Inflammation and Repair

Eric M. Mirandilla MD, DPSP

• Inflammation is a response of vascularized tissues to infections and
damaged tissues that brings cells and molecules of host defense from
the circulation to the sites where they are needed, in order to
eliminate the offending agents
• The typical inflammatory reaction develops through a series of
sequential steps:
• The offending agent, which is located in extravascular tissues, is recognized by
host cells and molecules.
• Leukocytes and plasma proteins are recruited from the circulation to the site
where the offending agent is located.
• The leukocytes and proteins are activated and work together to destroy and
eliminate the offending substance.
• The reaction is controlled and terminated.
• The damaged tissue is repaired.
Fundamental properties of inflammation
• Components of the inflammatory response
• Blood vessels and leukocytes
• Harmful consequences of inflammation
• Local and systemic inflammation
• Mediators of inflammation
• Acute and chronic inflammation
• Termination of inflammation and initiation of tissue repair
Causes of Inflammation
• Infections (bacterial, viral, fungal, parasitic)
• Tissue necrosis
• Foreign bodies (splinters, dirt, sutures)
• Immune reactions (also called hypersensitivity)
• Sensors of cell damage
• Circulating proteins
Acute Inflammation
• (1) dilation of small vessels leading to an increase in blood flow,
• (2) increased permeability of the microvasculature enabling plasma
proteins and leukocytes to leave the circulation,
• (3) emigration of the leukocytes from the microcirculation, their
accumulation in the focus of injury, and their activation to eliminate
the offending agent
Reactions of blood vessels in acute
inflammation
• Exudate
• extravascular fluid that has a high protein concentration and contains cellular
debris
• Transudate
• is a fluid with low protein content (most of which is albumin), little or no
cellular material, and low specific gravity.
Changes in Vascular Flow and Caliber
• Vasodilation is induced by the action of several mediators, notably
histamine, on vascular smooth muscle.
• increased permeability of the microvasculature
• engorgement of small vessels with slowly moving red cells, a
condition termed stasis
• blood leukocytes, principally neutrophils, accumulate along the
vascular endothelium
Increased Vascular Permeability (Vascular
Leakage)
• Contraction of venule endothelium to form intercellular gaps
• Most common mechanism of increased permeability
• Elicited by chemical mediators (e.g., histamine, bradykinin, leukotrienes, etc.)
• Occurs rapidly after injury and is reversible and transient (i.e., 15 to 30
minutes), hence the term immediate-transient response
Increased Vascular Permeability (Vascular
Leakage)
• Direct endothelial injury:
• Severe necrotizing injury (e.g., burns) causes endothelial cell necrosis and
detachment that affects venules, capillaries, and arterioles
• Recruited neutrophils may contribute to the injury (e.g., through reactive
oxygen species)
• Immediate and sustained endothelial leakage
• Increased transcytosis:
• Transendothelial channels form by interconnection of vesicles derived from
the vesiculovacuolar organelle
• Vascular endothelial growth factor (VEGF) and other factors can induce
vascular leakage by increasing the number of these channels
Increased Vascular Permeability (Vascular
Leakage)
• Leakage from new blood vessels:
• Endothelial proliferation and capillary sprouting (angiogenesis) result in leaky
vessels
• Increased permeability persists until the endothelium matures and
intercellular junctions form
Responses of Lymphatic Vessels
• In inflammation, lymphatic flow is increased to drain edema fluid,
leukocytes, and cell debris from the extravascular space
• In severe injuries, drainage may also transport the offending agent
Reactions of Leukocytes in Inflammation
• most forms of acute inflammation, neutrophils predominate during
the first 6 to 24 hours and are then replaced by monocytes after 24 to
48 hours
• The process of getting cells from vessel lumen to tissue interstitium is
called extravasation and is divided into three steps:
• Margination, rolling, and adhesion of leukocytes to the endothelium
• Transmigration across the endothelium
• Migration in interstitial tissues toward a chemotactic stimulus
Leukocyte Migration through Endothelium
• Transmigration (also called diapedesis) is mediated by homotypic
(like-like) interactions between platelet-endothelial cell adhesion
molecule-1 ¼ CD31 (PECAM-1) on leukocytes and endothelial cells.
• Once across the endothelium and into the underlying connective
tissue, leukocytes adhere to the extracellular matrix via integrin
binding to CD44.
Chemotaxis of Leukocytes
• After emigrating through interendothelial junctions and traversing the
basement membrane, leukocytes move toward sites of injury along
gradients of chemotactic agents (chemotaxis)
Recognition of Microbes and Dead Tissues
• Having arrived at the appropriate site, leukocytes distinguish
offending agents and then destroy them.
• inflammatory cells express a variety of receptors that recognize
pathogenic stimuli, and deliver activating signals thru:
• Receptors for microbial products: These include toll-like receptors (TLRs)
• G protein–coupled receptors: These receptors typically recognize bacterial
peptides containing N-formyl methionine residues
• Receptors for opsonins
• Cytokine receptors
Phagocytosis
• begins with leukocyte binding to the microbe
• facilitated by opsonins, the most important being the immunoglobulin Fc
fragment and the complement fragment C3b
• Engulfment
• cytoplasmic pseudopods enclose the particle and eventually pinch off to
make a phagosome vesicle.
• Subsequent fusion of phagosomes and lysosomes (forming a phagolysosome)
discharges lysosomal contents into the space around the microbe but can also
occasionally dump lysosomal granules into the extracellular space
Phagocytosis
• Killing and Degradation
• Killing of phagocytosed particles is most efficient in activated leukocytes, and
is accomplished largely by reactive oxygen species (ROS).
Defects in Leukocyte Function
• Genetic deficiencies in adhesion molecules: Leukocyte adhesion deficiency
type I is due to defective synthesis of b2 integrins (LFA-1 and Mac-1); type II
deficiency is due to a defect in fucose metabolism causing loss of sialyl-
Lewis X (ligand for E- and Pselectin).
• Genetic defects in phagolysosome formation: In Che´diak-Higashi
syndrome, neutrophils have aberrant organellar fusion with defective
lysosomal enzyme delivery to phagosomes.
• Genetic defects in microbicidal activity: In chronic granulomatous disease,
there are inherited defects in NADPH oxidase, leading to a defect in the
respiratory burst, superoxide and H2O2 production, and the MPO
bactericidal mechanism.
• Acquired deficiencies of neutrophils: Called neutropenia
Termination of the Acute Inflammatory
Response
• even as inflammation is developing, stop signals are also being
triggered
• These include a switch from pro-inflammatory arachidonate
metabolites (leukotrienes) to anti-inflammatory forms (lipoxins),
• production of anti-inflammatory cytokines such as transforming
growth factor-b (TGF-b) and interleukin-10 (IL-10),
• synthesis of fatty acid–derived anti-inflammatory mediators (resolvins
and protectins), and neural impulses that inhibit macrophage TNF
production
MEDIATORS OF INFLAMMATION
 Plasma protein-derived mediators
• Complement system
Plasma protein-derived mediators: Coagulation & kinin system

• Thrombin
• Product of clotting
• Present on platelet, edothelial and sm ms cells
• Promotes inflammation by engaging to receptors called protease activated
receptor
• Induces COX2; produces PG, PAF and NO
• Kinins
• Bradykinins – inc vascular permeability, Vd, pain
OUTCOMES OF ACUTE INFLAMMATION
MORPHOLOGIC PATTERNS
Hallmark: dilation of small blood vessels, slowing of
blood flow, accumulation of leukocytes and fluid in
extravascular tissue
• Serous inflammation
• Outpouring of thin fluid from plasma or secretions from mesothelial cells
lining the peritoneal, pleural and pericardial cavities (effusion)
• Fibrinous inflammation
• Due to greater inc in vascular permeability
• In the lining of body cavities such as meninges and pericardium
• Histo: eosinophilic meshwork of threads , amorphous coagulum
• Suppurative inflammation
• Large amount of pus or purulent exudate consisting of
neutrophils, liquefactive necrosis and edema fluid
• Ulcers
• a local defect, or excavation, of the surface of an organ or
tissue that is produced by the sloughing (shedding) of
inflammatory necrotic tissue
CHRONIC INFLAMMATION
• Inflammation of prolonged duration
• Inflammation, tissue injury and attempts at repair coexist
• May follow acute inflammation or may be insidous onset
CHRONIC INFLAMMATION: Causes
• Persistent infections by certain microorganisms
• low toxicity and evoke an immune reaction called delayed type hypersensitivity .
• sometimes takes a specific pattern called a granulomatous reaction
• Prolonged exposure to potentially toxic agents, either exogenous or
endogenous
• Silicosis
• Atherosclerosis
• Autoimmunity
• immune reactions develop against the individual's own tissues, leading to
autoimmune diseases
CHRONIC INFLAMMATION:
Morphologic features
• Infiltration with mononuclear cells
• Tissue destruction, induced by the persistent offending agent or by
the inflammatory cells
• Attempts at healing by connective tissue replacement of damaged
tissue
• proliferation of small blood vessels and fibrosis
• Chronic

• acute
Role of macrophage in chronic inflammation
Other cells
• Lymphocytes
• Activated T lymphocytes produce cytokines
• IFN-γ : major activator of macrophages
• Plasma cells develop from activated B lymphocytes and produce antibody directed either against
persistent antigen in the inflammatory site or against altered tissue component
• Eosinophils
• major basic protein
• Mast cells - in connective tissues and may produce cytokines that contribute to fibrosis
Granulomatous inflammation
• focal accumulations of activated macrophages, which often develop
an epithelial-like appearance
• epithelioid cells have a pale pink granular cytoplasm with indistinct
cell boundaries, often appearing to merge into one another
• nucleus is less dense, is oval or elongate
Systemic manifestations
• Fever
• in response to substances called pyrogens that act by stimulating PG synthesis
in the vascular and perivascular cells of the hypothalamus
• Acute-phase proteins are plasma proteins, mostly synthesized in the
liver, whose plasma concentrations may increase several hundred-fold
as part of the response to inflammatory stimuli
• CRP, serum amyloid A protein (SAA), fibrinogen
• Leukocytosis
• Neutrophilia
• Lymphocytosis
• Eosinophilia
• Leukopenia
Other manifestations of the acute phase response:
• decreased sweating
• rigors (shivering)
• chills (search for warmth)
• anorexia, somnolence, and malaise, probably because of the actions
of cytokines on brain cells
• In severe bacterial infections (sepsis),
• the large amounts of organisms and LPS in the blood stimulate the production
of enormous quantities of several cytokines, notably TNF and IL-1.
• circulating levels of these cytokines increase and the form of the host
response changes
Tissue Renewal and Repair:
Regeneration, Healing and
Fibrosis
Definition of terms
• Regeneration - refers to growth of cells and tissues to replace lost structures. (i.e
hematopoietic system)
• Healing - may restore original structures but involves collagen deposition and scar
formation. Usually in response to;
(1) to a wound (commonly in the skin)
(2) to inflammatory processes in internal organs
(3) to cell necrosis in organs incapable of regeneration
Definition of terms
• Healing by
• Regeneration
• Scar formation (laying down of fibrous tissue)
• Stem Cells
• Differentiation
• Apoptosis
CONTROL OF NORMAL CELL GROWTH

• Cell proliferation can be

stimulated by injury,
mechanical forces acting
on tissues or cell death
Molecular events in cell proliferation
• Protooncogenes
• Oncogenes
• Intercellular signalling
Cell surface
receptor binding
Signal transduction
system
• Transcription factors
CONTROL OF NORMAL CELL GROWTH
• Cells divided into
three groups
according to
proliferative
capacity
• Labile cells
• Quiescent cells
• Permanent cells
Cell cycle and the regulation of cell
proliferation
• G0
• G1 (Presynthetic)
• S (DNA Synthesis)
• G2 (Premitotic)
• M (mitotic)
Cell cycle and the regulation of cell
proliferation
• Cyclins and CDKs
• Checkpoints (ie.
p53)
• Growth Inhibition
• Growth Factors
Growth factors
• Act by endocrine,
paracrine, or autocrine
signaling and in addition
to their growth effects,
influence cell movement,
contractility and
differentiation
• EGF and TGF – a
• PDGF
• FGF
• VEGF
• TGF – b
• Cytokines
EXTRACELLULAR MATRIX AND
CELL MATRIX INTERACTION
Extracellular Matrix
• Forms a significant
proportion of the volume
of any tissue.
• Matrix proteins sequester
water that provides turgor
to soft tissues and
minerals that give rigidity
to skeletal tissues
• Reservoir for growth
factors controlling cell
proliferation
• Important for cell-to-cell
interactions and provides a
substratum for cells to
adhere, migrate, and
proliferate, directly
modulating cell form and
function.
COLLAGEN AND FIBER ASSEMBLY

Source: Robbins Pathologic Basis of Disease 7th ed

REPAIR
REPAIR BY CONNECTIVE TISSUE: FIBROSIS
• Replacement of lost cells
and tissues by connective
tissue
• The systematic process by
which unregenerated
damage is replaced by
fibrosis and scarring
• The initial response to a
wound consists of the
formation of granulation
tissue, which consists of a
richly vascular connective
tissue, containing new
capillaries, proliferating
fibroblasts and variable
numbers of inflammatory
cells
4 Components
• Angiogenesis
• Mediated by growth
factors and receptors (ie
VEGF, Angiopoietins and
PDGF)
• Regulated by ECM proteins
• Angiogenesis inhibitors
• Migration and
proliferation of fibroblasts
• Fibroplasia
• Deposition of ECM
• Maturation and
reorganization
WOUND HEALING
Wound Healing • Healing by First Intention
• 0 hours – incision is filled with
clot
• 3-24 hours – neutrophils from
the margins infiltrate the clot
• Day 3 – neutrophils are
replaced by macrophages
• Day 5 – incision is filled with
granulation tissue,
neovascularization and
epithelial proliferation is
maximal, collagen fibrils begin
to appear
• Week 2 – proliferation of
fibroblasts and continued
collagen accumulation to
produce a scar.
• Healing by Second Intention
Wound Healing
• Wound strength
• At end of the 1st week –
10% of normal
• 3rd month – 70-80%
Systemic that Influence Wound Healing
• Nutritional Status (e.g. protein and Vit C intake)
• Metabolic status (e.g. DM)
• Circulatory status or the adequacy of blood supply
• Hormones, concurrent glucocorticoid therapy
Local Factors that Influence Wound Healing
• Infection
• Mechanical factors
• Foreign bodies, which impede healing
• Size, Location and type of wound
Pathologic Aspects of Wound Healing
• Complications of wound healing may arise from abnormalities in any
of the basic repair process
• Deficient Scar formation
• Wound dehiscence
• Ulceration
• Excessive formation of repair components
• Formation of contractures