INFLAMMATION

 Ulcers

 Fistulas

 Granulomatous diseases

 Fibrotic diseases (Scaring)

 and combinations of the above

EXAMPLES OF SEVERE CHRONIC
INFLAMMATORY DISEASES
 Tuberculosis
 Sarcoidosis
 Rheumatoid arthritis and other connective tissue
diseases
 Inflammatory bowel diseases (Crohns disease,
ulcerative colitis)
 Peptic ulcer of the duodenum and stomach
 Liver cirrhosis
 Bronchial asthma
EXAMPLES IN ORAL REGION
 Tuberculosis (tongue)
 Sarcoidosis (lip)
 Rheumatoid arthritis and other connective
tissue diseases (TMJ)
 Inflammatory bowel diseases (Crohns disease,
ulcerative colitis)
 Periapical abscess
 Periapical granuloma
EG. CHRONIC PERIODONTITIS
 Virulence factors% composition of total bacterial
flora
 Virulence factors found in periodontal pockets
where is actively destroying pockets
 Egs. Endotoxin, exotoxin, enzymes, antigens

 Virulence factors can be tranferred to daughter

cells following cell division or from one
bactrerium to another
 In order to elicit periodontitis, microrganisms must :-
 Establish themselves near host tissues
 Avoid being eliminated by saliva/exudates
 Avoid defense mechanisms of host/other microrganisms
 Capable of destroying periodontal tissues
GOALS BACTERIAL FACTORS

Adhesion to host tissues Fimbriae

Colonization, proliferation Proteases for foodstuff metabolism

Host response – deceiving, inhibiting, Capsule, mucous, leukotoxins, Ig,

eliminating complements

Penetration into host tissues Invasins

Tissue damage-direct – enzymes, bone Collagenase, lipopolysaccharide

resorption, cellular toxins

Tissue damage - indirect Host inflammatory response to

microbial plaque antigens, regulation
of pro-inflammatory mediators eg. IL-
1, IL-6 PGE2, matrix
metalloproteinases (MMP)
GRANULOMATOUS INFLAMMATION
Granulomas - millimeter size nodules of
chronic inflammatory cells
Result of dealing with indigestible
substances or pathogens and walls them off
The essential component are modified
macrophages named epithelioid cell (because
of shape).

Epithelioid cells can form multinucleated giant

cells.
Epithelioid cells are surrounded by a collar of
lymphocytes and occasionally plasma cells.
Fibrous connective tissue often surrounds
granulomas (remodeling of tissue)
Areas within the granuloma can undergo
necrosis (prototype: caseous necrosis in
tuberculosis). Necrosis can lead to
calcification or liquefaction and formation of a
cavern if drained.
EXAMPLES
Tuberculosis
FOREIGN BODY REACTION
 FIBROSIS: RESULT OF CHRONIC INFLAMMATION AND REPAIR
Excessive accumulation of extracellular-
matrix components such as collagen
that is produced by local fibroblasts
leading to a permanent fibrotic scar

 Macrophages and fibroblasts are the

main effector cells involved in the
pathogenesis of fibrosis

 Pro-fibrotic mediators such as TGF-b

and IL-13 amplify this process

 The degradation of collagen is

controlled by Matrix-Metallo-proteinases
(MMPs) and are activated by IFN-g

 Therefore the net increase of collagen

within a wound is controlled by the
balance of these opposing mechanisms

 Although severe acute injuries can

cause marked tissue remodeling.
Fibrosis that is associated with chronic
injury (repetitive) is unique in that the
adaptive immune response is thought to
have an important role
FIBROTIC TISSUE REMODELING CAN RESULT IN
LOSS OF ORGAN FUNCTION

 Fibrotic changes can occur in various vascular

diseases including
 Cardiac diseases
 Peripheral vascular diseases
 Oral tissues

 They affect as well main organ systems like

 Skin
 Lung
 Liver
 Kidney
ORAL SUBMUCOUS FIBROSIS
TIGHT SKIN AND SKIN NECROSIS DUE TO SCLERODERMIA

Lung fibrosis
due to sarcoidosis
LIVER CIRRHOSIS

Liver cirrhosis macroscopic and microscopic normal liver histology

SUMMARY

 Body responses to stress/injury – various

sequelae (with various manifestations)
 Body responses to infection/any form of injury
via inflammatory (acute/chronic) processes
 Healing may ensue or not.

 If not  cell