Inflammation and Repair
Prof: Francis F. Dematera, MD, DPSP
Inflammation
- A protective response of vascularized tissues to
infections and damaged tissues that bring cells and
molecules from the circulation to the sites where they
are needed in order to eliminate the offending agents
- A complex reaction that consists of responses of
blood vessels and WBC
- Host cells and molecules recognize offending
agent
- Leukocytes and proteins work to destroy and
eliminate the offending agent
- Reaction is controlled and terminated
- Damaged tissue is repaired
- It can be acute or chronic
- Local or systemic
- Terminated when offending agent is eliminated
- Maybe harmful in some situations
- May contribute to diseases that are not thought to be
primarily due to abnormal host response (e.g. gout
sa gout naddeposit ang crystals. Sa inflammatory
reaction, the damage is doubled and it may contribute
to disease and may be harmful at times)
(redness and swelling)
*Inflammatory tissues have lost its function (refer to
the picture) hindi mo na magagamit/magagalaw
Stimuli of Acute Inflammation
Infection
- starts as acute (from neutrophils lymphocyte)
Tissue necrosis
- kelangan tanggalin yung necrotic tissue
Foreign bodies
Immune reaction or Hypersensitivity
- kasi ang immune complex na nadeposit sa tissue,
kelangan i-engulf/tanggalin kaya nagsstimulate ng
acute inflammatory reaction
- Sa acute inflammatory reaction, there has to be
response of the blood vessel kasi dapat vascularized or
palabasin ang cells
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- blood vessel will dilate (vasodilation) increase
in vascular permeability (for the cells to be able to
go out) emigration of WBC from
microcirculation stasis (madaming red cell)
vascular congestion
- In a normal process, there is retraction of the
endothelial cells for WBC to be able to go out and this
takes place in venules (not in arteriol or capillary)
- transcytosis fluids and proteins
- kapag may injury sa vessel, can be endothelial
injury (primary trauma) or leukocyte-mediated
injury (kasi doon palang sa loob ng vascular channels
nagrelease na ng mga mediators that can damage
tissue and leukocyte can be anywhere arteriol,
capillary or venule; Normally, venule only)
Three pools:
Storage
Circulating still needs to marginate for them
to roll adhere diapedesis chemotaxis
Marginating ready to go out of the vessel
and go on a battle; pinakamatapang
*Process: marginate roll attach to epithelial cell
detach attach again detach it will firmly adhere
to one endothelial cell wait for endothelial junctions
to have a gap diapadesis or transmigration go to
the site of injury (chemotaxis)
Rolling
- By the use of surface molecules (adhesion
molecules)
- selectin prominent
- Leukocytes have L-selectin can bind to GlyCam-1
or CD34
- Leukocytes also have SLX (Sialyl-LewisX) modified
protein can bind to E-selectin that is present on the
surface of endothelial cell and P-selectin present on
the surface of platelets
Adhesion
- Leukocytes have integrin can bind to members of
immunoglobulin family like ICam-1 (intercellular
adhesion molecule-1) or VCam-1 (vascular cell
adhesion molecule) they have constant and variable
region
Diapedesis
- they will have to go through the gaps
- then pag nasa labas na sila, they will move along a
concentration gradient (chemical gradient)
Chemotaxis
- Locomotion oriented along a chemical gradient
- Exogenous agent
- Microbial products
- Endogenous agents
- Cytokine (Chemokine family)
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 - Complement system component (C5a)
- AA metabolite (LTB4)
If there are macrophages, infection can be
recognized immediately, and if recognized
engulf lead to cytokine secretion stimulate
complement system activation leukotriene B4
production (arachidonic acid metabolite)
WBC will move to an area with higher
concentration of chemotactic agent
Recognition of Microbes and Dead Tissues
- If WBCs are already in the infected site, it can be
recognized through mannose receptors. WBC has
mannose receptors
- cell wall of the bacteria has mannose (not common in
eukaryotic cell)
- Scavenger receptors for acetylated LDL; usually
used for damaged tissues
- Receptors of Opsonins (IgG, C3b) opsonization
will happen (enhanced phagocytosis)
- G-protein coupled receptor able to recognize N-
formyl-methionyl residues of the organisms
- N-formyl-methionyl residues because first, we are
eukaryotes (we only have plain Met in our body, unlike
in the organisms, they have formulated residues,
Formyl)
- because organisms have Formyl residues, our
bodies have G-protein coupled receptor that can
detect prokaryotes (bacteria)
- when detected, phagocytosis will occur
Phagocytosis
Three steps:
1. Recognition and attachment
2. Engulfment with subsequent formation of a
phagocytic vacuole
- formation of phagosome
3. (pag nasa loob na) Killing or degradation of the
ingested material
- highly acidic substance will be formed
- H2O2-MPO-halide system hypochlorite
- Nitric oxide + superoxide anion peroxynitrite
Principal mediators
- what is important are the vasodilators because they
promote increase in vascular permeability
- Histamine, Prostaglandins, etc.
Together with the cells and the soluble factors,
in the context of inflammation and immunology,
soluble factor is something secreted by the cell
(immunoglobulins)
Edema
- excess fluid in interstitium or serous cavities
*can also be seen in:
- peritoneal cavity ascites
- pleural cavity pleural effusion
- heart pericardial effusion
o Exudative if the fluid is associated with
inflammation
- high protein
- with cellular debris
- increase in specific gravity
- e.g. pus (liquefactive necrosis, acute inflammation)
o Transudative if the fluid is NOT associated with
inflammation; secondary to passive process
(naharangan lang)
- low protein
- no cellular debris
- low specific gravity
Response of Lymphatic Vessels
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Lymphatic vessels
- functions to drain the interstitium of the excess fluid
that is present, together with leukocytes, cell debris,
and microbes that are present in the lymphatic tissue
o Lymphangitis inflammation of lymphatics
o Lymphadenitis inflammation of lymph nodes
Morphologic Hallmarks of Acute Inflammation
Dilation of small blood vessels
Slowing of blood flow bc of congestion
Accumulation of leukocytes and fluid in the
extravascular tissue
TYPES OF INFLAMMATIORY RESPONSE:
Serous inflammation
- usually seen in cavities (pericardial, peritoneal,
pleural)
- can come from secretion of mesothelial cell or can be
an outpouring of the plasma
o Effusion accumulation of the fluid in cavities
- e.g. skin blister
Fibrinous inflammation
- theres fibrin deposition
*an image of a heart with a rough surface, with fibrin
meshwork (not normal)
*reason: in an inflammatory reaction, may activation
ng inflammation and ng complement system (there
are fragments of the complement system that can
directly activate the coagulation cascade, fibrinogen
will be converted to fibrin, fibrin threads will be
deposited leading to fibrinous inflammation)
*complement system coagulation cascade
fibrinolysis
Suppurative or Purulent inflammation (Abscess)
- Production of large amounts of pus or purulent
exudate consisting of neutrophils, liquefactive
necrosis, and edema fluid
o Pyogenic bacteria pus-producing
o Abscess localized collection of purulent
inflammatory tissue
*an image of a lung with patches (abscesses) or
patches of inflammation
Ulcer
Layers:
1. Fibrinoid necrosis
2. Non-specific inflammation
3. Granulation tissue
4. Collagenous scar (lowermost)
- Local defect or excavation of the surface of an organ
or tissue that is produced by the sloughing (shedding)
of inflamed necrotic tissue
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- Occur only when tissue necrosis and resultant cells release IFN-gamma (most potent activator of
inflammation exist on or near a surface macrophages)
- Mucosa of the mouth, stomach, intestines, GUT; and o Engagement of TLRs
skin and subcutaneous tissue of the lower extremities o T cell derived signals (IFN-gamma)
in older persons who have circulatory disturbances o Foreign substances
that predispose to extensive ischemic necrosis o Host defense and inflammation
Alternative activation (M2)
Outcomes of Acute Inflammation - doesnt need IFN-gamma
- Complete resolution o Cytokines other than IFN-gamma
- Healing by connective tissue replacement (fibrosis or o Tissue repair
scarring)
- Progression to chronic inflammation Lymphocytes
TH (T helper cells)
- Cytokine production
- Classified based on their secretion profile
- Needs to activate itself further by producing receptor
for IL-2 (will lead to proliferation of the T H)
Causes of Chronic Inflammation o TH1 classical activation of macrophage
- Persistent infections (secretes IFN-gamma)
- Immune-mediated inflammatory diseases o TH2 tissue repair, eosinophil recruitment
(Hypersensitivity)
(secretes predominantly IL-4 supports
- Prolonged exposure to potentially toxic agents
production of IgE & IL-5 secretes eosinophil)
(exogenous or endogenous)
o TH17 chemokine secretion
B cell
Cells in Chronic Inflammation
- can differentiate to become plasma cells (effector
Macrophages cell) plasma cells will produce antibodies kills
Lymphocytes itself
Plasma cells
Eosinophils Macrophage will present antigen to T cell
Mast cells macrophage will secrete IL-1
The first signal that will activate the T
Macrophages lymphocyte is the engagement of the T cell
Classic activation (M1) receptor with MHC class II molecule carrying an
- tall-like receptors that are able to recognize antigen
organisms engulf present to T cells T helper The second will be costimulation

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 - CRP can act as an opsonin
Other cells Leukocytosis
Eosinophils Increase PR (Pulse rate) and BP (Blood pressure)
- IgE mediated immune reactions Severe bacterial infection Sepsis Septic
- Parasitic infections (MBP) shock
Mast cells - Due to continuous cytokine secretion
Neutrophils - Toxins can stimulate inflammatory response
- Persistence of microbes or by mediators (e.g. - Gram negative endotoxin
macrophage can produce IL-8 to recruit neutrophils) - Gram positive exotoxin
Granulomatous Inflammation Repair
- A distinct pattern of chronic inflammation - Restore of tissue architecture and function after
characterized by activated macrophages with T cells injury
and areas of necrosis o Regeneration
o Foreign body granuloma - Replacement of damaged components to
- Materials that cannot be phagocytosed return to a normal state by cellular proliferation
- Formed when the offending agents present in o Connective tissue deposition
the area are too big to be phagocytosed - Laying down of connective or fibrous tissue
o Immune granuloma scar formation
- With persistent T cell immune response - Fibrosis in organs
- Seen in TB - Organization in spaces occupied by
inflammatory exudates
Systemic Effects Three groups of Tissue
Fever Labile/Continuously Dividing
- Macrophages produce IL-1 and TNF (Tumor - e.g. squamous epithelium, RBCs, WBCs (not all
Necrosis Factor) can stimulate production of COX are continuously dividing lymphocytes), surface
(Cyclooxygenase) can convert AA (Arachidonic acid) epithelium, BM
to PGE2 (Prostacyclin) can promote increase in - Proliferate throughout life from adult stem cells
cAMP (cyclic AMP) of the cells reset temp Stable/Quiescent
setpoint (in the hypothalamus) - low-level replication, rapid with stimuli
- General barrier to prevent further metabolism to - e.g. liver, kidney, pancreas, fibroblasts, smooth
make the environment not conducive for the growth of muscle and endothelial cells, lymphocytes and other
the organisms leukocytes
Acute-phase reactants Permanent/Nondividing

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 - cannot undergo division
- e.g. neurons, skeletal muscles, cardiac muscles
Scar formation
- Deposition of collagen and other ECM (extracellular
matrix) components, causing the formation of a scar
- Basic Features:
o Angiogenesis formation of new blood vessels
Growth factors
VEGF (Vascular Endothelial Growth
Factor) migration and proliferation of
endothelial cells
FGF (Fibroblast Growth Factor)
proliferation of endothelial cells,
migration of fibroblasts and macrophages
o Formation of granulation tissue collagen
from fibroblast + new blood vessels =
granulation tissue (hallmark of tissue repair)
o Connective tissue remodeling
Connective tissue deposition
- Migration and proliferation of fibroblasts
- Deposition of ECM
- Growth factor: TGF-Beta
- most important cytokine for connective tissue
deposition
- fibroblast migration and proliferation
- increased synthesis of collagen and fibronectin
- inhibition of metalloproteinases can degrade ECM
Cutaneous wound healing
First intention/Primary Union
- wounds with opposed edges
- clean surgical and approximated incision
- minimal cell death and BM disruption
Secondary intention/Secondary Union
- wounds with serrated edges
- more extensive tissue loss (destruction of
basement membrane = more deposition of ECM)
- greater inflammatory response and granulation
tissue
- substantial scar deposition with thinned
overlying epidermidis
- wound contraction due to myofibroblasts
- more fibroblasts actin (cytoskeleton for
movement/contraction)
First intention (skin)
Wounding coagulation activation, increased
vascular permeability, edema, drying scab
24 hours neutrophils to clear the debris, BM
deposition, continuous epithelial layer
Day 3 macrophages replace neutrophils as
key cellular constituent of tissue repair, collagen
fiber deposition, granulation tissue in the
incision space
Day 5 peak of neovascularization
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 2nd week continuous collagen deposition and
fibroblast proliferation; diminished edema,
vascularity and leukocyte infiltrates
1st month cellular connective tissue devoid of
inflammatory cells and covered with epidermidis
Factors that influence tissue repair
Infection most important; if tissue is infected,
mas matagal ang healing
DM
Nutrition kulang ang substrates
Steroids inhibits TGF-Beta
Mechanical factors galaw ng galaw kahit
hindi pa dapat
Poor perfusion because no blood flow
Foreign bodies
Type and extent of injury
Location the more vascular the organ is, the
greater the probability that it will heal faster
Pathologic aspects of repair
Deficient scar formation
- wound dehiscence (hindi magdikit) and
ulceration
Excessive formation of repair components
o Hypertrophic scars - accumulation of
excessive amounts of collagen (doesnt
go beyond the boundaries)
o Keloid grows beyond the boundaries of
original wound and does not regress
(lumalaki)
Formation of contractures
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